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New drug combo shows early potential for treating pancreatic cancer

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Pancreatic cancer, which affects about 60,000 Americans every year, is one of the deadliest forms of cancer. After diagnosis, fewer than 10 percent of patients survive for five years. 

While some chemotherapies are initially effective, pancreatic tumors often become resistant to them. The disease has also proven difficult to treat with newer approaches such as immunotherapy. However, a team of MIT researchers has now developed an immunotherapy strategy and shown that it can eliminate pancreatic tumors in mice.

The new therapy, which is a combination of three drugs that help boost the body’s own immune defenses against tumors, is expected to enter clinical trials later this year.

“We don’t have a lot of good options for treating pancreatic cancer. It’s a devastating disease clinically,” says William Freed-Pastor, a senior postdoc at MIT’s Koch Institute for Integrative Cancer Research. “If this approach led to durable responses in patients, it would make a big impact in at least a subset of patients’ lives, but we need to see how it will actually perform in trials.”

Freed-Pastor, who is also a medical oncologist at Dana-Farber Cancer Institute, is the lead author of the new study , which appears today in Cancer Cell . Tyler Jacks, the David H. Koch Professor of Biology and a member of the Koch Institute, is the paper’s senior author.

Immune attack

The body’s immune system contains T cells that can recognize and destroy cells that express cancerous proteins, but most tumors create a highly immunosuppressive environment that disables these T cells, helping the tumor to survive.

Immune checkpoint therapy (the most common form of immunotherapy currently being used clinically) works by removing the brakes on these T cells, rejuvenating them so they can destroy tumors. One class of immunotherapy drug that has shown success in treating many types of cancer targets the interactions between PD-L1, a cancer-linked protein that turns off T cells, and PD-1, the T cell protein that PD-L1 binds to. Drugs that block PD-L1 or PD-1, also called checkpoint inhibitors, have been approved to treat cancers such as melanoma and lung cancer, but they have very little effect on pancreatic tumors.

Some researchers had hypothesized that this failure could be due to the possibility that pancreatic tumors don’t express as many cancerous proteins, known as neoantigens. This would give T cells fewer targets to attack, so that even when T cells were stimulated by checkpoint inhibitors, they wouldn’t be able to identify and destroy tumor cells.

However, some recent studies had shown, and the new MIT study confirmed, that many pancreatic tumors do in fact express cancer-specific neoantigens. This finding led the researchers to suspect that perhaps a different type of brake, other than the PD-1/PD-L1 system, was disabling T cells in pancreatic cancer patients.

In a study using mouse models of pancreatic cancer, the researchers found that in fact, PD-L1 is not highly expressed on pancreatic cancer cells. Instead, most pancreatic cancer cells express a protein called CD155, which activates a receptor on T cells known as TIGIT.

When TIGIT is activated, the T cells enter a state known as “T cell exhaustion,” in which they are unable to mount an attack on pancreatic tumor cells. In an analysis of tumors removed from pancreatic cancer patients, the researchers observed TIGIT expression and T cell exhaustion from about 60 percent of patients, and they also found high levels of CD155 on tumor cells from patients.

“The CD155/TIGIT axis functions in a very similar way to the more established PD-L1/PD-1 axis. TIGIT is expressed on T cells and serves as a brake to those T cells,” Freed-Pastor says. “When a TIGIT-positive T cell encounters any cell expressing high levels of CD155, it can essentially shut that T cell down.”

Drug combination

The researchers then set out to see if they could use this knowledge to rejuvenate exhausted T cells and stimulate them to attack pancreatic tumor cells. They tested a variety of combinations of experimental drugs that inhibit PD-1 and TIGIT, along with another type of drug called a CD40 agonist antibody.

CD40 agonist antibodies, some of which are currently being clinically evaluated to treat pancreatic cancer, are drugs that activate T cells and drive them into tumors. In tests in mice, the MIT team found that drugs against PD-1 had little effect on their own, as has previously been shown for pancreatic cancer. They also found that a CD40 agonist antibody combined with either a PD-1 inhibitor or a TIGIT inhibitor was able to halt tumor growth in some animals, but did not substantially shrink tumors.

However, when they combined CD40 agonist antibodies with both a PD-1 inhibitor and a TIGIT inhibitor, they found a dramatic effect. Pancreatic tumors shrank in about half of the animals given this treatment, and in 25 percent of the mice, the tumors disappeared completely. Furthermore, the tumors did not regrow after the treatment was stopped. “We were obviously quite excited about that,” Freed-Pastor says.

Working with the Lustgarten Foundation for Pancreatic Cancer Research, which helped to fund this study, the MIT team sought out two pharmaceutical companies who between them have a PD-1 inhibitor, TIGIT inhibitor, and CD40 agonist antibody in development. None of these drugs are FDA-approved yet, but they have each reached phase 2 clinical trials. A clinical trial on the triple combination is expected to begin later this year.

“This work uses highly sophisticated, genetically engineered mouse models to investigate the details of immune suppression in pancreas cancer, and the results have pointed to potential new therapies for this devastating disease,” Jacks says. “We are pushing as quickly as possible to test these therapies in patients and are grateful for the Lustgarten Foundation and Stand Up to Cancer for their help in supporting the research.”

Alongside the clinical trial, the MIT team plans to analyze which types of pancreatic tumors might respond best to this drug combination. They are also doing further animal studies to see if they can boost the treatment’s effectiveness beyond the 50 percent that they saw in this study.

In addition to the Lustgarten Foundation, the research was funded by Stand Up To Cancer, the Howard Hughes Medical Institute, Dana-Farber/Harvard Cancer Center, the Damon Runyon Cancer Research Foundation, and the National Institutes of Health.

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Boston Herald reporter Rick Sobey writes that a new drug combination has shown potential in treating pancreatic cancer. “The trio drug combination is a CD40 agonist antibody, a PD-1 inhibitor and a TIGIT inhibitor. The researchers found that this combination led to pancreatic tumors shrinking in about 50% of the animals that were given this treatment,” writes Sobey.

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Advances in the management of pancreatic cancer

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• Peer review
• Marco Del Chiaro , professor, division chief , clinical director 1 2 ,
• Toshitaka Sugawara , assistant clinical professor 1 3 ,
• Sana D Karam , professor 2 4 ,
• Wells A Messersmith , professor , division head, , associate director 2 5
• 1 Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora, CO, USA
• 2 University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA
• 3 Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
• 4 Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, USA
• 5 Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
• Corresponding Author: M Del Chiaro marco.delchiaro{at}cuanschutz.edu

Pancreatic cancer remains among the malignancies with the worst outcomes. Survival has been improving, but at a slower rate than other cancers. Multimodal treatment, including chemotherapy, surgical resection, and radiotherapy, has been under investigation for many years. Because of the anatomical characteristics of the pancreas, more emphasis on treatment selection has been placed on local extension into major vessels. Recently, the development of more effective treatment regimens has opened up new treatment strategies, but urgent research questions have also become apparent. This review outlines the current management of pancreatic cancer, and the recent advances in its treatment. The review discusses future treatment pathways aimed at integrating novel findings of translational and clinical research.

Introduction

Pancreatic cancer has been considered a deadly disease with a very small probability of long term survival. 1 Despite slow progress, long term survival rates have greatly improved, especially for resected patients. From 1975 to 2011, the five year survival for resected pancreatic cancer improved from 1.5% to 17.4%. 2 However, more recent data show that five year survival for all pancreatic cancers between 2012-18 reached only 11.5% in the United States. 3

As a systemic disease, the changes in the survival of patients with pancreatic cancer have been affected most by the improvements in systemic treatments. 4 5 Consequently, the anatomical factors influencing the resectability of pancreatic cancer, which are defined in the National Comprehensive Cancer Network (NCCN) clinical practice guidelines, 6 have diminished in importance owing to better local and systemic control with higher response rates.

This review summarizes and contextualizes recent studies on the management of pancreatic cancer, and discusses potential treatments that are on the horizon. A detailed discussion of the preclinical or translational studies of diagnosis tools, drugs, and procedures is outside the scope of this review.

Sources and selection criteria

We searched Pubmed, the Cochrane database, and the Central Register of Controlled Trials (clinicaltrials.gov) between January 2000 and December 2022 for English language literature. We used the following keywords and keywords combinations: “pancreatic cancer”, “molecular characteristics”, “biology”, “resectability”, “metastatic”, “treatment”, “surgery”, “chemotherapy”, “radiation therapy”, “immunotherapy”, “prevention”, “precursor”, and “risk factor”. We also included the NCCN clinical practice guidelines, 6 the European Society for Medical Oncology (ESMO) clinical practice guidelines, 7 and the clinical practice guidelines from the Japan Pancreas Society. 8 We included studies based on the level of evidence; randomized controlled trials, meta-analyses, systematic reviews, and large retrospective cohort studies were prioritized. Meta-analyses included retrospective and prospective studies unless otherwise specified. We prioritized the most recent studies and excluded narrative reviews, case series, and case reports. We included additional landmark studies published before January 2000, as well as after December 2022.

Epidemiology

Pancreatic cancer is reported to account for 495 773 new cases and 466 003 deaths worldwide as of 2020, with the incidence and mortality rates stable or slightly increased in many countries. 9 In the US, the estimated incidence of pancreatic cancer is increasing, with more than 50 000 new cases in 2020. Mortality rates have also increased moderately in men, to 12.7 per 100 000 men in 2020; but have remained stable in women, ranging from 9.3 to 9.6 per 100 000 women. Accordingly, pancreatic cancer is the third most common cause of cancer related death in 2023, and is predicted to become the second leading cause of cancer mortality by 2040. 3 10

Clinical presentation/features

Symptoms of pancreatic cancer are mostly non-specific, and generally manifest after the tumor has grown and metastasized. In a multicenter prospective study of 391 patients who were referred for suspicion of pancreatic cancer (119 had pancreatic cancer), the most common initial symptoms were decreased appetite (28%), indigestion (27%), and change in bowel habits (27%). 11 The initial symptoms were similar between the pancreatic cancer group and the non-cancer group, though several subsequent symptoms were associated with pancreatic cancer: jaundice (49% v 12%), fatigue (51% v 26%), decreased appetite (48% v 26%), weight loss (55% v 22%), and change in bowel habits (41% v 16%).

Risk factors

Box 1 summarizes the risk factors for pancreatic cancer. Research is continuing into subtypes and modifiers of familial syndromes.

Factors that increase the risk of pancreatic cancer

Family history.

Up to 10% of all pancreatic cancers are estimated to be familial (meaning that at least two first degree relatives have pancreatic cancer)

Patients who have two first degree relatives with pancreatic cancer have a standardized incidence ratio of 6.4 (lifetime risk 8-12%) 12

Patients who have three first degree relatives with pancreatic cancer have a standardized incidence ratio of 32.0 (lifetime risk 40%) 12

Approximately 20% of these families have a germline mutation that is already reported and known

Germline mutation and hereditary syndrome

LKB1/STK11: Peutz-Jeghers syndrome; relative risk 132 13

CDKN2A/p16: familial atypical multiple mole melanoma syndrome; relative risk 13-22 14

PRSS1/CPA1/CTRC/SPINK1: hereditary pancreatitis; relative risk 53-87 15

BRCA1 and BRCA2: hereditary breast ovarian cancer syndrome; relative risk 2 and 10, respectively 16

MLH1/MSH2/MSH6/PMS2: Lynch syndrome; relative risk up to 8.6 17

PALB2/ATM: relative risk unknown

Lifestyle factors

Smoking: current smoker relative risk 1.8; former smoker relative risk 1.2 18

Obesity: five unit increment in body mass index relative risk 1.10 19

Diabetes mellitus * : relative risk 1.94 20

Chronic pancreatitis: relative risk 16.16 21

*Diabetes mellitus is also a symptom of pancreatic cancer; new onset diabetes in older people could be an early sign of pancreatic cancer and can lead to early diagnosis. 22 The association between diabetes and pancreatic cancer is currently undergoing further research. 23

Precancerous lesion

Molecular research has proposed two evolutionary models of pancreatic cancer: the classic “stepwise” model, with gradual accumulation of driver gene mutations, and the novel “punctuated” model, 24 in which driver gene mutation occurs simultaneously by chromosomal rearrangements. The stepwise model is characterized by tumor evolution from a precancerous lesion (low grade or high grade dysplasia) to invasive cancer, and is believed to be the main evolutionary pattern. Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs) are well known precancerous lesions. By contrast to PanIN, which is a microscopic neoplastic lesion, IPMNs can be detected and followed by imaging studies. Consequently, extensive studies have been conducted to evaluate the association between imaging findings and pathological findings of IPMNs. Branch duct IPMNs have been reported to have a low malignant nature (1.0% patient years), 25 but harbor a risk of concomitant pancreatic cancer (0.8%). 26 Main duct IPMNs have been reported to be a high risk factor for pancreatic cancer (odds ratio 5.66). 27

Screening and early detection

Because early stage (ie, stage I, T1N0M0) disease or precancerous lesions are more likely to be curable, the goal of screening or surveillance for pancreatic cancer is to detect lesions of 2 cm or smaller, or patients with high grade dysplasia. 28 Several studies have estimated an interval of several years between a high grade dysplasia lesion (high grade PanIN and IPMN) and invasive cancer, which can give opportunities for early detection and intervention: 2.3-11 years for high grade PanIN, 29 30 and more than three years for high grade IPMN. 31 The International Cancer of the Pancreas Screening (CAPS) consortium has published consensus guidelines about screening for high risk patients who have high risk germline mutations or relatives with pancreatic cancer, or both. 28 A recent prospective cohort study (CAPS5) from the CAPS group including 1461 high risk patients showed positive results of surveillance 25 ; seven of nine patients (77.8%) who developed pancreatic cancer had stage I cancer. However, only three of the eight patients (37.5%) who had IPMNs with worrisome features had high grade dysplasia (five had low grade dysplasia). A multicenter retrospective study (n=2552) of the CAPS consortium showed that 13 of the 28 patients (46.4%) who developed high grade dysplasia or cancer developed the new lesion during the scheduled examination interval. 32 Regarding IPMNs in the general population, a recent retrospective study showed that only 177 of 1439 patients with resected IPMN (12.3%) had high grade dysplasia, and 497 (34.5%) had a diagnosis of invasive cancer. 33 These results suggest that a novel strategy distinct from current guidelines 34 35 is needed for IPMN lesions, and new diagnostic tests are needed to detect tiny tumors.

The United States Preventive Services Task Force (USPSTF) 36 recommends avoiding pancreatic cancer screening in asymptomatic adults with average risk, considering the relatively low prevalence (estimated 64 050 new cases in 2023). 36 However, the USPSTF does not discuss screening in patients with risk factors of age and lifestyle, and neither do the consensus guidelines of the CAPS consortium. A risk assessment model including all known risk factors ( box 1 ) could help to identify good candidates for pancreatic cancer screening.

Carbohydrate antigen 19-9 (CA19-9) is a cell surface tetrasaccharide often elevated in pancreatic cancer, as well as in other cancers and some benign diseases. Historically, CA19-9 has not been used for early detection, owing to its insufficient sensitivity for early stage pancreatic cancer. 37 We also know that 5-10% of the population does not synthesize CA19-9, owing to a deficiency of a fucosyltransferase enzyme. However, a recent large retrospective cohort study showed that CA19-9 levels increase from two years before diagnosis of pancreatic cancer, with a sensitivity of 50% and specificity of 99% within 0-6 months before diagnosis in early stage disease. In addition, in cases with CA19-9 levels below the cut-off value, the combination of LRG1 and TIMP1 could complement CA19-9, leading to the identification of cases missed by CA19-9 alone. 38 Novel tests (ie, cytology 39 and DNA alterations 40 ) using pancreatic juice and cystic fluid have been reported to play a promising role in identifying high grade dysplasia and invasive cancer with high specificity. However, the sensitivity of these tests is low (˂50%). Extensive studies have investigated the role of liquid biopsy in pancreatic cancer: circulating tumor cells, 41 circulating tumor DNA, 42 43 microRNA, 44 exosomes, 45 and methylation signatures of cell free DNA. 46 Although these new biomarkers show promise, many problems remain unsolved with regard to standardization of testing techniques and cut-off values ( table 1 ). However, advances in this field could increase survival drastically.

Summary of novel techniques for diagnosis and early detection of pancreatic cancer

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Diagnosis and evaluation

The performance of diagnosis tools is summarized in box 2 .

Imaging study and biomarker for diagnosis of pancreatic cancer

CT (computed tomography) is the standard modality; accuracy 89% (95% confidence interval 85 to 93) 47

MRI (magnetic resonance imaging) has a similar performance to CT; accuracy 90% (95% confidence interval 86 to 94) 47

PET (positron emission tomography) has a worse performance; accuracy 84% (95% confidence interval 79 to 89) 47

Endoscopic ultrasound has a similar performance to CT; accuracy 89% (95% confidence interval 87 to 92) 47

Endoscopic ultrasound can identify masses that are indeterminate by CT; accuracy 75% (95% confidence interval 67 to 82) 48

CA19-9 is the most widely used and validated biomarker; area under curve 0.83-0.91 49

Imaging study for evaluation

CT (computed tomography) is the standard tool to evaluate the extent of the primary tumor and determine its anatomical resectability. Two meta-analyses showed similar performance of CT (sensitivity 70%, specificity 95%) and MRI (magnetic resonance imaging) (sensitivity 65%, specificity 95%) in the diagnosis of vascular involvement. 50 51 A meta-analysis showed that endoscopic ultrasound performed similarly to CT in evaluating vascular invasion. 52 A multimodal approach (ie, CT plus MRI plus endoscopic ultrasound) provides a better assessment of resectability. Several studies have attempted to evaluate the response to chemotherapy with imaging studies to determine the course of treatment (ie, proceeding to surgery or continuing chemotherapy). However, the currently used response evaluation criteria in solid tumors (RECIST) are not sufficient to reassess local response after chemotherapy in pancreatic cancer, especially regarding the involvement of vessels. Distinguishing scar areas with fibrosis that occur with treatment from cancer cell death from viable tumor associated desmoplasia is challenging; both are common in pancreatic cancer. A meta-analysis including six studies with 217 patients showed the difficulty of using CT scans to predict margin negative resection after preoperative treatment; the sensitivity was 81% and specificity was as low as 42%. 53 MRI 54 55 and fluorodeoxyglucose PET (positron emission tomography)/CT or PET/MRI 56 have been reported to be associated with the pathological response to preoperative treatment, though the ability to evaluate the vessel involvement and resectability is unclear. However, it should also be noted that even in the setting of histological response assessment, moderate inter-rater reliability differences have been reported between pathologists. 57

Biomarker for evaluation

CA19-9 has been used to assess response to treatment and predict prognosis. A meta-analysis showed that CA19-9 was associated with the effect of preoperative treatment, and suggested that either normalization of CA19-9 or a decrease of more than 50% from the baseline level are positive predictors of survival. 58 A recent retrospective study analyzing the combination of CT and CA19-9 showed a good predictive performance of survival after chemoradiotherapy. 59 However, the optimal evaluation of response to treatment remains unclear. The ability of liquid biopsy ( table 1 ) to detect minimal residual disease following all planned treatment could identify a new subset of patients who require further treatment, and would lead to a true precision medicine approach, as has been achieved with other cancer types. 60

Cancer cell intrinsic and tumor microenvironment factor

Transcriptional studies have proposed several classifications of pancreatic cancer. A recent bioinformatic study 61 from The Cancer Genome Atlas research network supported the two subgroup model 62 : the basal-like subtype, which has low levels of GATA6 expression, and the classic subtype. In a prospective translational trial, the basal-like subtype was reported to be associated with a poor response to chemotherapy with FOLFIRINOX (combined leucovorin calcium (folinic acid), fluorouracil, irinotecan, and oxaliplatin) for patients with advanced cancer. 63 However, a more recent study using single cell analysis suggested that pancreatic cancer consists of a mixture of tumor cells with both molecular subtypes, and the composition is plastic and unstable. 64

In addition to the cancer cells themselves, the tumor microenvironment has been identified as being an essential factor associated with tumor progressions and tumor immunity. Pancreatic cancer is notorious for poor tumor cellularity and an abundant, fibrotic extracellular matrix. Although the dense extracellular matrix has been known to impair drug delivery and immune cell migration, it appears to have an essential role in maintaining the tumor microenvironment and supporting the progression of tumor cells. 65 Therefore, the efficacy of controlling the extracellular matrix by targeting its components (ie, collagen, cancer associated fibroblasts, and hyaluronan) and cytokines (ie, transforming growth factor β and sonic hedgehog) has been evaluated.

Figure 1 outlines the current management for pancreatic cancer based on the anatomic resectability of the tumor, with the first consensus statement defined in 2009, 66 before the advent of more effective systemic treatments. In primary resectable disease, upfront surgery followed by adjuvant chemotherapy has been considered the standard of care. By contrast, for borderline resectable and locally advanced diseases, preoperative treatment is generally proposed, because of the high likelihood of micrometastasis and the low likelihood of margin negative resection in these tumors. 67 However, the improvement of medical treatment is challenging this concept; neoadjuvant treatment for resectable diseases is under investigation. At present, the recommendation is that the decision for treatment should be made at a multidisciplinary conference at a high volume center.

Current management for pancreatic cancer. CA19-9=carbohydrate antigen 19-9

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Systemic treatment

The standard drug treatment for systemic treatment is still cytotoxic chemotherapy, and the efficacy of targeted treatment or immunotherapy remains unproven. Table 2 summarizes the clinical trials of medical treatment.

Summary of key studies of medical treatment of pancreatic cancer

Systemic treatment for metastatic disease

Gemcitabine became the standard chemotherapy drug for pancreatic cancer more than 20 years ago. In 1997, gemcitabine showed clinical benefit and marginally improved overall survival compared with fluorouracil (median survival 5.65 v 4.41 months) in a small randomized controlled trial that included 63 patients in each arm. 68 Consequently, several trials were performed investigating combinations with gemcitabine. 69 70 71 However, most studies did not show a significant improvement in overall survival; the combinations tested included fluorouracil, 72 irinotecan, 73 oxaliplatin, 74 75 cisplatin, 76 77 and capecitabine. 78 79 80 Unfortunately, the addition of targeted treatment to gemcitabine based chemotherapy also did not show a survival benefit, with any of tipifarnib, 81 cetuximab, 82 bevacizumab, 83 84 axitinib, 85 and vandetanib. 86 In 2011, a landmark randomized phase 2/3 trial (PRODIGE 4/ACCORD 11) defined a new standard chemotherapy for metastatic pancreatic cancer. 71 This multicenter trial enrolled 171 patients in each arm and showed a significant improvement in survival, with a median overall survival of 11.1 months in the FOLFIRINOX group, compared with 6.8 months in the gemcitabine group (hazard ratio 0.57; 95% confidence interval 0.45 to 0.73). FOLFIRINOX also had a higher response rate (31.6%) than gemcitabine (9.4%). Subsequently, the MPACT trial, a large randomized phase 3 study, showed another cytotoxic combination option (gemcitabine/nab-paclitaxel) for metastatic pancreatic cancer. 87 This study included 861 patients, and showed that gemcitabine/nab-paclitaxel improved survival compared with gemcitabine alone (median survival 8.5 v 6.7 months; hazard ratio 0.72; 95% confidence interval 0.62 to 0.83). FOLFIRINOX and gemcitabine/nab-paclitaxel have formed the cytotoxic “backbones” for multiple clinical trials.

Nanoliposomal irinotecan is a drug encapsulating irinotecan sucrosofate salt payload in tiny pegylated liposomal particles, which theoretically can enhance the exposure of irinotecan to tumor cells. A recent randomized phase 3 trial (NAPOLI-3) enrolled 770 patients with metastatic pancreatic cancer and compared NALIRIFOX (combined liposomal irinotecan, fluorouracil, folinic acid, and oxaliplatin) (n=383) to gemcitabine/nab-paclitaxel (n=387) as the first line treatment. 88 Preliminary results showed an improved overall survival (median 11.1 v 9.2 months; hazard ratio 0.84; 95% confidence interval 0.71 to 0.99), which was the primary endpoint, and an improved progression free survival (7.4 v 5.6 months; 0.70; 0.59 to 0.84). For Asian populations, S-1 (an oral fluoropyrimidine derivative) is another treatment option, after it showed non-inferiority to gemcitabine for advanced pancreatic cancer in a randomized phase 3 study (GEST). 89

Second line systemic treatment for advanced disease

Second line regimens after gemcitabine based chemotherapy for advanced pancreatic cancer have been studied in several trials. The CONKO-003 randomized phase 3 trial showed that the addition of oxaliplatin to folinic acid and fluorouracil (5FU/LV) significantly improved overall survival (median 5.9 v 3.3 months, hazard ratio 0.66; 95% confidence interval 0.48 to 0.91). 90 By contrast, another randomized phase 3 trial (PANCREOX) found a deleterious effect on survival of oxaliplatin (mFOLFOX6) over infusional fluorouracil/leucovorin (hazard ratio 1.78; 95% confidence interval 1.08 to 2.93) in the second line setting. 91

A large randomized phase 3 trial (NAPOLI-1) investigated the efficacy of nanoliposomal irinotecan to 5FU/LV for metastatic disease after gemcitabine based treatment. 92 The results showed that nanoliposomal irinotecan plus 5FU/LV incrementally improved survival compared with 5FU/LV (6.1 v 4.2 months, hazard ratio 0.67; 95% confidence interval 0.49 to 0.92). Patients who received nanoliposomal irinotecan monotherapy, however, had similar survival to those who received 5FU/LV (4.9 v 4.2 months, 0.99; 0.77 to 1.28). Further studies on second line regimens after FOLFIRINOX or gemcitabine/nab-paclitaxel are warranted.

Maintenance systemic treatment for advanced disease

A poly adenosine diphosphate ribose polymerase (PARP) inhibitor was investigated as the maintenance treatment in patients who had germline loss-of-function mutations in BRCA1 or BRCA2, and platinum sensitive advanced disease. A randomized double blind phase 3 trial (POLO) showed no survival benefit of olaparib (n=62) compared with placebo (n=92) (median overall survival 19.0 v 19.2 months; hazard ratio 0.83; 95% confidence interval 0.56 to 1.22), but did show an improvement in progression free survival, which resulted in US Food and Drug Administration approval. 93 94 Another PARP inhibitor, niraparib, combined with an anti-CTLA-4 (ipilimumab) drug, showed a median overall survival of 17.3 months (95% confidence interval 12.8 to 21.9 months) in a phase 1b/2 trial. 95 Maintenance treatment for non-BRCA mutated patients with metastatic diseases following FOLFIRINOX was evaluated in the PANOPTIMOX-PRODIGE 35 phase 2 trial. 96 This study randomly assigned 273 patients to six month FOLFIRINOX (n=91), four month FOLFIRINOX followed by leucovorin/5-FU maintenance (n=92), or a sequential treatment alternating gemcitabine and FOLFIRI.3 every two months (n=90). The results showed a comparable six month progression free survival rate and median progression free survival in the maintenance arm eliminating oxaliplatin (44%, 5.7 months), and the worst survival in the gemcitabine/FOLFIRI approach (34%, 4.5 months) compared with the six month FOLFIRINOX arm (47%, 6.3 months).

Adjuvant systemic treatment

Adjuvant systemic treatment is recommended for all eligible resected patients. The first large randomized phase 3 trial that showed the survival benefit of adjuvant chemotherapy was the ESPAC-1 trial, which assigned resected patients (n=289) to 5-FU/LV versus control. 4 97 Adjuvant chemotherapy prolonged the median overall survival by 4.6 months (hazard ratio 0.71; 95% confidence interval 0.55 to 0.92). 4 The CONKO-001 randomized phase 3 trial showed that adjuvant gemcitabine (n=179) improved overall survival compared with observation (n=172) (median 22.8 v 20.2 months; hazard ratio 0.76; 95% confidence interval 0.61 to 0.95). 98 When 5FU/LV and gemcitabine were compared head-to-head, no difference in overall survival was found, but gemcitabine had less toxicity in the ESPAC-3 randomized phase 3 trial. 99 Subsequently, multiple trials tried to find a new effective combination treatment with gemcitabine. A randomized phase 3 trial combining erlotinib with gemcitabine was negative, 100 but the addition of capecitabine had a survival benefit over gemcitabine alone (28.0 v 25.5 months; 0.82; 0.68 to 0.98) in the ESPAC-4 phase 3 trial. 101 However, this combination treatment was short lived; FOLFIRINOX drastically changed the survival of patients and became the new standard regimen for adjuvant treatment. The PRODIGE 24/CCTG PA6 phase 3 trial randomly assigned 493 resected patients to receive adjuvant modified (dose reduced) FOLFIRINOX (mFOLFIRINOX) or gemcitabine for 24 weeks. The mFOLFIRINOX group (n=247) showed a significantly improved median overall survival (53.5 v 35.5 months; 0.68; 0.54 to 0.85). 5 102 By contrast, gemcitabine/nab-paclitaxel failed to show a survival benefit over gemcitabine alone in a randomized phase 3 trial (APACT). 103 It did not meet the primary endpoint of disease free survival by central review, 103 although overall survival improved marginally in the gemcitabine/nab-paclitaxel group (40.5 v 36.2 months; 0.82; 0.680 to 0.996). In Asia, S-1 is the standard regimen, based on the results of a randomized phase 3 trial. 104 The role of adjuvant treatment after neoadjuvant chemotherapy and surgical resection is still debatable. A recent large retrospective study showed a potential benefit in survival for patients able to receive adjuvant chemotherapy after neoadjuvant and surgery. 105

Neoadjuvant systemic treatment

One of the underpinnings of neoadjuvant treatment is that 36% of patients with pancreatic cancer are unable to receive adjuvant chemotherapy after resection, 106 and surgical resection alone does not achieve long term survival for most patients. The rationale for neoadjuvant treatment is to increase the dose intensity and tolerance of planned systemic treatment before patients are weakened by surgery, and to avoid delayed treatment of micrometastatic disease, which is the main cause of mortality. 107 Two prospective single arm phase 2 studies showed the safety of neoadjuvant gemcitabine plus a platinum based drug. 108 109

The only published phase 3 trial of neoadjuvant systemic treatment (PREOPANC-1) randomly assigned 246 patients with resectable (54.1%) or borderline resectable disease (45.9%) to neoadjuvant chemoradiotherapy (n=119) or upfront surgery (n=127). 110 111 The neoadjuvant chemoradiotherapy arm received three cycles of neoadjuvant gemcitabine with 36 Gy radiotherapy in 15 fractions and four cycles of adjuvant gemcitabine, whereas the upfront surgery arm received six cycles of adjuvant gemcitabine. Long term results showed a consistent survival benefit of neoadjuvant treatment regardless of the resectability of the primary tumors, for borderline resectable diseases (hazard ratio 0.67; 95% confidence interval 0.45 to 0.99) and resectable diseases (0.79; 0.54 to 1.16). However, the chemotherapy regimen (gemcitabine alone) was outdated. The recent ESPAC-5 phase 2 trial 112 randomly assigned 90 patients with borderline resectable diseases to neoadjuvant treatment (n=56), which included multiagent neoadjuvant chemotherapy and single agent chemoradiotherapy, or upfront surgery (n=33). It showed a better one year overall survival in the neoadjuvant treatment groups compared with the upfront surgery group (76% v 39%; hazard ratio 0.29; 95% confidence interval 0.14 to 0.60), although it did not provide evidence of the optimal regimen owing to the small sample size.

Regarding resectable diseases, one concern of neoadjuvant treatment is the possibility of disease progression during neoadjuvant treatment, which could cause patients to miss the opportunity for surgical resection. Indeed, the role of neoadjuvant treatment for resectable disease is still under investigation. A randomized phase 2 trial (PACT-15) showed that neoadjuvant chemotherapy with the PEFG regimen (cisplatin, epirubicin, fluorouracil, and gemcitabine) improved overall survival compared with adjuvant gemcitabine and adjuvant PEFG regimen for resectable disease. 113 The Prep-02/JSAP-05 phase 2/3 trial randomly assigned patients with resectable (about 80%) or borderline resectable diseases to one month neoadjuvant gemcitabine plus S-1 (n=182), or upfront surgery (n=180). Both arms received six month S-1 as the adjuvant treatment. 114 The results showed improved overall survival in the neoadjuvant chemotherapy arm (36.7 v 26.6 months; hazard ratio 0.72; 95% confidence interval 0.55 to 0.94). Conversely, studies of FOLFIRINOX have not shown positive results. 115 116 The SWOG S1505 phase 2 study showed equivalent efficacy of neoadjuvant mFOLFIRINOX versus nab-paclitaxel/gemcitabine for three months for resectable disease. 115 The median overall survival in both arms (23.2 and 23.6 months) did not show improvement compared with previous trials of adjuvant treatment.

A recent phase 2 trial (NORPACT-1) randomly assigned 140 patients with resectable diseases to the neoadjuvant FOLFIRINOX arm (n=77) or the upfront surgery arm (n=63), and found no survival benefit of neoadjuvant FOLFIRINOX. However, the results have several problems. While not significant, the median survival was 13.4 months shorter (25.1 v 38.5 months) in the neoadjuvant FOLFIRINOX arm, despite the higher rates of node negative (N0) and margin negative (R0) resection in that arm. Given the high resection rate (n=63, 82%) despite the low completion rate of neoadjuvant chemotherapy (n=40, 52%), and the high rate of adjuvant chemotherapy other than FOLFIRINOX (75%) in the neoadjuvant group, it seems that the neoadjuvant group did not receive sufficient FOLFIRINOX chemotherapy. In addition, whether two months is sufficient for neoadjuvant FOLFIRINOX is unclear. Three ongoing large randomized phase 3 trials might provide some insight into the optimal sequence and the number of cycles of FOLFIRINOX; two are recruiting patients (ALLIANCE-A021806 and PREOPANC-3), and one recently opened ( NCT05529940 ). The first two trials plan to enrol more than 300 patients with resectable disease to assess the overall survival of perioperative FOLFIRINOX (eight cycles of neoadjuvant and four cycles of adjuvant) compared with adjuvant FOLFIRINOX (12 cycles). The NCT05529940 trial plans to enrol more than 600 patients and evaluate the two year survival of perioperative FOLFIRINOX (six cycles of neoadjuvant and six cycles of adjuvant) compared with adjuvant FOLFIRINOX (12 cycles).

Systemic treatment for locally advanced disease

After the positive results of FOLFIRINOX and gemcitabine/nab-paclitaxel for metastatic disease, several studies have investigated its efficacy in locally advanced diseases. A systematic review that analyzed 315 patients with locally advanced diseases from 11 studies between 1994 and 2015 showed that FOLFIRINOX was associated with a longer median overall survival of 24.2 months (95% confidence interval 21.7 to 26.8 months). 117 The proportion of patients who underwent surgical resection after FOLFIRINOX ranged from 0-43%. A phase 2 study (LAPACT) investigated gemcitabine/nab-paclitaxel for 106 patients 118 ; the median overall survival was 18.8 months (90% confidence interval 15.0 to 24.0 months). In total, 62 patients (58%) completed induction gemcitabine/nab-paclitaxel, and 17 patients (16%) underwent surgical resection. Another randomized phase 2 study (NEOLAP-AIO-PAK-0113) showed high surgical conversion rates of gemcitabine/nab-paclitaxel (23/64, 35.9%) and gemcitabine/nab-paclitaxel followed by FOLFIRINOX (29/66, 43.9%). 119 No survival differences were observed between the two arms (hazard ratio 0.86; 95% confidence interval 0.55 to 1.36). These results suggest a new potential treatment strategy for surgical conversion of locally advanced disease, which could achieve longer survival in selected patients.

Surgical treatment

Pancreatectomy, especially pancreaticoduodenectomy, has been considered a high risk surgery. The centralization of pancreatectomy has played an essential role in the improvement of perioperative outcomes. The 90 day mortality is reported to be under 5-10% in experienced high volume centers. 120 121 A recent meta-analysis including 46 retrospective studies (2015-2021) showed a significantly lower postoperative morbidity rate in high volume centers compared with low volume centers (47.1% v 56.2%; odds ratio 0.75; 95% confidence interval 0.65 to 0.88). 121

Surgery for locally advanced and borderline disease

Some experts have pushed for more aggressive operations for patients with borderline resectable and locally advanced diseases with the advent of more effective systemic drugs. Resection after neoadjuvant treatment was reported to have similar short term outcomes compared with upfront resection in a meta-analysis 122 including randomized controlled trials and a subgroup report of a randomized phase 3 trial. 123 However, data on arterial resection and reconstruction are more controversial, and depend on the resected artery and the technical approach; the mortality rates were reported as 5.7% for resection of the superior mesenteric artery, 124 and 1.7% for resection of the celiac axis. 125 More recently, arterial divestment has been proposed as an alternative to arterial resection in selected patients. A retrospective study of a high volume center reported a mortality rate of 7.0% for arterial resections and 2.3% for arterial divestment from 2015 to 2019, although the breakdown of resected arteries was not shown by periods. 126 To be clear, these aggressive procedures should be performed only when long term survival is expected. A previous meta-analysis including 13 studies (2005-2015) with 355 locally advanced tumors showed no significant association between the resection rate after chemotherapy and overall survival. 117 However, large, retrospective studies recently showed that conversion surgery for locally advanced diseases after FOLFIRINOX was associated with improved survival in a selected subgroup. 127 128 Further studies are expected.

Surgery for patients with metastatic disease

Macroscopic distant metastasis is a contraindication to surgical resection in general. However, several studies have reported a potential role of resection in highly selected patients with limited metastatic diseases. A meta-analysis including three retrospective studies (2016-2019) showed a longer overall survival (23-56 months v 11-16 months) in patients with synchronous liver metastasis who underwent resection after chemotherapy (n=44) compared with those who did not (n=166). 129 In another review, lung metastasectomy was associated with a longer survival with a median overall survival after resection ranging from 18.6 to 38.3 months. 130 A large retrospective study suggested that only patients who achieved a complete pathological response of metastasis could derive a survival benefit from resection. 131 Further studies are expected to provide data on patient selection criteria and metastatic sites. A single arm phase 2 study ( NCT04617457 ) and a randomized phase 3 trial ( NCT03398291 ) are recruiting patients with oligometastasis in liver from pancreatic cancer to evaluate the efficacy of resection after chemotherapy.

Minimally invasive surgery

Minimally invasive surgery for pancreatic cancer had until recently been lagging behind that for other cancers. Results of a recent randomized trial 132 (n=656) and a meta-analysis of three randomized controlled trials 133 (n=224) showed that laparoscopic pancreatoduodenectomy was associated with a shorter hospital stay, but a similar postoperative morbidity rate. Box 3 summarizes the studies comparing robotic pancreatoduodenectomy with open or laparoscopic pancreatoduodenectomy. Notably, all studies on pancreatoduodenectomy to date have included patients with diseases other than pancreatic cancer. Another meta-analysis including 12 randomized or matched studies (n=4346) showed a similar morbidity rate, but a higher margin negative resection rate (odds ratio 1.46) and shorter time to adjuvant treatment, in the laparoscopic distal pancreatectomy group. 139 Most recently, an international randomized trial (DIPLOMA) 140 including 117 patients with resectable pancreatic cancer in the minimally invasive distal pancreatectomy group and 114 patients in the open distal pancreatectomy group showed the non-inferiority of the oncological safety of minimally invasive distal pancreatectomy: a higher margin negative resection rate (73% v 69%) and comparable lymph node yield and intraperitoneal recurrence.

Comparison between robotic pancreaticoduodenectomy and open pancreatoduodenectomy or laparoscopic pancreatoduodenectomy

Robotic pancreatoduodenectomy ( v open pancreatoduodenectomy ) 134 135 136 | robotic pancreatoduodenectomy ( v laparoscopic pancreatoduodenectomy ) 135 137 138.

R0 resection: Comparable 135 136 or higher 134 | Comparable 135

Lymph nodes harvested: Comparable 135 136 or more 134 | Comparable 135 or more 137 138

Operating time: Longer 134 135 136 | Comparable 135 137 138

Estimated blood loss: Less 134 135 136 | Comparable 138 or less 135 137

Conversion rate: Not applicable | Lower 137 138

Overall mortality rate: Comparable 134 or lower 136 | Comparable 138

Overall morbidity rate: Comparable 134 135 or lower 136 | Comparable 135 137 138

Surgical site infection: Less 134 135 | Comparable 135 138

Pancreatic fistula: Comparable 134 135 or less 136 | Comparable 135 137 138

Hemorrhage: Comparable 135 | Comparable 135

Delayed gastric emptying: Comparable 134 136 or less 135 | Comparable 135 137 138

Length of stay: Comparable 134 135 or longer 136 | Comparable 135 137 or shorter 138

Radiotherapy

Radiotherapy is used as a part of local treatment for pancreatic cancer, generally combined with chemotherapy. Since the gold standard for this disease remains surgical resection, 67 the role of radiotherapy has been logically examined in both the adjuvant setting and in locally advanced inoperable patients. The neoadjuvant application of radiotherapy has also been investigated in several studies. In this setting, however, high level evidence comparing the role of radiotherapy in a head-to-head design to neoadjuvant chemotherapy is lacking. The true efficacy of radiotherapy on long term survival remains unclear, especially when combined with modern multiagent systemic treatments and surgical resection. Another concern in many radiotherapy studies is the heterogeneity of the treatment technique and dose used. For example, the techniques have evolved from conventional treatments to intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), more ablative approaches with adaptive planning platforms. Box 4 summarizes the characteristics of radiotherapy by types and doses. Table 3 summarizes the clinical studies of radiotherapy.

Characteristics of radiotherapy for pancreatic cancer by types and doses

3 dimensional conformal radiation therapy (3d-crt).

Using multiple beams shaped to conform to a tumor that is identified its size, shape, and location by 3D imaging (ie, CT, MRI)

Generally used dose:* 45.0-56.0 Gy in 1.75-2.20 Gy fractions

Image guided radiation therapy (IGRT)

An adjunctive technique to adjust the tumor location difference by using 3D imaging (ie, CT, MRI) performed immediately before each radiation treatment

Intensity modulated radiation therapy (IMRT)

Possible to adjust the irradiation intensity within a target volume

Possible to deliver a concentrated dose to a tumor and better spare the normal tissue

Stereotactic body radiotherapy (SBRT)

Accurately irradiate a tumor with high dose radiation in three dimensions from multiple directions

High local control rate, comparable toxicity 141

Generally used dose:* 30.0-40.0 Gy in 6.00-8.00 Gy fractions

*Based on the ASTRO clinical practice guideline. 142

Summary of key studies of radiotherapy for pancreatic cancer

Adjuvant radiotherapy

In theory, the purpose of adjuvant radiotherapy is to reduce the risk of local recurrence. NCCN guidelines recommend considering adjuvant chemoradiation treatment for patients with positive surgical margins. 67 However, prospective studies that support adjuvant radiotherapy are lacking, regardless of the surgical margin status. The aforementioned large randomized phase 3 trial (ESPAC-1) included 289 resected patients: 51 (17.6%) had positive resection margins. The results showed worse survival in the chemoradiotherapy arm (n=145) than in the non-radiotherapy arm (n=144) (median overall survival 15.9 v 17.9 months; hazard ratio 1.28; 95% confidence interval 0.99 to 1.66). 4 This study has discouraged further studies of adjuvant radiotherapy in Europe. However, the study had two major drawbacks. Firstly, the chemotherapy regimen was different in the chemotherapy arm (fluorouracil/leucovorin) and the chemoradiotherapy arm (fluorouracil). Secondly, the total dose of radiotherapy (20 Gy) did not reach 45 Gy, which represents the treatment dose of conventional, fractionated external beam radiotherapy. 67 Two randomized phase 2 studies investigated adjuvant gemcitabine plus radiotherapy for patients with negative resection margins. The first study administered 50.4 Gy in 28 fractions of radiotherapy, and found a lower local alone recurrence rate (11% v 24%), but did not show a difference in overall survival or disease free survival between the two arms (45 patients each). 143 The other small study (n=38) used a modern SBRT technique (25 Gy in five fractions), but showed no difference in any of the survival endpoints (recurrence free survival, locoregional recurrence free survival, or overall survival), even in the node positive subgroup. 144 An older systematic review included five randomized controlled trials (1985-2005) of adjuvant chemoradiotherapy consisting of fluorouracil based chemotherapy plus conventional radiotherapy, and showed no survival benefit of chemoradiation (pooled hazard ratio 1.09; 95% confidence interval 0.89 to 1.32). 145 The subgroup analysis in this study showed a possible efficacy of adjuvant chemoradiotherapy in patients with positive resection margins.

The RTOG0848 trial is a randomized phase 2/3 study that enrolled 322 resected patients. The ongoing phase 3 of this trial assesses the survival benefit of added radiotherapy (50.4 Gy) after six cycles of adjuvant gemcitabine based chemotherapy. However, because the standard of care regimen of adjuvant chemotherapy has changed to FOLFIRINOX, the results of this study might have a limited impact on clinical practice. Ultimately, the role of adjuvant radiotherapy is still ambiguous.

Neoadjuvant radiotherapy

One of the primary goals of neoadjuvant radiotherapy is to reduce the rate of positive margin resection, which is a risk factor for local recurrence. Two single arm phase 2 studies showed the tolerability and feasibility of concurrent radiotherapy combined with fluorouracil plus cisplatin 146 (n=41) and gemcitabine (n=41). 147 However, the evidence on the efficacy of neoadjuvant radiotherapy is inconsistent. A meta-analysis of three randomized controlled trials (n=189) that investigated chemoradiotherapy (fluorouracil based chemotherapy with a radiotherapy dose of 45-50.4 Gy) did not show any difference in overall survival between neoadjuvant chemoradiotherapy and adjuvant chemoradiotherapy (hazard ratio 0.93; 95% confidence interval 0.69 to 1.25). 148 The aforementioned PREOPANC-1 phase 3 trial, which showed a survival benefit of neoadjuvant chemoradiation for borderline resectable disease, did not evaluate effects with and without radiation. 110 Regarding neoadjuvant chemoradiotherapy with FOLFIRINOX, a phase 2 trial (n=48) showed that neoadjuvant FOLFIRINOX plus chemoradiotherapy in borderline resectable disease showed a high rate of margin negative resection, and prolonged median progression free survival and even median overall survival. 149 By contrast, a randomized phase 2 trial (ALLIANCE-A021501) showed worse survival in the patients with borderline resectable disease who were allocated to the neoadjuvant mFOLFIRINOX plus radiotherapy (SBRT or hypofractionated image guided radiotherapy) arm (n=56) compared with those who allocated to the neoadjuvant mFOLFIRINOX alone arm (n=70) (median overall survival 17.1 v 29.8 months; median event free survival 10.2 v 15.0 months). 150 However, the number of patients was modest, and the dropout rates were high in both the chemotherapy arm (71.4%) and the chemoradiation arm (82.1%). A meta-analysis comprising 15 studies (512 patients) of neoadjuvant FOLFIRINOX with or without radiotherapy for resectable and borderline resectable disease showed a better rate of margin negative resection in the chemoradiotherapy group (97.6% v 88.0%). 151 No differences were observed in resection rate, overall survival, or pathological outcomes. The PANDAS-PRODIGE 44 study, a randomized phase 2 study, assigned 130 patients with borderline resectable diseases to mFOLFIRINOX or mFOLFIRINOX plus conformal external radiation (50.4 Gy). This ongoing study aims to evaluate the histological negative margin resection rate as the primary endpoint.

Radiation for locally advanced disease

For locally advanced pancreatic cancer, radiation is used as the primary modality for local control and, on rare occasions, to facilitate margin negative resection in select patients who achieve good responses to treatment. 67 Trials for locally advanced diseases have reported various levels of efficacy. A randomized trial assigned 37 patients to receive chemoradiotherapy (gemcitabine, 50.4 Gy) and 34 patients to receive gemcitabine alone. The trial showed improved overall survival in the chemoradiotherapy group (11.1 v 9.2 months). 152 Progression free survival was not different, but the sample size was notably small. The LAP07 trial was a large randomized phase 3 trial that aimed to investigate the survival benefit of adding radiotherapy to chemotherapy (54 Gy plus capecitabine) compared with chemotherapy (gemcitabine or gemcitabine plus erlotinib) after four months of gemcitabine based induction chemotherapy. 153 The results showed no differences in overall (median 15.2 v 16.5 months; hazard ratio 1.03; 95% confidence interval 0.79 to 1.34) or progression free survival (9.9 v 8.4 months; 0.78; 0.61 to 1.01) between the chemoradiotherapy group (n=133) and the chemotherapy group (n=136). An older randomized phase 3 trial (2000-01 FFCD/SFRO) also compared gemcitabine chemotherapy (n=60) to chemoradiotherapy with fluorouracil and cisplatin (60 Gy) (n=59), 154 and showed worse overall survival (median 8.6 v 13.0 months) and progression free survival in the chemoradiotherapy group. 154 The study, however, suffered from major inconsistencies in the proportion of patients who received at least 75% of the planned dose of induction chemotherapy, being only 42.4% in the chemoradiotherapy group compared with 73.3% in the chemotherapy group.

Given that conventional fractionated radiotherapy techniques combined with gemcitabine based chemotherapy have failed to show a significant survival advantage, the focus of research has moved to SBRT and FOLFIRINOX. A meta-analysis of 1147 patients from 21 studies including randomized controlled trials (2002-2014) compared conventional external beam techniques to SBRT. 141 The estimated two year overall survival was higher in the SBRT group (26.9% v 13.7%), with less acute grade 3/4 toxicity (5.6% v 37.7%) and similar late grade 3/4 toxicity (9.0% v 10.1%). A phase 2 trial (LAPC-1) enrolled 50 patients to receive eight cycles of FOLFIRINOX followed by SBRT (40 Gy in five fractions). 155 In total, 39 patients underwent SBRT (78.0%) and seven (14.0%) patients underwent surgical resection; all had negative margins and pathological N0 stage. The overall survival in the resected patients was longer than in the unresected patients (median 24 v 15 months; three year survival rate 43% v 6.5%). A systematic review including 2446 patients from 28 phase 2/3 studies also showed a similar resection rate of 12.1% (95% confidence interval 10.0% to 14.5%). Therefore, this newest chemoradiotherapy approach could give the best chance of curative intent surgery, and achieve long term survival in a highly selected subgroup of patients.

Four phase 2/3 trials are ongoing. The CONKO-007 trial is a large randomized phase 3 trial enrolling 525 patients to evaluate chemoradiotherapy (50.4 Gy with gemcitabine) after induction chemotherapy with FOLFIRINOX (n=402) or gemcitabine (n=93) for three months; the primary endpoint was margin negative resection rate. The first results came out in 2022, and showed a higher rate of margin negative resection (resection and circumferential resection margin) (9.0% v 19.6%) in the chemoradiation arm (n=168, 61 underwent surgery) compared with the chemotherapy arm, which was continuing FOLFIRINOX or gemcitabine (n=167, 60 underwent surgery). 156 However, the total surgical resection margin negativity rate and survival did not reach statistical significance. The publication is pending. The other three trials are phase 2 trials and are still recruiting patients (SCALOP-2, 157 MASTERPLAN, 158 and GABRINOX-ART 159 ). These studies could provide more data about gemcitabine/nab-paclitaxel and SBRT for locally advanced pancreatic cancer. However, we are unable to draw a conclusion without well designed phase 3 trials using the latest technology and chemotherapy regimen.

Supportive care and palliative care

Weight loss is seen in more than half of patients at diagnosis of pancreatic cancer 11 ; as a result, the rates of malnutrition 160 161 (33.7-70.6%) and sarcopenia 162 (up to 74%) are high. Malnutrition and sarcopenia have been reported to be associated with poor outcomes of surgical resection and chemotherapy. 163 Given that the majority of patients suffer from metastatic diseases, palliative care, including pain management and nutrition support, is essential to their quality of life, and even prognosis. Table 4 highlights major studies on these topics.

Summary of studies on supportive/palliative care for pancreatic cancer

Emerging diagnostic tools and treatments

Diagnostic tools.

Fibrosis, both chemoradiotherapy induced and cancer associated, has been reported to be associated with overall survival. An MRI probe targeting chemoradiotherapy induced collagen (type I collagen) can detect this change in fibrosis. 170 Radiolabeled fibroblast activation protein inhibitors (FAPI) can target the expression of fibroblast activation protein in cancer associated fibroblasts, which is abundant in pancreatic cancer. 171 A meta-analysis showed superior performance of FAPI PET over FDG PET/CT/MRI for the determination of tumor, node, metastases (TNM) classification and peritoneal carcinomatosis. 172 A phase 2 trial is recruiting patients to evaluate the efficacy of FAPI PET/CT in patients with locally advanced disease ( NCT05518903 ).

Radiomics using machine learning or deep learning (artificial intelligence) is a new field of research, driven by advances in computer systems. Theoretically, a computer can learn and identify features and differences that a human cannot. A systematic review showed that radiomics models of the primary tumors had good performance in predicting patient prognosis. 173 Further studies with larger sample sizes for training and validating models with risk factors, images, and biomarkers will yield more conclusive results in this regard.

In the era of neoadjuvant chemotherapy, a new question has emerged of how to manage patients who have tumor progression during neoadjuvant treatment. A phase 2 trial ( NCT03322995 ) is recruiting patients (n=125) with resectable and borderline resectable disease to evaluate the efficacy of adaptive modification of neoadjuvant treatment (four months). Based on the results of restaging after four cycles of FOLFIRINOX, a decision will be made to either continue the same regimen, or switch to a gemcitabine based regimen and chemoradiotherapy. For locally advanced pancreatic cancer, the NEOPAN phase 3 trial successfully enrolled 171 patients with locally advanced pancreatic cancer to compare the progression free survival of FOLFIRINOX (12 cycles) with gemcitabine (four cycles), with preliminary results expected soon. Few data exist on the comparison of FOLFIRINOX with gemcitabine/nab-paclitaxel for both localized and advanced cancer. A randomized phase 2 study (PASS-01) is recruiting patients (planned n=150) with metastatic disease to investigate the difference in progression free survival between the two regimens. Moreover, genomic factors and putative biomarkers will be explored using whole genome sequencing and RNA sequencing, and patient derived organoids.

Immunotherapy has been largely ineffective in pancreatic cancer, potentially owing to both tumor cell intrinsic and tumor microenvironment factors. Recent trials have taken a combined approach. CISPD3, a randomized phase 3 trial (n=110), showed an improved objective response rate (50.0% v 23.9%; P=0.010) by adding sintilimab (a monoclonal antibody against programmed cell death protein 1) to FOLFIRINOX for metastatic patients, 174 albeit without superior overall survival and progression free survival. The same group is conducting a phase 3 trial to evaluate the same regimen in patients with borderline resectable and locally advanced diseases ( NCT03983057 ). Given the results of basic research in pancreatic cancer showing that the extracellular matrix plays an essential role in the tumor microenvironment and progression, several new agents have been introduced. A phase 2 trial ( NCT03336216 ) combining an immune checkpoint inhibitor with chemotherapy (FOLFIRINOX or gemcitabine based regimen) and cabiralizumab (a colony stimulating factor 1 receptor inhibitor that suppresses the activities of tumor associated macrophages) has been conducted. However, a 2020 press release 175 176 announced that this study missed the primary endpoint of progression free survival.

Pamrevlumab, a recombinant human monoclonal antibody against connective tissue growth factor, has been investigated in a randomized phase 3 trial (LAPIS) combined with FOLFIRINOX or gemcitabine/nab-paclitaxel (up to six cycles) for locally advanced tumors. The study has completed recruitment (n=284) and is continuing to evaluate the primary endpoint of overall survival. Most recently, a phase 1 trial proposed a notable approach to stimulating cancer immunity in pancreatic cancer, with promising results. 177 The study adopted the messenger RNA (mRNA) vaccine technique to make a personalized mRNA vaccine encoding five or more neoantigens, which were bioinformatically predicted from the resected primary tumor. This adjuvant treatment consisted of one dose of atezolizumab (anti-PDL1 (programmed death ligand 1) antibody) and eight doses (one week) of mRNA neoantigen vaccines, followed by 12 cycles of mFOLFIRINOX. In total, 16 of 28 resected patients received personalized vaccines, and eight patients responded to the vaccines, with no recurrence among responders after a median follow-up of 18.0 months. Larger studies will help establish whether this is a breakthrough in immunotherapy for pancreatic cancer.

Treatment strategies targeting specific genomic alterations have been explored in various molecularly defined patient subsets. Given the positive results for metastatic cancer in the POLO trial, 93 olaparib is being studied in a randomized phase 2 trial (APOLLO) to evaluate the additional benefit of one year of treatment on recurrence free survival in patients with a pathogenic BRCA1, BRCA2, or PALB2 mutation, who have received at least three months of multi-agent chemotherapy after curative resection. KRAS is an attractive target owing to its high rate of mutation (90%) in pancreatic cancer. 178 Although KRAS G12C mutations are rare (1.6% of pancreatic ductal adenocarcinoma (PDAC) cases), the ability to create covalent G12C inhibitors led to FDA approval in non-small cell lung cancer, and promising initial results in PDAC. Sotorasib, a KRAS G12C inhibitor, showed a median progression free survival of four months, and an objective response rate of 21% in metastatic patients with KRAS G12C mutations who received at least two lines of chemotherapy in a phase 1/2 trial. 179 Another KRAS G12C inhibitor, adagrasib, showed a median progression free survival of 6.6 months, and an objective response rate of 50% (5/10 patients), in patients with advanced pancreatic cancer in a phase 1/2 trial (KRYSTAL). 180

By contrast to the low mutation rate in BRCA1 (1.08%), BRCA2 (1.48%), PALB2 (0.54%), and KRAS G12C (1-2%), other KRAS mutations are quite common, and pan-KRAS inhibitors are under investigation. Two phase 1 studies of pan-RAS inhibitors are recruiting patients ( NCT04678648 and NCT05379985 ). Further studies on other KRAS targeting approaches are expected.

Radiotherapy has been suggested to have synergistic effects on local and even distant tumors when combined with immunotherapy. 181 182 A large randomized phase 3 trial showed that chemoradiotherapy followed by durvalumab (PDL1 inhibitor) had significantly longer overall survival than placebo in locally advanced, non-small cell lung cancer. 183 Recently, a phase 2 trial (CheckPAC) assigned 84 patients with refractory metastatic pancreatic cancer to receive SBRT/nivolumab (n=41) or SBRT/nivolumab/ipilimumab (n=43). 184 The SBRT/nivolumab/ipilimumab arm had a higher disease control rate (37.2% v 17.1%). Further studies with an immunotherapy–SBRT backbone are anticipated in locally advanced and metastatic disease settings.

Figure 2 summarizes all the data discussed above, and gives perspective on the future of the management of pancreatic cancer.

Precision medicine for pancreatic cancer. PanIN=pancreatic intraepithelial neoplasm

Several national and international guidelines for the management of pancreatic cancer have been published. Recommendations of those guidelines are proposed considering the evidence and the healthcare system of each country. We reviewed two major guidelines of the US and Europe, and also included the recent 2022 updated Japanese guideline. 6 7 8 All recommendations of these guidelines are made based on the metastatic status and the anatomical resectability of the primary tumors. Regarding treatments for resectable diseases, the NCCN guidelines list neoadjuvant chemotherapy as an option for high risk patients, and the Japan Pancreas Society guidelines recommend neoadjuvant for all patients. The ESMO guidelines recommend only upfront surgery. The NCCN and ESMO guidelines recommend mFOLFIRINOX as the first option of adjuvant chemotherapy, although S-1 monotherapy is recommended by the Japan Pancreas Society guidelines. Conversion surgery for locally advanced disease is an option in the NCCN and Japan Pancreas Society guidelines. No recommendation is made for conversion surgery for metastatic disease in any of the three sets of guidelines. Radiotherapy is listed as an option for non-metastatic diseases in the NCCN guidelines, while the other guidelines do not recommend it for resectable diseases. The NCCN guidelines recommend genetic testing of inherited mutations for all patients with pancreatic cancer, but no clear recommendations are made in the other sets of guidelines.

Conclusions

In the US and Europe, the incidence of pancreatic cancer has been increasing consistently, and this trend is estimated to continue for several decades. Advances in the combination of cytotoxic drugs have resulted in improvements in survival for all stages of the disease, and are changing treatment algorithms. Further investigation into the role of immuno-oncology agents and radiation could help a subset of patients. In addition, extensive efforts need to focus on risk assessment, screening, and early detection.

Research questions

・In patients treated with upfront systemic treatment, what is the optimal duration of systemic treatment and patient selection for surgical resection?

・How can immuno-oncology and targeted treatment be made effective?

・What is the optimal combination and sequence of radiotherapy, and who are the ideal targets?

・What is the specific population that needs routine screening and what is an effective combination of tests to detect precancerous lesions?

Glossary of abbreviations

NCCN: National Comprehensive Cancer Network

ESMO: European Society for Medical Oncology

PanIN: pancreatic intraepithelial neoplasia

IPMN: intraductal papillary mucinous neoplasm

CAPS: International Cancer of the Pancreas Screening

USPSTF: United States Preventive Services Task Force

CA19-9: carbohydrate antigen 19-9

RECIST: response evaluation criteria in solid tumors

FOLFIRINOX: combined leucovorin calcium (folinic acid), fluorouracil, irinotecan, and oxaliplatin

NALIRIFOX: combined liposomal irinotecan, fluorouracil, folinic acid, and oxaliplatin

mFOLFIRINOX: modified FOLFIRINOX

PEFG regimen: cisplatin, epirubicin, fluorouracil, and gemcitabine

IMRT: intensity modulated radiation therapy

SBRT: stereotactic body radiation therapy

3D-CRT: 3 dimensional conformal radiation therapy

IGRT: image guided radiation therapy

FAPI: fibroblast activation protein inhibitors

PDAC: pancreatic ductal adenocarcinoma

PDL1: programmed death ligand 1

State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors.

Competing interests : We have read and understood the BMJ policy on declaration of interests and declare the following interests: MDC receives grants from Haemonetics, and is the primary investigator of a Boston Scientific sponsored study. TS does not have conflicts of interest to declare. SDK receives investigator initiated clinical trial funding from Genentech and AstraZeneca. She also receives preclinical research support from Roche and Amgen. WAM receives institutional clinical trial funding from Genentech, Beigene, Pfizer, NGM, Gossamer, ALX, Exelixis, EDDC/D3, Mirati, RasCal Therapeutics, and CanBAS. He is also a Data and Safety Monitoring Board member of QED, Amgen, and Zymeworks.

Funding: This study is supported by funding sources: R01 DE028529-01 (SDK), R01 DE028282-01 (SDK), 1R01CA284651-01 (SDK), 1P50CA261605-01 (SDK), and the V Foundation Translational Research Award. The funders had no role in considering the study design or in the collection, interpretation of data, writing of the manuscript, or decision to submit the article for publication.

Contributors: Authors MDC and TS are joint first authors. The design, literature search, review, and writing of this manuscript was led by MDC and TS, and supported by SDK and WAM. MDC is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

We thank Hiroyuki Ishida for his drawings in figure 2 , and Michael J Kirsch for his assistance in proofreading this manuscript.

Patient involvement: No patients were involved in the writing of this review.

Provenance and peer review: commissioned; externally peer reviewed.

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Nih research matters.

May 23, 2023

An mRNA vaccine to treat pancreatic cancer

At a glance.

• A personalized mRNA vaccine against pancreatic cancer created a strong anti-tumor immune response in half the participants in a small study.
• The vaccine will soon be tested in a larger clinical trial. The approach may also have potential for treating other deadly cancer types.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is one of the deadliest cancer types. Despite modern therapies, only about 12% of people diagnosed with this cancer will be alive five years after treatment.

Immunotherapies—drugs that help the body’s immune system attack tumors—have revolutionized the treatment of many tumor types. But to date, they have proven ineffective in PDAC. Whether pancreatic cancer cells produce neoantigens—proteins that can be effectively targeted by the immune system—hasn’t been clear.

An NIH-funded research team led by Dr. Vinod Balachandran from Memorial Sloan Kettering Cancer Center (MSKCC) have been developing a personalized mRNA cancer-treatment vaccine approach. It is designed to help immune cells recognize specific neoantigens on patients’ pancreatic cancer cells. Results from a small clinical trial of their experimental treatment were published on May 10, 2023, in Nature .

After surgery to remove PDAC, the team sent tumor samples from 19 people to partners at BioNTech, the company that produced one of the COVID-19 mRNA vaccines. BioNTech performed gene sequencing on the tumors to find proteins that might trigger an immune response. They then used that information to create a personalized mRNA vaccine for each patient. Each vaccine targeted up to 20 neoantigens.

Customized vaccines were successfully created for 18 of the 19 study participants. The process, from surgery to delivery of the first dose of the vaccine, took an average of about nine weeks.

All patients received a drug called atezolizumab before vaccination. This drug, called an immune checkpoint inhibitor, prevents cancer cells from suppressing the immune system. The vaccine was then given in nine doses over several months. After the first eight doses, study participants also started standard chemotherapy drugs for PDAC, followed by a ninth booster dose.

Sixteen volunteers stayed healthy enough to receive at least some of the vaccine doses. In half these patients, the vaccines activated powerful immune cells, called T cells, that could recognize the pancreatic cancer specific to the patient. To track the T cells made after vaccination, the research team developed a novel computational strategy with the lab of Dr. Benjamin Greenbaum at MSKCC. Their analysis showed that T cells that recognized the neoantigens were not found in the blood before vaccination. Among the eight patients with strong immune responses, half had T cells target more than one vaccine neoantigen.

By a year and a half after treatment, the cancer had not returned in any of the people who had a strong T cell response to the vaccine. In contrast, among those whose immune systems didn’t respond to the vaccine, the cancer recurred within an average of just over a year. In one patient with a strong response, T cells produced by the vaccine even appeared to eliminate a small tumor that had spread to the liver. These results suggest that the T cells activated by the vaccines kept the pancreatic cancers in check.

“It’s exciting to see that a personalized vaccine could enlist the immune system to fight pancreatic cancer—which urgently needs better treatments,” Balachandran says. “It’s also motivating as we may be able to use such personalized vaccines to treat other deadly cancers.”

More work is needed to understand why half the people did not have a strong immune response to their personalized vaccines. The researchers are currently planning to launch a larger clinical trial of the vaccine.

—by Sharon Reynolds

Related Links

• Using mRNA Technology for a Universal Flu Vaccine
• Experimental mRNA HIV Vaccine Shows Promise in Animals
• Experimental Vaccine Protects Against Multiple Coronaviruses
• Method for Early Detection of Pancreatic Cancer
• Can mRNA Vaccines Help Treat Cancer?
• Pancreatic Cancer
• Cancer Treatment Vaccines

References:  Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, Patterson E, Lihm J, Ceglia N, Guasp P, Chu A, Yu R, Chandra AK, Waters T, Ruan J, Amisaki M, Zebboudj A, Odgerel Z, Payne G, Derhovanessian E, Müller F, Rhee I, Yadav M, Dobrin A, Sadelain M, Łuksza M, Cohen N, Tang L, Basturk O, Gönen M, Katz S, Do RK, Epstein AS, Momtaz P, Park W, Sugarman R, Varghese AM, Won E, Desai A, Wei AC, D'Angelica MI, Kingham TP, Mellman I, Merghoub T, Wolchok JD, Sahin U, Türeci Ö, Greenbaum BD, Jarnagin WR, Drebin J, O'Reilly EM, Balachandran VP. Nature . 2023 May 10:1-7. doi: 10.1038/s41586-023-06063-y. Online ahead of print. PMID: 37165196.

Funding:  NIH’s National Cancer Institute (NCI); Stand Up to Cancer; Lustgarten Foundation; Damon Runyon Cancer Research Foundation; Ben and Rose Cole Charitable PRIA Foundation; Mark Foundation; Pershing Square Sohn Cancer Research Alliance; Pew Charitable Trusts; Cycle for Survival; Marie-Josée and Henry R. Kravis Center for Molecular Oncology; Memorial Sloan Kettering Cancer Center; imCORE Network; Genentech; BioNTech.

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People with pancreatic cancer are living longer, thanks to improved approaches

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By Jessica Saenz

A diagnosis of pancreatic cancer is almost synonymous with hopelessness. As the least survivable type of cancer, the perception is understandable. "As soon as patients were diagnosed, they were often told by their physician to start making arrangements," says Mark Truty, M.D. , a surgical oncologist at Mayo Clinic who specializes in pancreatic surgery.

But the tides are turning, thanks to new and improved treatment methods that are helping people with pancreatic cancer live longer. Dr. Truty and Robert McWilliams, M.D. , a medical oncologist at Mayo Clinic, talk about Mayo Clinic's approach to pancreatic cancer care , and how it's leading to improved survival and quality of life.

Capturing the full picture from the time of diagnosis and beyond

Before moving forward with treatment, Dr. Truty says it's critical to understand as much about each person's cancer as possible. "When a patient is first diagnosed, they need really good imaging and molecular testing to see, not just where the tumor is, but if there's any evidence of spread. We do a lot of tests at the beginning and throughout to make sure that the cancer is truly localized and has not spread."

In most instances, a CT scan or MRI scan is used to identify the location of the cancer and possible spread, but Dr. Truty says standard scans are just one piece of the puzzle. "Historically, patients have gotten a scan where the tumor appears to be localized, and then they underwent surgery. But that paradigm has not resulted in the outcomes we wanted."

This is where PET scans and additional molecular testing play an important role.

Dr. Truty says that PET scans and newer genetic testing are key to staging the cancer and assessing its behavior accurately. They can help determine if treatment is working effectively to shrink the tumor, whereas traditional CT scans have distinct limitations in assessing response in pancreatic primary tumors. "If we see a response we’re anticipating on the PET scan, those are the patients that do very well. If we're not seeing a response, then we have to pivot and switch their therapy to see if we can achieve a better outcome," he says. "We've also been using novel genetic testing developed at Mayo Clinic to test the blood of patients, as well as the fluid of the abdomen through laparoscopy , to see if we can pick up some cancer DNA."

This method is helping cancer experts at Mayo Clinic determine who might be at risk for pancreatic cancer recurrence and individualize their treatment to reduce the risk of the cancer returning. "We're the first center to do this routinely for every single patient we see," Dr. Truty says.

Tailoring testing and treatment for each person

Initial testing and staging of pancreatic cancer can help uncover weaknesses or potential threats for each unique pancreatic cancer case. "As we've learned more about the genetics of pancreatic cancer — and how to find patients who can benefit — we've been able to tailor therapies according to the patient's genetics and their DNA, or the DNA changes that are specific to the cancer itself," says Dr. McWilliams.

In a study led by Mayo Clinic Center for Individualized Medicine , researchers found that nearly 1 in 6 people diagnosed with pancreatic cancer had an inherited cancer-related gene mutation that may have predisposed them to pancreatic cancer. The most common genetic mutation in those patients was the BRCA2 gene, which is linked to breast cancer.

Niloy Jewel Samadder, M.D. , a Mayo Clinic gastroenterologist and hepatologist, and the study's senior author, said that patients with mutations had a 50% longer survival. Data from this study and others have led to recent changes in guidelines that advocate for genetic testing for all pancreatic cancer patients, regardless of their cancer stage or family history of cancer.

Though the majority of people with pancreatic cancer do not have a germline mutation, Dr. McWilliams says it's important to use all the tools available for each patient. While it may not achieve a cure, it can help select therapies to improve quality of life so patients can live longer and more comfortably.

"There's a national trial, called the POLO Trial , which showed that patients on chemotherapy with BRCA1 or BRCA2 mutations are eligible for a maintenance therapy with just a pill, rather than IV chemotherapy, which is really good from a side effects standpoint," says Dr. McWilliams.

Redefining what is considered inoperable

Dr. Truty says patients who are able to have surgery to remove their pancreatic cancer can live significantly longer, but in cases where the tumor has grown outside of the pancreas to encase critical blood vessels, pancreatic cancer has been considered inoperable.

About one-third of pancreatic cancer tumors grow to surround blood vessels outside the pancreas. "Those patients have historically not been considered for surgery," he says. "Theoretically, 50% of patients with diagnosed pancreatic cancer have the potential to undergo an operation. The question is: How do we get them to surgery? And how do we optimize their outcomes to make sure that they live as long as they possibly can?"

Drs. Truty, McWilliams and pancreatic cancer experts at Mayo Clinic use an approach called neoadjuvant therapy, which delivers chemotherapy — or a combination of chemotherapy and radiation — to destroy microscopic cancer cells in the body before surgery. By combining this method with personalized surgery for each patient's anatomy, they can remove tumors entirely and reconstruct blood vessels as needed. This has resulted in the ability to operate on patients who previously did not have that option, leading to better results than ever before.

"We're creating custom surgeries for each patient that aren't being done anywhere else on the planet. That's why so many people come to us after they've been told their tumors are inoperable," says Dr. Truty.

Though surgery can lead to the best outcomes in many cases, Dr. Truty emphasizes that the goal of pancreatic cancer treatment is not surgery. "The goal for anyone with cancer is to extend their life and maintain a reasonable quality of life. Sometimes an operation is necessary to achieve this, and sometimes it will decrease the likelihood of one or the other, or both. That's why before we even consider an operation, we have to make sure that operation has the highest probability that we'll achieve both of those goals."

Pancreatic cancer continues to have the highest mortality rate, but Dr. McWilliams says there's plenty of reason for patients to be hopeful. "It's a very serious cancer. It's something that is life-threatening for a lot of people, but it's not necessarily a death sentence," he says. "It's something that we have treatments for, and our treatments are only getting better."

And this progress, he says, is driven by clinical trials. "Clinical trials are how we advance the science. For patients who are looking for the latest and greatest, and want to help advance the options for their cancer, participation in clinical trials is crucial."

Dr. Truty says he hopes more people with pancreatic cancer seek out second opinions from cancer centers who are leveraging new approaches and providing patients more options. "Historically, it's been such a nihilistic disease, but things have really changed. We have not settled for the standard of care — this results in standard outcomes which have not been good. We have to treat patients differently — starting from the beginning," he says. "And if you can do that all the way through treatment, then those patients really do have exceptional outcomes."

Learn more about panc r eatic cancer and find a pancreatic cancer clinical trial at Mayo Clinic.

Read these articles:

• " 5 things to know about pancreatic cancer "
• " PET/MRI biomarkers guide personalized treatment for people with pancreatic cancer, study finds "
• " Identifying inherited gene mutations in pancreatic cancer can lead to targeted therapies, better survival "
• " Aggressive Approach to Pancreatic Cancer Yields Outstanding Outcome "

Also watch this video: " Mayo Clinic Minute: Advances in pancreatic cancer treatment extending lives

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Pancreatic Cancer Vaccine Shows Promise in Small Trial

Using mRNA tailored to each patient’s tumor, the vaccine may have staved off the return of one of the deadliest forms of cancer in half of those who received it.

By Benjamin Mueller

Five years ago, a small group of cancer scientists meeting at a restaurant in a deconsecrated church hospital in Mainz, Germany, drew up an audacious plan: They would test their novel cancer vaccine against one of the most virulent forms of the disease, a cancer notorious for roaring back even in patients whose tumors had been removed.

The vaccine might not stop those relapses, some of the scientists figured. But patients were desperate. And the speed with which the disease, pancreatic cancer, often recurred could work to the scientists’ advantage: For better or worse, they would find out soon whether the vaccine helped.

On Wednesday, the scientists reported results that defied the long odds. The vaccine provoked an immune response in half of the patients treated, and those people showed no relapse of their cancer during the course of the study, a finding that outside experts described as extremely promising.

The study, published in Nature, was a landmark in the yearslong movement to make cancer vaccines tailored to the tumors of individual patients.

Researchers at Memorial Sloan Kettering Cancer Center in New York, led by Dr. Vinod Balachandran, extracted patients’ tumors and shipped samples of them to Germany. There, scientists at BioNTech, the company that made a highly successful Covid vaccine with Pfizer, analyzed the genetic makeup of certain proteins on the surface of the cancer cells.

Using that genetic data, BioNTech scientists then produced personalized vaccines designed to teach each patient’s immune system to attack the tumors. Like BioNTech’s Covid shots, the cancer vaccines relied on messenger RNA. In this case, the vaccines instructed patients’ cells to make some of the same proteins found on their excised tumors, potentially provoking an immune response that would come in handy against actual cancer cells.

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Investigational mRNA Vaccine Induced Persistent Immune Response in Phase 1 Trial of Patients With Pancreatic Cancer

By Jim Stallard Sunday, April 7, 2024

Dr. Vinod Balachandran says mRNA vaccines could stimulate the immune system to recognize and attack pancreatic cancer cells.

An experimental approach to treating pancreatic cancer with the messenger RNA (mRNA)-based therapeutic cancer vaccine candidate autogene cevumeran continues to show potential to stimulate an immune response that may reduce the risk of the disease returning after surgery .

New results from a phase 1 clinical trial show that the cancer vaccine candidate activated immune cells that persisted in the body up to three years after treatment in certain patients. In addition, a vaccine-induced immune response correlated with reduced risk of the cancer coming back.

“The latest data from the phase 1 trial show that we are on the right track. This investigational mRNA vaccine can trigger T cells — the cells that mobilize anti-tumor immune responses — that may recognize pancreatic cancers as foreign,” says Memorial Sloan Kettering Cancer Center (MSK) pancreatic cancer surgeon-scientist Vinod Balachandran, MD . “Moreover, we continue to detect vaccine-stimulated T cells at substantial frequencies in patients’ blood up to three years after vaccination.”

Autogene cevumeran (BNT122, RO7198457) was developed through a collaboration between BioNTech, an immunotherapy company, and Genentech, a member of the Roche Group. Dr. Balachandran, who led the phase 1 trial, presented the latest results at the American Association for Cancer Research Annual Meeting in San Diego.

Pancreatic cancer is one of the deadliest cancers, and even with surgery, only about 12% of patients are alive five years after diagnosis. Chemotherapy , radiation , targeted therapy , and current immunotherapies are also largely ineffective against pancreatic cancer, so new therapies are urgently needed for patients who face this disease.

The investigational mRNA cancer vaccines were custom-made for every participant in the phase 1 clinical trial based on the mutational profile of each individual tumor. The cancer vaccines teach T cells to recognize proteins called neoantigens that are found exclusively in each patient’s pancreatic tumor. In this way, these vaccines alert the immune system that the cancer cells are foreign. The goal of this approach is to train the body to protect itself against cancer cells.

Initial results from the phase 1 trial, reported May 2023 in Nature , showed the vaccine was well tolerated and that it activated immune cells in half of treated patients. The latest results are based on following patients for a median of three years after the investigational treatment. The team was able to track vaccine-induced T cells with the help of computational biologist Benjamin Greenbaum, PhD .

“Our findings thus far show that this vaccine candidate can induce a lasting immune response — up to three years — in some patients,” explains Dr. Balachandran, a member of the Human Oncology and Pathogenesis Program and the David M. Rubenstein Center for Pancreatic Cancer Research at MSK. “As these are critical features of an effective cancer vaccine, the results continue to support the approach of using customized mRNA vaccines to target neoantigens in each patient’s tumor.”

New Clinical Trial Results for mRNA Pancreatic Cancer Vaccine Candidate

The investigator-initiated, single-center trial involved studying 16 MSK patients who received autogene cevumeran ,  along with an immunotherapy drug called atezolizumab and a chemotherapy regimen called mFOLFIRINOX. At the three-year median follow-up:

• In 8 patients, the investigational cancer vaccine activated a T cell response, and 6 of these patients had not seen their cancers return during the follow-up window. The other 2 patients relapsed. Meanwhile, cancer returned in 7 of the 8 patients whose immune systems did not respond to the vaccine during the study period. Researchers do not yet know if the vaccines caused the delay in cancer recurrence; investigating this question is a goal of an ongoing randomized phase 2 clinical trial.
• In the 8 patients who responded, the vaccines induced T cells specific to vaccine-encoded neoantigens. By studying tissue and blood from these patients before and after vaccines were given, the team found that 98% of the T cells specifically activated by the cancer vaccines were not present before vaccination. In addition, more than 80% of the vaccine-induced T cells persisted from two to up to three years after treatment. These data suggest the investigational cancer vaccine stimulated a durable T cell response.

Phase 2 Trial Is Ongoing To Evaluate the RNA Vaccine Candidate in a Larger Patient Group

A phase 2 clinical trial (NCT05968326) , sponsored by Genentech in collaboration with BioNTech, will evaluate the efficacy and safety of autogene cevumeran in a larger patient group. The new study, which began in July 2023, will enroll approximately 260 patients at various sites around the world, including MSK.

“Given the positive data from our phase 1 trial, we are excited to evaluate individualized mRNA cancer vaccine candidates in more pancreatic cancer patients,” Dr. Balachandran says.

The phase 2 trial will study whether the mRNA approach works better than the current standard treatment. Patients will be randomly split into two groups:

• One group will receive standard treatment, which is surgery followed by chemotherapy. This will be the control group.
• The other group will receive the experimental treatment, which is surgery followed by autogene cevumeran (mRNA vaccine), an immunotherapy drug called a checkpoint inhibitor , and chemotherapy. (The phase 1 study followed a similar treatment plan but did not have a control group receiving standard treatment for comparison.)
• The mRNA vaccines will be custom-made for each patient and given in two phases: Doses at the beginning of treatment prime the immune system, and later doses provide a boost.

The trial is open to people with newly diagnosed pancreatic cancer eligible for surgery, who have not had other treatment (such as chemotherapy , immunotherapy , or radiation therapy ) and who fit other specific criteria.

The Story of the mRNA Cancer Vaccine Study in Pancreatic Cancer

Here, Dr. Balachandran explains how this new approach has been developed to treat one of the deadliest cancers. It all began with discoveries in his lab about pancreatic cancer and a global collaboration with Genentech and BioNTech in the middle of the COVID-19 pandemic.

What was the inspiration for using a vaccine against pancreatic cancer?

There has been great interest in using immunotherapy for pancreatic cancer because nothing else has worked very well. We thought immunotherapy held promise because of research we began about eight years ago. A small subset of patients with pancreatic cancer manage to beat the odds and survive after their tumor is removed. We looked at the tumors taken from these select patients and saw that the tumors had an especially large number of immune cells in them, especially T cells. Something in the tumor cells seemed to be sending out a signal that alerted the T cells and drew them in.

What causes the protective T cell response?

We later found that these signals were proteins called neoantigens that T cells recognize as foreign, triggering the immune system attack. When tumor cells divide, they accumulate these neoantigens, which are caused by genetic mutations. In most people with pancreatic cancer, these neoantigens are not detected by immune cells, so the immune system does not perceive the tumor cells as threats. But in our study, we saw that neoantigens in the long-term pancreatic cancer survivors were different — they did not escape notice. They, in effect, uncloaked the tumors to T cells, causing the T cells to recognize them.

We found that T cells recognizing these neoantigens circulated in the blood of these rare patients for up to 12 years after the pancreatic tumors had been removed by surgery. The T cells had memory of the neoantigens as a threat.

How did the neoantigen discovery lead to a pancreatic cancer vaccine?

My colleagues and I published our findings about immune protection in long-term pancreatic cancer survivors in Nature in November 2017. While working on this, we were also looking for ways to deliver neoantigens to patients as vaccines. We were particularly interested in mRNA vaccines, a technology that we thought was quite promising. The vaccines use mRNA, a piece of genetic code, to teach cells in your body to make a protein that will trigger an immune response.

Coincidentally, at this time, BioNTech co-founder and CEO Uğur Şahin, MD, emailed us that he had read our paper and was interested in our ideas. He and his team were working with Genentech on individualized neoantigen-based mRNA immunotherapies. In late 2017, we flew to Mainz, Germany, where BioNTech is based. We discussed the potential of therapeutic mRNA cancer vaccines for pancreatic cancer — as well as the possible use of the mRNA platform they have developed.

What makes creating an individualized cancer vaccine challenging?

Designing a cancer vaccine tailored to an individual is complex. Because cancers arise from our own cells, it is much harder for the immune system to distinguish proteins in cancer cells as foreign compared with proteins in pathogens like viruses. But important advances in cancer biology, the development of novel biotechnologies, and genomic sequencing now make it possible to design vaccines that can tell the difference.

This builds on important work done at MSK that has shown how critical tumor mutations are to triggering an immune response. In parallel with our work, major discoveries in mRNA technology over the past decades by scientists such as professor Şahin and BioNTech co-founder and Chief Medical Officer Özlem Türeci, MD, paved the way to use mRNA in medicine. We all felt optimistic about the potential and decided to move ahead.

How is the investigational mRNA pancreatic cancer vaccine made? How is it tailored to each individual tumor?

After a patient has a pancreatic tumor surgically removed, the tumor is genetically sequenced to look for up to 20 mutations that have the highest likelihood to produce the best neoantigens — those that look the most foreign to the immune system. The cancer vaccine candidate is manufactured with mRNA specific to these neoantigens found in that individual’s tumor.

The process to design and manufacture individualized vaccines for cancer treatment is more complex than making a preventive vaccine for an infectious disease, where each vaccine is the same and can be manufactured in large batches. An individualized therapeutic mRNA cancer vaccine must be tailored to each patient’s tumor. To do this, we take a sample of the tumor that is removed during the required cancer surgery and ship the sample to BioNTech in Germany. They analyze the tumor sample, and design and manufacture the cancer vaccine candidate, which is then sent back to New York.

How is the mRNA vaccine given to patients? How does it trigger the immune response?

The vaccine is infused into a person’s bloodstream. In some patients it can cause immune cells called dendritic cells to make the neoantigen proteins. And in some cases, the dendritic cells also train the rest of the immune system, including T cells, to recognize and attack tumor cells that express these same proteins. With the T cells on high alert to destroy cells bearing these proteins, the cancer may have a lower chance of returning.

How are you working to make the cancer mRNA vaccines more effective?

In patients treated in the phase 1 study, we are continuing to examine if vaccine-induced T cells last and remain functional long-term and how these features associate with patient outcomes.

This story was originally posted in July 2023 and has been updated.

The phase 1 clinical trial was sponsored by Memorial Sloan Kettering Cancer Center. 

The clinical trials and biomarker studies were funded by imCORE, Genentech, BioNTech, Stand Up To Cancer, the Lustgarten Foundation, the Ben and Rose Cole Charitable PRIA Foundation, and the National Cancer Institute Pancreatic Cancer Microenvironment Network.

Dr. Balachandran reports honoraria and research support from Genentech, and research support from Bristol Myers Squibb.

Drs. Balachandran and Greenbaum report patent applications for related work on antigen cross-reactivity, tracking vaccine-expanded T-cell clones, and neoantigen quality modeling.

Dr. Greenbaum has received honoraria for speaking engagements from Merck, Bristol Myers Squibb, and Chugai Pharmaceuticals; has received research funding from Bristol Myers Squibb, Merck, and ROME Therapeutics; and has been a compensated consultant for Darwin Health, Merck, PMV Pharma, Shennon Biotechnologies, Synteny, and Rome Therapeutics, of which he is a co-founder.

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FDA Approves New First-line Treatment Option for Metastatic Pancreatic Cancer: What You Need to Know

by Erin Post  —  Feb 13, 2024

For the first time in more than a decade, the FDA has approved a new first-line treatment for patients with metastatic pancreatic cancer . After a clinical trial showed a positive survival benefit, the combination chemotherapy called NALIRIFOX is now approved for patients who have not received any previous treatment. For a disease with limited treatment options, today’s FDA announcement is exciting news.

“We are pleased that the U.S. Food and Drug Administration has issued this new approval of the NALIRIFOX regimen. With each new approved treatment, there is more hope for those who will be diagnosed in the future and people currently living with pancreatic cancer may have more time with their loved ones,” said PanCAN President and CEO Julie Fleshman, JD, MBA, in a press release from the pharmaceutical company Ipsen announcing the approval. “We are thankful to the patients who participated in this clinical trial as they play a crucial role in advancing treatments for pancreatic cancer.”

Here, PanCAN answers questions related to this new treatment option.

What is NALIRIFOX?

NALIRIFOX is a chemotherapy treatment. It is a combination of three previously approved pancreatic cancer drugs, liposomal irinotecan (Nal-IRI or Onivyde®), made by the pharmaceutical company Ipsen, plus 5 fluorouracil (5-FU)/leucovorin and oxaliplatin. NALIRIFOX will be delivered intravenously (IV, through a vein under the skin).

What does this FDA approval mean?

NALIRIFOX has been approved by the FDA as a new first-line treatment for metastatic pancreatic cancer. This means patients whose cancer has spread and who have not had treatment yet can now receive this drug combination.

Are these new drugs?

No. All of the drugs in NALIRIFOX have already been approved for other purposes; what is new is the combination of these drugs together as a first-line treatment.

Liposomal irinotecan, in combination with 5-FU/leucovorin, is already approved for people with metastatic pancreatic cancer that has continued to grow after being treated with another chemotherapy called gemcitabine (Gemzar®). Oxaliplatin has also been approved and used to treat other cancers for a long time.

NALIRIFOX is a combination of liposomal irinotecan, 5-FU/leucovorin and oxaliplatin. This combination has now been approved for a new group of patients, those with metastatic pancreatic cancer who have not had any other treatment. This is the first approval for a first-line treatment for metastatic pancreatic cancer in over ten years.

What is the survival benefit?

In a clinical trial, the NALIRIFOX regimen was compared to gemcitabine (Gemzar) plus nab-paclitaxel (Abraxane®), which is one of the current standard-of-care treatments for patients with metastatic pancreatic cancer. The results, published in October 2023 , showed that patients treated with NALIRIFOX had an overall survival of 11.1 months, which was a statistically significant improvement over the 9.2-month overall survival with gemcitabine and nab-paclitaxel.

What are the side effects?

In the clinical trial, patients took NALIRIFOX for a median of six weeks longer than those receiving gemcitabine and nab-paclitaxel, showing that NALIRIFOX was relatively well tolerated. The most frequent side effects reported in the NALIRIFOX group included neutropenia (low levels of a type of immune cell called neutrophils) and hypokalemia (low potassium level), and gastrointestinal disorders like diarrhea and nausea.

Is NALIRIFOX the same as FOLFIRINOX?

The combination chemotherapy FOLFIRINOX is composed of 5-FU, leucovorin, irinotecan and oxaliplatin. In 2010, a clinical trial showed that FOLFIRINOX was effective for the treatment of metastatic pancreatic cancer in people who hadn’t received prior treatment.

The drug liposomal irinotecan replaces irinotecan to make NALIRIFOX. Liposomal irinotecan is a modified form of irinotecan, designed to stay in the body longer before it gets broken down.

Does insurance cover this treatment?

FDA approval means this drug combination is safe and effective, and although the FDA does not decide what is covered by insurance, when a drug gets FDA approval Medicare and Medicaid will usually cover it.  Coverage for chemotherapy drugs will vary based on the specific plan and insurance company a person uses.

Contact PanCAN Patient Services for more information on financial assistance programs for those experiencing or anticipating cost-related barriers to care.

I am a patient with pancreatic cancer interested in NALIRIFOX. What should I do?

People diagnosed with pancreatic cancer should talk to their healthcare team about this treatment option. Since this approval is for first-line treatment (the first or initial treatment a person receives after diagnosis), it will impact people who have not received treatment for their pancreatic cancer yet.

For people who have already received treatment with a drug called gemcitabine, a similar chemotherapy containing one of the drugs in NALIRIFOX, liposomal irinotecan, is also approved.

Contact PanCAN Patient Services for additional information and support, including information on what questions to ask and how to seek out a second opinion. Our Case Managers can help you understand your options and connect you with resources to learn more.

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Molecular pathway that impacts pancreatic cancer progression and response to treatment detailed

June 6, 2024

Researchers at UNC Lineberger Comprehensive Cancer Center and colleagues have established the most comprehensive molecular portrait of the workings of KRAS, a key cancer-causing gene or “oncogene,” and how its activities impact pancreatic cancer outcomes. Their findings could help to better inform treatment options for pancreatic cancer, which is the third leading cause of all cancer deaths in the United States.

The research was published as two separate articles in Science .

“Because less than 40% of pancreatic cancers respond to treatment with KRAS inhibitors, if we can establish molecular markers to predict which patients will respond, we can better provide them with specific treatments, which should improve their outcomes,” said UNC Lineberger’s Channing J. Der, PhD , Sarah Graham Kenan Distinguished Professor at UNC School of Medicine’s Department of Pharmacology and a corresponding author of both articles. “From diagnosis to death, the average pancreatic cancer patient treated with chemotherapy lives 6 to 12 months, so there’s a very limited time to offer a treatment which will work.”

KRAS is one of the most commonly mutated genes in human cancers and it is found in more than 90% of pancreatic cancer tumors. Exactly how it spurs cancer growth, however, is poorly understood. That’s why UNC Lineberger researchers embarked on their extensive efforts to figure out what other genes and proteins make KRAS expression so lethal.

They demonstrated, in the most detailed analysis to date, that the molecular pathway most responsible for the cancer-driving functions of KRAS is highly dependent on a protein called ERK that has dual functions in regulating which genes are expressed and which proteins are active. While ERK has been one of the most intensively studied cancer pathways, and it is well-established that ERK is among the significant players in KRAS function, its relative importance and precisely how ERK carries out its role have been unclear.

Indeed, a core finding of the Science papers was that activation of the ERK protein alone is the key driver of resistance to drugs that inhibit KRAS. Taking advantage of improved methods to study cellular signaling, the researchers demonstrated that the ERK protein regulates the expression of a remarkably complex array of thousands of genes and changes the activity of thousands of proteins. Excitingly, the researchers confirmed that their findings in cancer models could accurately reflect responses in patients treated with ERK and KRAS therapies for their pancreatic, colorectal and lung cancers.

Currently, two KRAS drugs have been approved for cancer treatment, and many more are currently being evaluated in ongoing clinical trials. In related studies, Der and colleagues contributed to two articles published in Nature in April about a promising anti-KRAS drug that is effective against many different KRAS mutations. They found that the MYC oncogene can cause resistance to KRAS therapies. Closing the circle, the new Science papers established that MYC is a significant component of how KRAS and ERK support cancer growth and a driver of resistance to KRAS and ERK therapies.

“Our next steps are elucidating more aspects of basic and foundational research regarding KRAS,” said Der, who is a member of the UNC Lineberger Pancreatic Cancer Center of Excellence . “We will continue to mine the growing body of scientific knowledge we have developed, with the ultimate goal of helping advance the clinical development of newer and better KRAS inhibitors.”

Authors and disclosures

In addition to Der, Jeffrey A. Klomp, PhD, assistant professor of pharmacology at UNC Lineberger and UNC School of Medicine, was the co-corresponding author of the article “Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.” Clint A. Stalnecker, PhD, assistant professor of pharmacology at UNC Lineberger and UNC School of Medicine, was the co-corresponding author of the article “Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer,” and Jennifer E. Klomp, PhD, a postdoctoral research associate at UNC Lineberger, was first author.

A complete list of authors, their disclosures and funders of support of the research is published in the papers.

Media contact: Bill Schaller, [email protected] , (617) 233-5507

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Researchers detail molecular pathway that impacts pancreatic cancer progression and treatment response

by University of North Carolina Health Care

Researchers at UNC Lineberger Comprehensive Cancer Center and colleagues have established the most comprehensive molecular portrait of the workings of KRAS, a key cancer-causing gene or "oncogene," and how its activities impact pancreatic cancer outcomes. Their findings could help to better inform treatment options for pancreatic cancer, which is the third leading cause of all cancer deaths in the United States.

The research was published as two separate articles in Science titled " Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers " and " Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer ."

"Because less than 40% of pancreatic cancers respond to treatment with KRAS inhibitors, if we can establish molecular markers to predict which patients will respond, we can better provide them with specific treatments, which should improve their outcomes," said UNC Lineberger's Channing J. Der, Ph.D., Sarah Graham Kenan Distinguished Professor at UNC School of Medicine's Department of Pharmacology and a corresponding author of both articles.

"From diagnosis to death, the average pancreatic cancer patient treated with chemotherapy lives 6 to 12 months, so there's a very limited time to offer a treatment which will work."

KRAS is one of the most commonly mutated genes in human cancers and it is found in more than 90% of pancreatic cancer tumors. Exactly how it spurs cancer growth, however, is poorly understood. That's why UNC Lineberger researchers embarked on their extensive efforts to figure out what other genes and proteins make KRAS expression so lethal.

In the most detailed analysis to date, they demonstrate that the molecular pathway most responsible for the cancer-driving functions of KRAS is highly dependent on a protein called ERK that has dual functions in regulating which genes are expressed and which proteins are active.

While ERK has been one of the most intensively studied cancer pathways, and it is well-established that ERK is among the significant players in KRAS function, its relative importance and precisely how ERK carries out its role have been unclear.

Indeed, a core finding of the Science papers was that activation of the ERK protein alone is the key driver of resistance to drugs that inhibit KRAS. Taking advantage of improved methods to study cellular signaling, the researchers demonstrated that the ERK protein regulates the expression of a remarkably complex array of thousands of genes and changes the activity of thousands of proteins.

Excitingly, the researchers confirmed that their findings in cancer models could accurately reflect responses in patients treated with ERK and KRAS therapies for their pancreatic, colorectal and lung cancers.

Currently, two KRAS drugs have been approved for cancer treatment, and many more are currently being evaluated in ongoing clinical trials. In related studies, Der and colleagues contributed to two articles published in Nature in April about a promising anti-KRAS drug that is effective against many different KRAS mutations.

They found that the MYC oncogene can cause resistance to KRAS therapies. Closing the circle, the new Science papers established that MYC is a significant component of how KRAS and ERK support cancer growth and a driver of resistance to KRAS and ERK therapies.

"Our next steps are elucidating more aspects of basic and foundational research regarding KRAS," Der said. "We will continue to mine the growing body of scientific knowledge we have developed, with the ultimate goal of helping advance the clinical development of newer and better KRAS inhibitors."

Jennifer E. Klomp et al, Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer, Science (2024). DOI: 10.1126/science.adk0850 . www.science.org/doi/10.1126/science.adk0850

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• Published: 29 June 2021

Advancing on pancreatic cancer

Nature Reviews Gastroenterology & Hepatology volume  18 ,  page 447 ( 2021 ) Cite this article

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• Pancreatic cancer

Pancreatic cancer is a notoriously lethal condition characterised by aggressive malignancy and dismal outcomes. However, translational advances are showing us that hope is on the horizon.

The global burden of pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, has doubled in the last quarter century and is projected to be the second leading cause of cancer deaths in the USA in the next 20–30 years 1 . Outcomes in PDAC make for grim reading: 5-year survival has only just reached double digits in some regions 2 ; current chemotherapeutics lead to survival in the range of months; and ~50% of new diagnoses are the metastatic form of PDAC, with an average survival of less than a year 1 . Such bleak statistics are driven by a disease that often has non-specific symptoms until it is too late; most diagnoses are made once the opportunity for surgical intervention has passed.

Despite this situation, there are reasons to be hopeful. Research investment in pancreatic cancer in the USA has increased more than any other cancer site, driving cutting-edge translational research that aims to enhance strategies towards PDAC detection and treatment 3 . In this Focus Issue of Nature Reviews Gastroenterology & Hepatology , we provide an overview of some of these advances in a series of Reviews and commentaries, which are also available online in a Collection . Each of these articles features a different aspect of PDAC that highlights the inherent challenges of the disease, but each also reveals how advancements are paving the way for improved patient care.

A key feature of the PDAC microenvironment is its dense, hypoxic and immunosuppressive stroma that limits infiltration by immune cells and therapeutics. Adding to our understanding of the mechanisms underlying the stroma, Encarnación-Rosado and Kimmelman explain how it mediates a reprogramming of PDAC metabolism to facilitate tumour survival. By understanding how metabolism is rewired in PDAC and by identifying the metabolic dependencies, new strategies for targeted therapeutic interventions could be revealed.

PDAC is one of the most aggressive and chemoresistant forms of cancer, largely due to the diversity of genetic mutations that give rise to a highly heterogenic disease. Hayashi, Hong and Iacobuzio-Donahue examine the PDAC genome and discuss how our understanding has advanced beyond the common driver genes and major hereditary components. By examining genomic PDAC studies in the context of its cellular origins and evolutionary growth dynamics, they show how distinct genomic events are associated with phenotypes that indicate therapeutic vulnerabilities.

The low prevalence of PDAC in the general population presents further challenges towards a feasible, cost-effective solution to population screening. In their Review, Klein summarises the epidemiology of pancreatic cancer, including modifiable risk factors as well as those that could help identify high-risk individuals and focus screening procedures. Other efforts aiming to improve detection of the disease early in its natural history are detailed by Singhi and Wood . They discuss the precursor lesions of pancreatic cancer and approaches and challenges to their early detection using DNA-based molecular techniques, which demonstrate the promise of technology for overcoming the fundamental problem of late presentation in PDAC.

Another technological advancement, single-cell RNA sequencing, forms the basis of a Comment by Han, DePinho and Maitra . The authors explore how in-depth cellular profiling in PDAC has furthered our understanding of the molecular underpinnings of the disease but also the potential mechanisms responsible for therapeutic resistance. A final reason to be hopeful comes in the form of immunotherapy. Although this field seems poised to revolutionise cancer treatment, PDAC is known to be resistant to many current approaches. However, as discussed in a Comment by Rojas and Balachandran , promising strategies to unlock the potential of immunotherapy in PDAC are underway.

There is encouraging progress towards improving the lives of patients and families affected by PDAC

There is encouraging progress towards improving the lives of patients and families affected by PDAC. However, more investment in both data repositories such as biobanks and high-visibility research is urgently needed, particularly in Europe where pancreatic cancer is relatively neglected 4 despite the increasing burden. Improved awareness of the early signs and risk factors of PDAC will be crucial to increase early diagnosis, as will coordinated cooperation between academia, patient organisations, scientific societies and advocacy groups. Leveraging these stakeholders will be critical in maintaining the momentum needed to translate these hopeful advances to the clinic, where their benefits can be seen.

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Prades, J. et al. Bratislava Statement: consensus recommendations for improving pancreatic cancer care. ESMO Open 5 , e001051 (2020).

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Advancing on pancreatic cancer. Nat Rev Gastroenterol Hepatol 18 , 447 (2021). https://doi.org/10.1038/s41575-021-00479-5

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Pancreatic cancer: A review of epidemiology, trend, and risk factors

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Intensive Care Unit (ICU), Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China

Cheng-Fei Zhao

School of Pharmacy and Medical Technology, Putian University, Putian 351100, Fujian Province, China

Key Laboratory of Pharmaceutical Analysis and Laboratory Medicine in University of Fujian Province, Putian University, Putian 351100, Fujian Province, China. moc.361@902iefgnehcoahz

Wen-Biao Chen

Department of Basic Medicine, Quanzhou Medical College, Quanzhou 362011, Fujian Province, China

Department of Reproductive Medicine Centre, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, China

Department of Priority Laboratory for Zoonoses Research, Fujian Center for Disease Control and Prevention, Fuzhou 350001, Fujian Province, China

Department of Pathology, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, China

Supported by Fujian Province Medical Health Young and Middle-aged Talents Training Project, No. 2020GGA079 ; National Natural Science Foundation of China, No. 81572442 ; and Natural Science Foundation of Fujian Province, No. 2018J01195 .

Corresponding author: Cheng-Fei Zhao, MD, Associate Professor, School of Pharmacy and Medical Technology, Putian University, No. 1133 Xueyuan Road, Chengxiang District, Putian 351100, Fujian Province, China. moc.361@902iefgnehcoahz

Despite rapid advances in modern medical technology and significant improvements in survival rates of many cancers, pancreatic cancer is still a highly lethal gastrointestinal cancer with a low 5-year survival rate and difficulty in early detection. At present, the incidence and mortality of pancreatic cancer are increasing year by year worldwide, no matter in the United States, Europe, Japan, or China. Globally, the incidence of pancreatic cancer is projected to increase to 18.6 per 100000 in 2050, with the average annual growth of 1.1%, meaning that pancreatic cancer will pose a significant public health burden. Due to the special anatomical location of the pancreas, the development of pancreatic cancer is usually diagnosed at a late stage with obvious clinical symptoms. Therefore, a comprehensive understanding of the risk factors for pancreatic cancer is of great clinical significance for effective prevention of pancreatic cancer. In this paper, the epidemiological characteristics, developmental trends, and risk factors of pancreatic cancer are reviewed and analyzed in detail.

Core Tip: Pancreatic cancer is still a highly lethal gastrointestinal cancer with a low 5-year survival rate and difficulty in early detection. A comprehensive understanding of the risk factors for pancreatic cancer is of great clinical significance for effective prevention of pancreatic cancer. In this review, the latest epidemiology, future trends, and various risk factors of pancreatic cancer are analyzed and summarized, which will provide more guidance and suggestions for the prevention and control of this malignancy.

INTRODUCTION

The pancreas is an about 15-cm-long, spongy, tube-shaped organ located in the upper abdomen between the stomach and spine[ 1 ]. A normal healthy pancreas consists of acinar cells secreting digestive enzyme, ductal cells secreting bicarbonate, centro-acinar cells that are the transitional region between acinar and ductal cells, endocrine islets secreting hormone, and relatively inactive stellate cells[ 2 ]. Pancreatic cancer occurs when abnormal DNA mutations in the pancreas cause pancreatic cells to uncontrollably grow and divide, forming tumors[ 3 ]. Pancreatic cancer is characterized as a fatal disease and one of the most aggressive and lethal malignancies[ 4 , 5 ]. By the time of diagnosis, pancreatic cancer often presents at an advanced stage, and has often spread to other parts of the body. Clinically, pancreatic cancer is the general term for malignant tumor formed in the epithelial cells of glandular structures in the pancreatic ductal cells, referred to as adenocarcinoma[ 6 ], and pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of pancreatic cancers[ 7 ]. Due to the poor survival outcomes, PDAC is the seventh leading cause of global cancer death despite being the 10th most common cancer[ 8 ]. Other less common exocrine pancreatic cancers include adenosquamous carcinoma, squamous cell carcinoma, giant cell carcinoma, acinar cell carcinoma, and small cell carcinoma. At present, pancreatic cancer remains a devastating disease whose prognosis has remained largely unchanged over the last two decades[ 9 ]. Improvement in patient outcomes will depend on clear knowledge of epidemiology, reasonable prevention, and scientific regulation of early detection[ 4 ]. Therefore, it is necessary to understand the epidemiological characteristics, development trends, and risk factors of pancreatic cancer in detail, which will eventually establish rational prevention approaches for clinical benefit.

EPIDEMIOLOGY OF PANCREATIC CANCER

Assessing the latest epidemiologic trends in pancreatic cancer is necessary because it is of great importance for preventive measures and clinical care[ 10 ]. Therefore, we present a review of the latest epidemiology of pancreatic cancer.

Pancreatic cancer ranks consistently last among all cancers in terms of prognostic outcomes for patients and is predicted to become the second leading cause of cancer death in some regions[ 11 ]. A study including 84275 patients with at least 5 years of follow-up showed that actual 5-year survival rate in patients rose from 0.9% in 1975 to 4.2% in 2011 for all stages of pancreatic cancer, while in surgically resected patients, it increased from 1.5% to 17.4%[ 12 ]. In non-resected patients, the actual 5-year survival rate was 0.8% in 1975 and 0.9% in 2011, meaning that it remained roughly the same between 1975 and 2011[ 12 ]. The 5-year relative survival rate of pancreatic cancer was 7.2% in China and the lowest level in all cancers[ 13 ]. Cancer Stat Facts showed that the 5-year survival rate at the time of diagnosis is approximately 10% in the United States based on data from Surveillance, Epidemiology, and End Results Program 18 between 2010 and 2016[ 14 ]. Pancreatic cancer has a poor 5-year survival rate, ranging from 2% to 9%, with little difference between high-income countries and low-income and middle-income countries[ 11 , 15 ]. Therefore, the 5-year survival rate of pancreatic cancer varies globally in different regions and countries, but does not exceed 10%. And it is predicted that patients with nonoperative pancreatic cancer have a lower 5-year survival rate.

According to Cancer Statistics 2021, the American Cancer Society reported approximately 60430 new cases and 48220 deaths for pancreatic cancer in the United States, ranking third after lung and bronchus cancer and colorectal cancer[ 16 ]. In the 28 countries of the European Union (EU), it was estimated that approximately 111500 people (55000 in males and 56500 in females) will die from pancreatic cancer by 2025, and the number of recorded deaths from the cancer in 2010 will increase by almost 50% (45% in men and 49% in women), and it has been projected that pancreatic cancer may become the third leading cause of cancer death in the EU after lung and colorectal cancers[ 17 ]. Global Cancer Statistics 2018 showed that the incidence and mortality of pancreatic cancer were 458918 and 432242 in 2018 in the world, respectively, and deaths account for about 94.2% of new cases[ 18 ]. Pancreatic cancer remains the seventh leading cause of cancer death globally, and Global Cancer Statistics 2020 showed that, globally, a total of 495773 new cases and 466003 related deaths were reported for pancreatic cancer in 2020, with almost as many mortality as incidence[ 19 ]. The systematic analysis for the 2017 Global Burden of Disease Study showed that the number of incident cases and deaths from pancreatic cancer in both genders increased 2.3-fold from 195000 incident cases and 196000 deaths in 1990 to 448000 incident cases and 441000 deaths in 2017 globally[ 15 ]. These reports indicate a gradual increase in the number of incident cases and deaths from pancreatic cancer.

Average age-standardized rates (ASRs) of pancreatic cancer incidence and mortality vary widely across regions of the world[ 19 ]. The ASR of the incidence was highest in Eastern Europe, with 9.9 per 100000, followed by Western Europe (9.8), Northern America (9.3), Southern Europe (8.4), Northern Europe (8.3), Australia/New Zealand (7.9), Micronesia/Polynesia (7.7), and Western and Eastern Asia (7.0)[ 19 ]. The ASR of the mortality was highest in Western Europe, with 7.4 per 100000, followed by Northern America (6.9), Northern Europe (6.7), Australia/New Zealand (6.7), Southern Europe (8.4), Eastern Europe (5.6), Eastern Asia (4.8), and Western Asia (4.4)[ 19 ]. The human development index (HDI) is a composite index that measures three dimensions: Life expectancy, education period, and access to essential sources for a suitable and reasonable life[ 20 ]. The ASRs of pancreatic cancer incidence and mortality in regions with a very high HDI were significantly higher than medium or low HDI regions[ 19 ]. The low ASRs of the incidence and mortality were found mainly in South-Central Asia (1.5 per 100000, 0.9 per 100000), Eastern Africa (2.0, 1.7), Middle Africa (2.0, 1.2), Western Africa (2.2, 1.8), Melanesia (2.9, 1.7), and South-Eastern Asia (2.9, 1.8), all of which are medium or low HDI regions[ 19 ]. The top six countries for pancreatic cancer incidence were Hungary (ASR, 11.2), Uruguay (ASR, 10.7), Japan (ASR, 9.9), Slovakia (ASR, 9.6), Czechia (ASR, 9.5), and Austria (ASR, 9.0), with 9.0 and greater per 100000, and a total of 21 countries, including the United States (ASR, 8.2), had an ASR of the incidence between 8.1 and 8.9 per 100000, as shown in Figure ​ Figure1A 1A [ 21 ]. The ASR of pancreatic cancer mortality was highest in Hungary and Uruguay, both at 10.2 per 100000, and a total of 26 countries, not including the United States (ASR, 6.6), had an ASR of the incidence between 7.2 and 8.6 per 100000, as shown in Figure ​ Figure1B 1B [ 21 ]. The proportion of estimated new cases for pancreatic cancer in China was relatively high in East China (9.4 per 100000), Northeast (9.4), Northwest (6.8), and North China (5.3), and was comparatively low in Central China (5.2), Southwest (4.3), and South China (3.6), having obvious regional characteristics[ 13 ]. Age-standardized rates of pancreatic cancer were 3-fold to 4-fold higher in higher HDI countries, compared with lower HDI countries[ 18 ]. The higher incidence and mortality rates of pancreatic cancer were reported in countries and regions with higher levels of HDI and Gross Domestic Product (GDP) per capita, and the coefficients of determination (R 2 ) of HDI and GPD per capita were high for the incidence and mortality[ 22 ]. The higher incidence and mortality rates of pancreatic cancer in countries with higher HDI indicates the importance that paying more attention and implementing appropriate programme to reduce risk factors acts as an effective measure to control the incidence and mortality of the cancer[ 23 ].

Maps showing estimated age-standardized rates of incidence and mortality for pancreatic cancer worldwide in 2020, including both sexes and all ages. A: Incidence; B: Mortality. Citation: Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F. Global Cancer Observatory: Cancer Today. [cited 20 Jan 2021]. In: International Agency for Research on Cancer [Internet]. Available from: https://gco.iarc.fr/today . Copyright ©International Agency for Research on Cancer 2021. Published by World Health Organization[ 21 ].

TRENDS OF PANCREATIC CANCER

Over the two decades from 2001 to 2020, the estimated new cases and deaths of pancreatic cancer have been increasing year by year in the United States, and the same trend has been observed among men and women, as shown in Figure ​ Figure2. 2 . Using statistical models for analysis, in the United States, age-adjusted rates of new cases for pancreatic cancer remained stable from 2008 to 2017, and age-adjusted rates of death increased by an average of 0.3% each year from 2009 to 2018[ 14 ]. Prediction of pancreatic cancer incidence burden from the 28 member states of the EU and other selected countries around the world showed that in 2025, 2030, 2035, and 2040, the incidence will be 557688, 639030, 726740, and 815276, respectively, with growth rates of 21.5%, 39.2%, 58.4%, and 77.7%[ 24 ]. The incidence and mortality of pancreatic cancer in Africa will increase by 18327 and 17744 in 2040, respectively, with growth rates of 114.1% and 114.8%, the rates of which will be highest in the world, followed by Latin America and the Caribbean (incidence: + 99.3%; mortality: 101.0%)[ 25 ]. However, in 2040, the growth rates of the incidence and mortality in Europe will be lowest at 29.3% and 31.6%, respectively[ 25 ]. Based on China and India, both countries in Asia with more than one billion population, the incidence and mortality in Asia will increase by 190532 and 182127 in 2040, respectively, which will be the largest increase in terms of number[ 25 ]. In addition, standardized mortality rate of pancreatic cancer increased from 1.30 per 100000 to 3.32 per 100000 over 1991-2014 and might reach the peak in the ensuing 5 years in China, and the mortality rate was higher among elderly people and in urban and northeast/eastern regions than among young people and in rural and middle/western regions[ 26 ]. The incidence of pancreatic cancer was 12.1 per 100000 in 2010 and is predicted to increase to 15.1 and 18.6 per 100000 in 2030 and 2050, respectively, with an average annual growth of 1.1%[ 27 ]. In the age-stratified analysis, the over 65 years group will have the highest projected incidence (31.9 per 100000) in 2050, and the incidence is projected to increase gradually in the sex-stratified analysis, with an average annual growth of 1.3% in males and 0.9% in females[ 27 ].

Estimated new cases and deaths from 2001 to 2020 in the United States. The data is from Cancer Statistics that the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States from 2001 to 2020[ 16 , 28 - 47 ].

The number of years of life lost (YLL) is a measure of premature mortality, taking into account simultaneously the number of deaths and life expectancy at age of death, and projection of YLL due to premature mortality ( i.e. , time-based approach) provides a comprehensive outlook of the fatal burden at a population level[ 27 ]. Due to premature death in individuals with pancreatic cancer, the total YLL was 5604 years in 2010 and is projected to increase to 9784 in 2030 and 14247 in 2050, with an average annual growth of 2.1%[ 27 ]. In the age-stratified analysis, the 40-64 years group will have the highest projected YLL (7588 years) in 2050, and the YLL is projected to increase gradually in the sex-stratified analysis, with an average annual growth of 2.1% in males and 2.2% in females[ 27 ].

In conclusion, pancreatic cancer, like other cancers such as lung, liver, and stomach cancer, will cause a huge economic burden to all countries and related populations in the next 20 years, especially China having a huge population, which is still a developing country. In order to reverse these trends and improve the prognosis of patients with pancreatic cancer, the most simple, direct, and effective way is to understand the risk factors affecting the occurrence and development of pancreatic cancer in detail, which provides comprehensive and reasonable guidance and suggestions for the prevention of pancreatic cancer, and offers reliable and feasible ideas for the early screening of pancreatic cancer.

CAUSES AND RISK FACTORS OF PANCREATIC CANCER

Pancreatic intraepithelial neoplasias (PanINs) are noninvasive epithelial proliferations in smaller pancreatic ducts, which progress from PanIN-1 (low-grade) to PanIN-2 (intermediate-grade) to PanIN-3 (high-grade)[ 48 ]. The differentiation of normal epithelium into PanIN-1/PanIN-2 and then into PanIN-3/invasive pancreatic cancer requires a considerable period of development, while the development process before high-grade PanIN-3 and invasive pancreatic cancer is the golden stage of preventing pancreatic cancer through effective interventions. Therefore, a thorough and comprehensive understanding of pancreatic cancer risk factors is of great practical significance for the prevention of pancreatic cancer. The exact cause of pancreatic cancer is unknown, but many non-modifiable and modifiable risk factors are associated with development of pancreatic cancer. Non-modifiable risk factors include age, gender, ethnicity, ABO blood group, microbiota, diabetes mellitus (DM), and family history and genetic susceptibility, while modifiable risk factors include smoking, alcohol drinking, dietary factors, pancreatitis, obesity, infection, and socioeconomic status and insurance. The influence of these factors on the occurrence, progression, and invasion of pancreatic cancer is analyzed and summarized as follows.

NON-MODIFIABLE RISK FACTORS

Both 89.4% of new cases of pancreatic cancer and 92.6% of deaths occur in patients over 55 years of age in the United States, the new cases are most frequently diagnosed among people 65-74 years of age with a median age at diagnosis of 70 years, and the percent of deaths is also highest among people of the same age group with a median age at death of 72 years[ 14 ]. The proportions at 40-64 years and over 65 years of age were 47.9% and 48.6% in diagnosed patients with pancreatic cancer in China[ 49 ]. The mortality rates of patients aged under 30, 30-44, 45-59, 60-74, and 75 and above among males are 0.1, 1.4, 10.1, 19.3, and 14.6 per 100000 in China, respectively[ 50 ], meaning that male pancreatic cancer population over 60 years of age has a higher mortality rate. The reference does not provide the mortality rates of pancreatic cancer in the five broad age groups in women and both sexes[ 50 ]. Worldwide, it is extremely rare for pancreatic cancer to be diagnosed before the age of 30, so it is typically a disease of the elderly. The risk factor also determines the need for screening and early detection of pancreatic cancer among the population over a certain age.

In the United States, the new cases of pancreatic cancer is 31950 among males and 28480 among females in 2020, and the deaths is 25270 among males and 22950 among females[ 16 ]. In China, the age-standardized respective incidence and mortality rate are 52.2 and 45.6 per 100000 among men in 2015, and 37.9 and 33.8 per 100000 among women[ 50 ]. On a global scale, the new cases are 243033 among men and 215885 among women in 2018, and the deaths are 226910 among men and 205332 among women[ 18 ]. The global respective incidence and mortality rates are 5.5 and 5.1 per 100000 among men in 2018, and 4.0 and 3.8 per 100000 among women[ 18 ]. Globally, the respective cumulative risk of developing pancreatic cancer and dying from it from birth to 74 years is 0.65% and 0.59% among males in 2018, and 0.45% and 0.41% among females[ 18 ]. The ratio of male to female for estimated new cases and deaths increased in the United States from 2001 to 2020, as shown in Figure ​ Figure3. 3 . Thus, the worldwide incidence and mortality of pancreatic cancer are higher among males than females.

Ratio of male to female for estimated new cases and deaths from 2001 to 2020 in the United States. The data is from Cancer Statistics that the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States from 2001 to 2020[ 16 , 28 - 47 ].

ABO blood group

The ABO antigens were first described by Landsteiner as erythrocyte antigens in 1900[ 51 ]. The antigens of ABO blood group are glycoproteins that are expressed on red blood cells and various epithelial cells, including the urothelium and gastrointestinal mucosa[ 52 ]. The phenotypic A and B antigens are terminal carbohydrates synthesized by the addition of monosaccharides catalyzed by a series of specific glycosyltransferases, and the phenotype O is characterized by deficiency of A and B glycosyltransferases[ 52 ]. There is growing evidence that ABO blood group may also be associated with carcinogenesis or progression of pancreatic cancer. A consortia-based evaluation and replication study showed that non-O blood group was associated with an increased risk of pancreatic cancer compared with blood group O[ 53 ]. A register-based cohort study showed that blood group A was associated with an increased risk of pancreatic cancer[ 54 ]. There was a significantly higher risk for developing pancreatic cancer in Chinese patients with the A or AB blood types than for those with type O[ 55 ]. El Jellas et al [ 56 ] reported that the prevalence of blood type A and subtype A1 was highest among the unresected cases, the unresected cases had the lowest frequency of blood group O, and patients with blood group O survived longer than non-O patients in the group of unresected cases. A study at Shanghai Pancreatic Cancer Institute showed that Chinese Han population with blood type A were more likely to develop pancreatic cancer, but people with blood type B were less likely to develop pancreatic neuroendocrine tumors and other types of pancreatic masses, compared with those with blood type O[ 57 ]. Hofmann et al [ 51 ] reported that patients with blood type O had more often well-differentiated PDAC compared with blood type non-O, and they elucidated the novel interaction between blood type immunoglobulin M isoagglutinins and PDAC O-GalNAc glycoproteins, which may contribute to the pathogenesis and progression of pancreatic cancer. Accordingly, the risk for people with blood type O to develop pancreatic cancer is lower than those with other blood types. In addition, the ABO allele that determines blood type A has two major subtypes, namely, A1 and A2, and the association of A1 but not A2 with pancreatic cancer could therefore suggest that the activity of blood type A glycosyltransferase plays a role in carcinogenesis[ 56 ]. The study showed that the A2 subtype has a single base deletion near the carboxyl terminal, and introducing the single base deletion into the expression construct of A1 transferase cDNA significantly reduced the activity of A transferase in DNA-transfected HeLa cells[ 58 ]. Therefore, clarifying the etiological mechanism between the risk of pancreatic cancer and ABO blood type may provide a new perspective for the treatment of this disease.

The burden of exocrine pancreatic disease, including pancreatic cancer, pancreatitis, and pancreatic cyst, differs among various ethnicities, and African-Americans and certain indigenous populations are at the greatest risk of developing these diseases[ 59 ]. Huang et al [ 60 ] observed that African-Americans, Native Americans, and Japanese-Americans had higher rates of developing pancreatic cancer, but no difference between Latino- and European-Americans, and found that African-Americans had a 20% greater risk of pancreatic cancer than European-Americans even after adjusting for known risk factors. In the studies including few minority patients, the neutrophil-to-lymphocyte ratio (NLR) is associated with a reduced overall survival in pancreatic cancer patients, and NLR > 5 was significantly associated with a worse overall survival compared with NLR ≤ 5[ 61 ]. Patients with an NLR ≤ 5 were also more likely to develop locally advanced disease than metastatic cancers and primary tumor located in the head or neck of the pancreas, while patients with an NLR > 5 were more likely to have liver metastases and albumin < 3.4 g/dL, suggesting that elevated NLR is an independent marker for poor prognosis and a potentially valuable factor[ 61 ]. Patients with an NLR ≤ 5 were more likely to be non-Hispanic Black, while patients with an NLR > 5 were more likely to be non-Hispanic White or Hispanic[ 61 ], suggesting that there are different predispositions and outcomes for pancreatic cancer between non-Hispanic Black and non-Hispanic White or Hispanic. Gad et al [ 62 ] found that the incidence of pancreatic cancer among Asian-Americans, especially malignancies of the body and tail of the pancreas, as well as the mortality based on the incidence, was overall on the rise in an epidemiological study, without respect to age, sex, or stage subgroup. Amaral et al [ 63 ] also emphasized the importance of the influence of ethnicity on somatic mutations in Brazilian patients with PDAC. To elucidate the reasons for the racial differences in the incidence of pancreatic cancer may help us improve the understanding and prevention of this disease.

Oral microbiota: Several epidemiological studies have found the direct relationship between oral bacteria and pancreatic cancer[ 64 ]. Farrell et al [ 65 ] reported that the levels of two bacteria biomarkers ( Neisseria elongate and Streptococcus mitis ) were lower in patients with pancreatic cancer than in healthy controls, and found that the combination of the two bacteria biomarkers distinguished pancreatic cancer patients from healthy subjects with an area under the curve value of 0.90, sensitivity of 96.4%, and specificity of 82.1%. Torres et al [ 66 ] found that the ratio of Leptotrichia to Porphyromonas in the saliva of pancreatic cancer patients was significantly higher than that in healthy individuals or those with other disease. Fan et al [ 67 ] found that Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were associated with a higher risk of pancreatic cancer, and phylum Fusobacteria and its genus Leptotrichia were associated with a decreased risk of this cancer. Olson et al [ 68 ] reported that the mean relative proportions of Firmicutes and related taxa were higher in patients with pancreatic cancer, while the mean relative proportions of Proteobacteria and related taxa were higher in controls.

Gut microbiota: Studies have confirmed that gut microbiota is associated with recognized risk factors for pancreatic cancer, such as obesity and type II diabetes, suggesting the relationship between gut bacteria and pancreatic cancer[ 64 ]. In recent decades, multiple and highly complex effects of gut microbiota on pancreatic cancer have been identified as potential risk factors for the development and progression of this tumor[ 69 ]. A prospective study, for the first time, analyzed gut microbial profile in Chinese pancreatic cancer cohorts by MiSeq sequencing, revealing a significant decline in gut microbial diversity and a unique microbial profile in pancreatic cancer, due in part to the decline in alpha diversity[ 70 ]. Additionally, the microbial profile changed in pancreatic cancer, with an increase in certain pathogens and lipopolysaccharides (LPS)-producing bacteria and a decrease in probiotics and butyrate-producing bacteria[ 70 ]. LPS might play a pro-inflammatory pro-tumor role by activating the nuclear factor-κappa B (NF-κB) pathway, producing proinflammatory cytokines [tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-1] and leading to liver inflammatory and oxidative damage[ 71 ]. After LPS treatment, Ras activity in cells prepared from acinar-Ras mice was greatly elevated and maintained at a high level for a long time, and severe chronic pancreatitis and PanIN lesions were induced in acinar-Ras mice, accompanied by sustained elevated Ras activity, whereas there was no observed effects in control mice, suggesting that LPS treatments led to fibrosis and PanIN formation in the presence of oncogenic Ras[ 72 ]. Therefore, LPS may have a greater pathological impact on patients carrying cells expressing oncogenic RAS, which may explain individual differences in response to infection, suggesting the association between chronic bacterial infectious diseases and colon and pancreatic cancers[ 72 ]. As a member of the RAS family of GTP-binding proteins, KRAS mediates a wide variety of cellular functions including proliferation, differentiation, and survival[ 73 ], and the prevalence of oncogenic KRAS mutation in PDAC ranges from 88% to 100%[ 74 ]. Consistent with a central pathogenic role of the KRAS G12D mutation, mice engineered with pancreas-specific expression of this activated KRAS allele sustain classical PanIN lesions that can progress to PDAC in the appropriate tumor suppressor background[ 73 ]. Thomas et al [ 75 ] found that the proportion of poorly differentiated PDAC in the microbiota-intact mice was higher than that in microbiota-depleted mice (89.75 vs 34.8%, respectively), demonstrated that the intestinal microbiota accelerated pancreatic carcinogenesis in the KRAS G12D /PTEN lox/+ mice model of pancreatic cancer, and considered that the intestinal microbiota had a long-distance role on PDAC progression. In addition, based on crucial genera associated with pancreatic cancer, gut microbial markers might achieve an excellent classification capacity between pancreatic cancer and healthy controls, suggesting that the specific alterations of gut microbiota might become non-invasive biomarkers for pancreatic cancer diagnosis[ 70 ].

Pancreatic microbiota: A number of different bacterial taxa are found in pancreatic tissue contents, including those known to inhabit the oral cavity, which suggest that the pancreas is not a sterile organ[ 76 ]. The relative abundance of bacterial taxa at the genus level in the pancreas has a substantial between-person variability, and bacterial composition of the pancreatic duct, head, and tail as well as the duodenum was highly similar in the same individuals[ 76 ]. The study showed that the community composition of the microbiota in the human pancreas failed to discriminate between normal and disease states, and that the acquisition of pancreatic bacteria is not a physiologic process, even under conditions of intestinal inflammation[ 75 ]. Del Castillo et al [ 76 ] found that the presence and relative abundance of Lactobacillus were lower in pancreatic tissue of cancer subjects and the relative abundance of periodontal-related pathogens was higher in cancer subjects, when compared with noncancer subjects. Pushalkar et al [ 77 ] found that the bacteria ( Enterococcus faecalis and Escherichia coli ) could migrate into the pancreas, confirmed that the abundance of intrapancreatic bacteria in both mice and patients with PDAC was markedly greater compared with normal pancreas by 16S rRNA fluorescence in situ hybridization and qPCR analysis, and consider that the bacteria promote the progression of pancreatic oncogenesis in both preinvasive and invasive models[ 77 ]. Maekawa et al [ 78 ] mainly detected Enterococcus and Enterobacter species in bile, demonstrating that Enterococcus and Enterobacter can survive in pancreatic juice and/or bile, and found that 29 of 36 pancreatic juice samples were positive for bacterial DNA[ 78 ]. Enterococcus faecalis was also found in pancreatic tissue from patients with chronic pancreatitis and pancreatic cancer, and serum antibodies to capsular polysaccharide of Enterococcus faecalis were elevated in patients with chronic pancreatitis[ 78 ]. They demonstrated that Enterococcus faecalis is involved in the progression of chronic pancreatitis using the model mice with caerulein-induced chronic pancreatitis, which may ultimately result in the development of pancreatic cancer[ 78 ].

In addition, Pushalkar et al [ 77 ] also found that the microbiome regulates immunogenicity in PDAC and programs tumor-associated macrophages via Toll-like receptor signaling to induce immune tolerance, and bacterial communities are distinct between early and advanced PDAC. Geller et al [ 79 ] demonstrated that bacteria are a component of the PDAC tumor microenvironment, and estimated that bacteria colonized PDAC samples had an average of one bacterium per 146 human cells. Their results indicated that PDACs contain bacteria that can potentially modulate tumor sensitivity to gemcitabine, and they considered that the bacteria play a critical role in mediating resistance to chemotherapy[ 79 ]. By studying colon cancer models, they found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form (2′,2′-difluorodeoxyuridine), which depends on the expression of a long isoform of bacterial cytidine deaminase, seen primarily in γ-proteobacteria[ 79 ].

The above various microorganisms have different influences on the occurrence, development, and invasion of pancreatic cancer in different ways. Therefore, the study on the influence of microorganisms on pancreatic cancer will provide more new insights to reveal its etiology. And studying the effects of microorganisms on pancreatic cancer has the potential to be used as a target for the regulation of disease progression and treatment.

Family history and genetic susceptibility

Hereditary pancreatic cancer includes inherited cancer syndromes with a recognized known germline mutation associated with an increased risk of pancreatic cancer and familial pancreatic cancer with two or more cases of pancreatic cancer in their families[ 80 ]. Pancreatic cancer associated with hereditary syndromes or familial pancreatic cancer accounts for about 10% of cases[ 81 ]. Family history of pancreatic cancer was associated with an increased pancreatic cancer risk when compared with cancer-free family history, with the risk being greater when ≥ 2 first-degree relatives suffered pancreatic cancer and among current smokers[ 82 ]. Members of familial pancreatic cancer kindreds having at least one first-degree relative affected by pancreatic cancer had a 9-fold increased risk of developing pancreatic cancer, whereas members of sporadic pancreatic cancer kindreds having a first-degree relative with pancreatic cancer did not have an increased risk[ 83 ]. Risk was higher among members of familial pancreatic cancer kindreds with a young-onset patient (< 50 years) in the kindred than those without a young-onset case in the kindred[ 84 ].

Genetic mutations associated with an increased risk of pancreatic cancer include STK11/LKB1 , CDKN2A (p16) , BRCA1/2 , PRSS1/SPINK1/CFTR , mismatch repair genes ( MLH1/MSH6/MSH2/PMS2 ), ATM , and PALB2 (a new pancreatic cancer susceptibility gene)[ 85 ]. And pancreatic cancer is also found to be associated with these familial cancer syndromes for which genetic mutations correspond, such as Peutz-Jeghers syndrome ( STK11/LKB1 ), familial atypical multiple mole melanoma ( CDKN2A ), hereditary breast cancer ovarian cancer syndrome ( BRCA1/2 ), and hereditary non-polyposis colorectal carcinoma syndrome ( MLH1/MSH6/MSH2/PMS2 )[ 25 , 85 ].

A study from Mayo Clinic showed that the aggregate prevalence was 36/302 (11.9%) for all cases with any positive PDAC family history[ 86 ]. Seven PDAC-associated genes ( ATM , BRCA1 , BRCA2 , CDKN2A , MSH2 , PALB2 , and PMS2 ) and four genes with no known PDAC association ( BARD1 , CHEK2 , MUTYH/MUY , and NBN ) were identified as pathogenic variants in the study[ 86 ]. Kindreds with at least one pair of first-degree relatives who were affected by PDAC were considered FPC, and kindreds with at least two affected blood relatives that did not meet the FPC definition were considered “familial non-FPC”[ 86 ]. Thirty-six (12%) patients carried at least one pathogenic variant in one of 11 genes, and the probabilities of carriers with pathogenic variant among FPC patients and familial non-FPC patients were 14% and 9%, respectively[ 86 ]. Pathogenic variants (n) identified in PDAC patients were BRCA2 (11), ATM (8), CDKN2A (4), CHEK2 (4), MUTYH/MYH (3 heterozygotes, not biallelic), BRCA1 (2), and 1 each in BARD1 , MSH2 , NBN , PALB2 , and PMS2 [ 86 ]. Regardless of FPC status, multiple susceptibility gene testing may be necessary in PDAC patients with a family history of pancreatic cancer, which will provide genetic risk counseling for families[ 86 ]. Therefore, the study of the family characteristics and genetic features of pancreatic cancer is of great clinical significance in identifying the susceptible population of pancreatic cancer, screening the high-risk individuals of pancreatic cancer, and early diagnosis of pancreatic cancer.

Diabetes mellitus

In comparison with patients without diabetes, those who were recently diagnosed with diabetes had an nearly 7-fold increase in risk of developing pancreatic cancer[ 87 ]. Either hyperglycaemia or diabetes is found among as many as 80% of patients, both of which can be detected in the presymptomatic phase, and on the contrary, older patients with new-onset diabetes have about an 8-fold higher risk of developing pancreatic cancer than the general population, suggesting a “dual causality” between diabetes and PDAC[ 88 ], in that both long-standing type 2 DM (T2DM) is a risk factor of developing PDAC and PDAC is assumed to be a cause of diabetes in many cases[ 89 ]. A multiethnic cohort study also showed that recent-onset diabetes is a manifestation of pancreatic cancer and long-standing diabetes is a risk factor of developing this cancer[ 90 ]. At present, the prevalence of diabetes in China is on the rise and has the largest diabetes epidemic worldwide, and in 2013, the estimated total prevalence was 10.9% for diabetes and 35.7% for prediabetes among adults in China, indicating the importance of diabetes as a public health problem in China[ 91 ]. In 2011-2012, the prevalence of diabetes was estimated from 12% to 14% among US adults, and participants who were non-Hispanic black, non-Hispanic Asian, and Hispanic had a higher prevalence[ 92 ]. The global spread of this enormous medical burden further highlights the necessity to better understand the pathophysiological relationship between T2DM and pancreatic cancer.

A growing body of epidemiological and experimental evidence shows that chronic hyperinsulinaemia increases the risk of cancers of the colon and endometrium, and probably other tumours (such as pancreas and kidney)[ 93 ]. Hyperinsulinemia, especially intrapancreatic, due to obesity and insulin resistance in patients with prediabetes or early T2DM may believably conduce to the observed increased risk of developing PDAC[ 89 ]. The high level of islet hormones in blood directly reaches groups of acinar and ductal cells and acts on insulin-like growth factor-1 (IGF-1) receptors to promote survival and proliferation of acinar and ductal cells[ 89 ]. The characteristics of T2DM patients and the overwhelming majority of obese individuals are insulin resistance with ensuing hyperinsulinemia and high levels of IGF-1, which can act as potent growth-promoting factors[ 94 ]. In addition, Butler et al [ 95 ] reported that replication of pancreatic duct cells in lean subjects with T2DM had a 4-fold increase compared with lean non-diabetic controls, suggesting that the increased risk of pancreatitis and pancreatic cancer in T2DM is driven by replication of chronically increased pancreatic duct cell replication[ 95 ].

The desmoplastic response attribute to production and proliferation of extracellular matrix proteins in tumor-associated fibroblasts, activating pancreatic stellate cells (PaSC)[ 94 ]. Yang et al [ 96 ] reported that progression of high-fat diet-induced PDAC in mice is associated with hyperglycemia, hyperinsulinemia, and PaSC activation, and found that the pancreas from patients with T2DM showed substantial collagen deposition and activated PaSC in islet and peri-islet exocrine pancreas compared with normal control[ 96 ]. Both quiescent and activated PaSC coexpress insulin and IGF-1 receptors, the expression of which was modulated by both insulin and glucose[ 96 ]. Insulin induces rapid tyrosine autophosphorylation of insulin/IGF-1 receptors at specific kinase domain activation loop sites, activates Akt/mTOR/p70S6K signaling, and inactivates FoxO1, a transcription factor suppressing cell growth[ 96 ]. In activated PaSC, insulin promotes cell proliferation and production of extracellular matrix proteins, and specific inhibition of mTORC1 and mTORC2 can abolish the above effects, suggesting that increased local glucose and insulin concentrations are associated with obesity and T2DM promotes PaSC growth and fibrosing responses[ 96 ]. In premalignant H6c7-kras cells, hyperglycemia increases secretion and signaling of transforming growth factor beta1 (TGF-β1) and induces properties of cancer stem cells depending on TGF-β1-signaling, suggesting that hyperglycemia promotes pancreatic ductal epithelial cells to acquire the properties of mesenchymal and cancer-stem cells by activating TGF-β signaling[ 97 ]. Li et al found that patients with A blood type who also had DM had a greater odds of having pancreatic cancer, and further research is needed to confirm the results and to identify the mechanisms by which A blood type and DM jointly contribute to the risk of pancreatic cancer progression and development[ 55 ].

There are many mechanisms that explain the effect of DM on pancreatic cancer and the relationship between the two. However, in order to reveal the real relationship between diabetes and pancreatic cancer, it still needs to be further studied to provide new strategies for the prevention of pancreatic cancer.

MODIFIABLE RISK FACTORS

Epidemiological studies have shown that many causative factors are associated with pancreatic cancer, and cigarette smoking has the strongest positive association with the risk of developing the cancer[ 98 ]. Due to smoking, the estimated prevalence was about 30% in many parts of the world and the risk of pancreatic cancer was doubled in smokers, whereas the population-attributable risk caused by smoking is about 25% for pancreatic cancer, meaning that the overall burden of this cancer would be reduced if smoking was completely eliminated[ 99 ]. Patients with pancreatic cancer who smoked prior to diagnosis had an about 40% increased hazard for death compared with those who never smoked[ 100 ]. And long-term smoking portended worse outcomes for current smokers, but former smokers experienced outcomes similar to those who had never smoked, suggesting that quitting smoking can have potential beneficial effects[ 100 ]. A large European case-control study confirmed that current smokers had a 72% increased risk of developing pancreatic cancer compared with never-smokers, and the study also endorsed that around 16% of all pancreatic cancer diagnoses could be avoided through tobacco preventive measures in terms of attributable risk[ 101 ]. And analysis of dose-response relationships confirmed that higher smoking intensity, longer smoking duration, and increased cumulative dose levels were associated with a further increased risk of pancreatic cancer, whereas smoking cessation led to a gradual decline in the risk of pancreatic cancer[ 101 ]. Smoking also notably increases the risk of developing pancreatic cancer in individuals with a family history of this cancer[ 82 ]. These studies suggest that smoking cessation has a potential benefit to improve survival for patients with pancreatic cancer and helpfully prevent pancreatic cancer in those at risk.

As an avoidable risk factor, smoking is of particular concern, and elucidating the mechanisms involved would significantly reduce the number of PDAC cases diagnosed each year[ 102 ]. Smoking-induced inflammation was accompanied by enhanced activation of PaSC and elevated levels of serum retinoic acid-binding protein 4, suggesting increased bioavailability of retinoic acid that is conducive to differentiation of myeloid-derived suppressor cells to tumor-associated macrophages and dendritic cells[ 103 ]. And smoking exposure also leads to partial suppression of the immune system in the early progression of pancreatic cancer[ 103 ]. In xenografts of patient-derived pancreatic cancer, nicotine intervention promoted growth and metastasis of tumor, and it was confirmed that nicotine reduced survival by enhancing paracrine HGF-MET signaling in the pancreatic cancer microenvironment[ 104 ]. In addition, nicotine induced dedifferentiation of acinar cells by activating AKT-ERK-MYC signaling, thereby inhibiting the activity of Gata6 promoter and losing GATA6 protein, and subsequently causing loss of acinar differentiation and over-activation of oncogenic K-Ras[ 105 ]. And metformin could inhibit nicotine-induced carcinogenesis of the pancreas and tumor growth by up-regulating GATA6 expression and promoting programmed differentiation of acinar cell[ 105 ]. Benzo(a)pyrenes, polycyclic aromatic hydrocarbons, and tobacco-specific nitrosamines are several carcinogens identified in tobacco smoke, most of which play a genotoxic role by formation of DNA adducts and generation of reactive oxygen species, leading to mutations in vital genes such as K-Ras and p53 [ 106 ]. Nicotine and other carcinogenic components in tobacco smoke can directly promote growth of tumor cells, change cross-talk between tumor and stromal cells within the tumor microenvironment, and enhance infiltration of myeloid-derived suppressor cells[ 100 ]. Therefore, the study and elucidation of carcinogenic mechanism of carcinogens in tobacco smoke will contribute to the treatment and prevention of pancreatic cancer caused by related factors.

Alcohol drinking

East Asians have a high proportion in inefficient metabolism of acetaldehyde, so alcohol drinking may play a more important role in the developing pancreatic cancer among East Asians[ 107 ]. According to many studies, there is no doubt that the risk of pancreatic cancer is associated with high alcohol consumption (more than three drinks per day), but no association was found with low-to-moderate alcohol consumption[ 25 ]. A population-based study demonstrated that heavy alcohol consumption and binge drinking increased estimated risk of developing pancreatic cancer among males but not among females[ 108 ]. It may also be the reason why pancreatic cancer has a higher incidence and mortality in men than in women. And the study also suggested that either binge or consistent heavy alcohol consumption persistently increased the risk of developing pancreatic cancer regardless of the temporal proximity between alcohol consumption and diagnosis of pancreatic cancer[ 108 ]. A large prospective study suggested that baseline and lifetime alcohol consumption was positively associated with the risk of developing pancreatic cancer, and the estimated risk for beer and spirits/liquors was more apparent than wine[ 109 ]. Alcohol plays an independent role in promoting PDAC associated with fibrosis formed by a stellate cell-independent mechanism and further boosts formation of PanIN lesion and induction of M2 macrophages in the context of chronic pancreatitis[ 110 ]. This is an important finding, namely, M2 macrophages suppress the directed immune mechanisms of cancer and block the recruitment of T cells into the tumor, further promoting cancer progression[ 111 ]. Mice that expressed mutant K-ras gene developed early and advanced forms of the most common pancreatic cancer in humans[ 112 ]. Specific mutations in the K-ras oncogene may be more commonly found in alcohol consumers with pancreatic cancer, and may be initiators or terminators of pancreas cancer associated with heavy alcohol consumption[ 108 ]. Additionally, alcohol might promote the development of cancer by inducing oxidative stress and lipid peroxidation, and alcohol abuse may also accelerate the progression of tumor by boosting pancreatic inflammation[ 112 ].

Two NAD-dependent enzymes, namely, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), are mainly involved in alcohol metabolism in human[ 113 ]. In the body, alcohol is first converted into acetaldehyde by ADH oxidation, and acetaldehyde is then converted into non-toxic acetate by ALDH oxidation for excretion[ 113 ]. In the human liver, there are two kind of ALDHs, including ALDH1 (cytosolic) and ALDH2 (mitochondrial), and only mitochondrial ALDH2 oxidizes acetaldehyde to acetate at physiological concentrations[ 114 ]. The variant ALDH2*2 allele can significantly decrease ALDH2 enzyme activity and affect alcohol response, which is a striking genetic polymorphism[ 113 ].

In many East Asian countries, the ALDH2*2 allele associated with reduced enzyme activity is found in 30%-50% of the population, resulting in the inefficient metabolism of the carcinogenic acetaldehyde generated from alcohol metabolism[ 107 ]. Thus, acetaldehyde accumulates in ALDH2*2 carriers, even after a moderate intake of ethanol (0.5 g/kg)[ 115 ], also leading to a higher risk of developing alcohol-related cancers in individuals carrying the ALDH2*2 allele. Kanda et al [ 116 ] found that the impact of alcohol on pancreatic cancer risk was associated with rapid production or high accumulation of acetaldehyde, indicating that acetaldehyde may play a substantial role in the potential mechanism of pancreatic cancer[ 116 ]. This can also provide guidance and help to prevent pancreatic cancer for people of different groups and races.

Dietary factors

In general, diets high in fruits, vegetables, and other plant-based foods can reduce the risk of developing pancreatic cancer, while dietary patterns rich in meat and animal products can increase the risk of the cancer[ 107 ]. Intake of meat, especially red meat, cooked meat at high temperature, and meat-associated heterocyclic amines, and overall mutagenic activity may induce the development of exocrine pancreatic cancer[ 117 ]. Foods are often heat processed and may contain advanced glycation end products (AGEs) that can be formed by a nonenzymatic reaction between reducing sugars and free amino groups on proteins, peptides, and amino acids[ 118 ]. When the carbonyl group of reducing sugar like glucose or its oxidation or lipid peroxidation products react with the ε-amino group of lysine or the guanidino group of arginine, AGEs can be formed, including imidazolones, pentosidine, pyrraline, and N ε -(carboxymethyl)lysine (CML)[ 118 ]. AGEs accumulate in sera and tissues during the ageing process because of glycolytic and oxidative reactions, reduced activity of the detoxification systems, cigarette smoking, and consumption of high-temperature-processed foods[ 8 ]. Excessively high concentrations of AGEs in human tissue and circulation accelerate oxidative stress and inflammation, which may play a pathogenic role[ 118 ]. Exogenous AGEs, in particular those derived from the diet, have been claimed to contribute to several disease processes, including cancer in general and, specifically PDAC[ 8 ]. CML is frequently used as a marker for AGEs in general[ 119 ]. Jiao et al [ 120 ] proposed a novel mechanism that consumption of heat-treated red meat can cause chronic inflammation and subsequently lead to pancreatic cancer, and considered that consumption of dietary CML-AGE was associated with a modest increase in risk of pancreatic cancer for men, which might partly explain the positive correlation between red meat and pancreatic cancer. A model experiment showed that AGEs markedly accelerated the development of pancreatic cancer and inhibition of AGE prevented the tumor-promoting effect of diabetes[ 8 ]. Therefore, exogenous AGEs from processed/ grilled/baked foods may be involved in the genesis and development of pancreatic cancer.

Many nutrients and phytochemicals in fruits and vegetables have antioxidant, anti-mutagenic, and anti-carcinogenic properties, especially for water-soluble vitamins[ 121 ]. Additionally, isothiocyanates found in cruciferous vegetables powerfully induce the detoxification enzymes, and assist in the removal of potential carcinogens[ 121 ]. Higher intake of fruit and vegetables is associated with a reduced risk of pancreatic cancer[ 122 ], and cruciferous vegetable intake might be inversely associated with pancreatic cancer risk[ 123 ]. A meta-analysis of epidemiological studies showed that high intake of dietary fiber was associated with a risk reduction of pancreatic cancer[ 124 ]. A European Prospective Investigation Into Cancer-Norfolk study showed that high-fiber diet altered a positive correlation between red/processed meats and the PDAC development but not those with lower fiber intake, and fiber intake made few alteration for the PDAC risk in past and current smokers[ 125 ]. This study showed that fiber intake may be beneficial for those with high meat intake, but the findings do not suggest that high fiber intake can protect against the PDAC development[ 125 ]. Therefore, further prospective cohort studies are needed to investigate the effect of fiber intake on the development and progression of pancreatic cancer. A low-fat dietary intervention was associated with a reduced incidence of pancreatic cancer in overweight or obese women in the Women’s Health Initiative Dietary Modification trial[ 126 ]. Therefore, it is of great significance for the prevention of pancreatic cancer by adjusting the diet of pancreatic cancer susceptible population. And it is worth further investigating how both diet and lifestyle may work together to promote or inhibit pancreatic cancer.

Pancreatitis

The majority of burden in exocrine pancreatic disease arises from acute pancreatitis, chronic pancreatitis, and pancreatic cancer[ 127 ]. Acute pancreatitis, an inflammatory disease of exocrine pancreas, is associated with injury and necrosis of tissue[ 128 ]. It has been reported that acute pancreatitis may be an early symptom of pancreatic cancer[ 129 ]. A nationwide matched-cohort study in Denmark showed that patients hospitalized with acute pancreatitis had an increased risk of developing pancreatic cancer compared with age- and gender-matched controls in the general population[ 130 ]. Rijkers et al [ 131 ] found that patients who suffered a first incident of acute pancreatitis and had no further progression to chronic pancreatitis had a 0.4% risk of developing pancreatic cancer, but the risk of pancreatic cancer increased 9-fold for those who progressed to chronic pancreatitis, suggesting that screening for pancreatic cancer after a first incident of acute pancreatitis, especially in patients who had further progression to chronic pancreatitis, could potentially result in more curable resections and improved survival[ 131 ]. The risk of pancreatic cancer increased markedly after an initial diagnosis of acute pancreatitis, regardless of its type, and gradually decreases with passage of time[ 132 ]. An increase in the number of recurrent episodes of acute pancreatitis was associated with an increased risk of developing pancreatic cancer[ 132 ].

Patients who have an episode of acute pancreatitis are 20%-30% more likely to have one or more relapse, and approximately 10% of the relapsing cases progress to chronic pancreatitis[ 133 ]. Chronic pancreatitis is a progressive inflammatory disease, and causes pancreatic parenchyma to be replaced by fibrous tissue, resulting in a loss of acinar and islet cells[ 134 ]. Chronic pancreatitis may cause mild or asymptomatic debilitating pain, attack(s) of acute pancreatitis, endocrine and/or exocrine deficiency, local and/or systemic complications, and pancreatic cancer[ 135 ]. In recent decades, there is accumulating evidence that longstanding pre-existing chronic pancreatitis is a strong risk factor of developing pancreatic cancer[ 25 ]. Low body mass index and pancreatic exocrine insufficiency in patients with chronic pancreatitis define a high-risk population with latent PDAC[ 136 ]. In comparison with the general population, patients with chronic pancreatitis had a significantly increased risk of pancreatic cancer, especially those with an older age at onset and a > 60 pack-year smoking history[ 137 ]. Five years after diagnosis, the risk of pancreatic cancer increased nearly 8-fold in patients with chronic pancreatitis, but the association diminishes with long-term follow-up[ 138 ]. The same risk trend was observed in patients with recurrent acute pancreatitis and chronic pancreatitis, suggesting the need for close follow-up in the first few years after diagnosis of these two types of pancreatitis to avoid neglect of pancreatic cancer. Patients who need surgery to treat chronic pancreatitis have a very high risk of developing pancreatic cancer, and early surgical intervention can play a role in preventing the progression of chronic pancreatitis to pancreatic cancer[ 139 ]. Chronic pancreatitis patients with de novo postoperative diabetes have a high suspicion index of developing pancreatic cancer after surgery[ 139 ].

Patients with early-onset pancreatitis caused by genetic factors appear to have a higher risk of developing pancreatic cancer[ 140 ]. Mutations of susceptibility genes in chronic pancreatitis can determine hereditary pancreatitis, idiopathic chronic pancreatitis, and cystic fibrosis, and Cazacu et al [ 140 ] found that mutations of cystic fibrosis transmembrane conductance regulator ( CFTR ) genes modestly increase the risk of pancreatic cancer in a meta-analysis. A total of 50080 patients were diagnosed with pancreatic cancer, of which 14.8% (7420 cases) were diagnosed with idiopathic pancreatitis prior to the diagnosis of cancer[ 141 ]. After pancreatitis diagnosis, six risk factors significantly associated with pancreatic cancer diagnosis included age between 40 and 90 years, African-American race, male sex, smoking, obesity, and DM, suggesting that it may be warranted to screen patients older than 40 years with unclear etiology of pancreatitis, especially for African-Americans and male population[ 141 ].

The study of the promoting effect of pancreatitis on the development of pancreatic cancer is beneficial to the early detection of pancreatic cancer, and can provide more guidance for the prevention of pancreatic cancer. However, in order to better understand the promoting role of pancreatitis on pancreatic cancer, more studies are needed to clarify the mechanism of pancreatitis in the development of pancreatic cancer.

Obesity has been more and more recognized as a strong but modifiable risk factor for pancreatic cancer[ 142 ]. Relevant studies have confirmed that obesity is associated with an increased incidence of pancreatic cancer and potentially worse outcomes of this cancer[ 142 ]. A cohort study with pooled analysis found that central obesity was associated with increased mortality of pancreatic cancer, independent of body mass index, and also suggested that being overweight or obese during early adulthood may have a significant impact on the mortality risk of pancreatic cancer later in life[ 143 ]. A nationwide study including 1.79 million Israeli adolescents showed that obesity (≥ 95 th percentile) was associated with an increased risk of pancreatic cancer later in life among both men and women compared with normal weight (5 th to- < 85 th percentile)[ 144 ].

There have been two biological mechanisms that were proposed to explain the underlying association between obesity and risk of pancreatic cancer, including inflammation and hormonal misbalance[ 142 ]. Many human cancers result directly from chronic inflammation, and inflammation has emerged to be a key mediator of pancreatic cancer development[ 145 ]. Changes in the fibro-inflammatory microenvironment are the major feature of obesity-associated pancreatic tumors[ 146 ]. Obesity is a pro-inflammatory condition, and both hypertrophied adipocytes and immune cells (primarily lymphocytes and macrophages) residing in adipose tissue contribute to increased circulating levels of pro-inflammatory cytokines like TNF-α, IL-6, leptin, and adiponectin[ 147 ]. The imbalance between these finely regulated pro-inflammatory and anti-inflammatory bioactive molecules leads to changes in tissue microenvironment, which further have influence on cell proliferation, apoptosis, cell invasion, and angiogenesis[ 148 ]. For example, Hertzer et al [ 149 ] reported that conditional KRAS G12D mice with a high fat, high calorie diet exhibited significantly increased inflammation in the peri-pancreatic fat accompanied by elevated levels of several inflammatory cytokines, such as IL6, IL13, and IFN-γ, suggesting that obesity-associated inflammation in peri-pancreatic fat may accelerate pancreatic neoplasia in the model mice[ 149 ].

Obesity is also often associated with insulin resistance and T2DM, along with raised levels of insulin and IGF-1[ 142 ]. Insulin resistance is a hallmark of T2DM, in which insulin fails to trigger adequate glucose uptake, resulting in accumulation of glucose in bloodstream and raised levels of insulin[ 150 ]. Hyperglycemia can enhance the availability of nutrients to cancer cells which metabolize glucose through the Warburg effect[ 151 ]. Islet adaptation enhances hormone production, processing, and secretion in the setting of obesity[ 146 ]. Even moderate overall and abdominal obesity and weight gain during adulthood were independently associated with an increased risk of developing hyperinsulinemia in non-diabetic middle-aged men[ 152 ]. Hyperinsulinemia causes a rise of IGF-1 which activates PI3K/MAPK/mTOR pathways after binding with its receptor, or the IGF receptor[ 148 ]. Overactivation of these pathways can activate the Ras/ERK pathway, leading to an increase in cell division, and IGF-1 activating PI3K/AKT/mTOR pathways promotes proliferation and inhibits apoptosis[ 142 ].

The mutation of oncogenic KRAS is the major event in pancreatic cancer and permanently activates KRAS protein, and then the protein serves on a molecular switch to activate various signaling pathways and transcription factors in cells, inducing cell proliferation, migration, transformation, and survival[ 153 ]. In comparison with lean KC mice, the pancreas of obese KC mice showed an increase in activation of KRAS downstream pathways, including MAPK and PI3K/AKT/ mTORC1[ 154 ]. Chung et al [ 146 ] found that β-cell aberrantly expressed peptide hormone cholecystokinin in response to obesity and showed that islet cholecystokinin promoted oncogenic KRAS-driven tumorigenesis in pancreatic duct.

Helicobacter pylori ( H. pylori ) found mainly in the stomach is a Gram-negative microaerophilic pathogen that chronically infects as much as half the world's population[ 155 ]. H. pylori infection is associated with a variety of malignancies, such as gastric cancer, premalignant lesions of the stomach (atrophic gastritis and intestinal metaplasia), gastric lymphoma, pancreatic cancer, colorectal cancer, and laryngeal cancer[ 156 ]. With an estimated prevalence between 25% and 50% in Westernized countries, H. pylori could result in 4% to 25% of all cases with pancreatic cancer in these countries[ 157 ]. H. pylori infection is closely, albeit weakly, associated with the development of pancreatic cancer, and the association is prominent in Europe and East Asia, but less so in North America[ 158 ]. Cytotoxin-associated antigen A (CagA), a 120-145-kDa protein, was for the first time described as a virulence factor of H. pylori related to peptic ulcers[ 159 ]. A risk of pancreatic cancer increased in individuals with seropositivity for CagA-negative H. pylori , whereas the risk decreased in individuals with seropositivity for CagA-positive H. pylori [ 160 ]. CagA-negative strains of H. pylori might be a causative factor of pancreatic cancer[ 161 ]. Xiao et al [ 158 ] reported that CagA-positive H. pylori strains appear not to be associated with pancreatic cancer.

The net effects of H. pylori colonization in the gastric antrum are paracrine disinhibition of antral G-cell function, hypergastrinemia, and hyperacidity[ 162 ]. The risk of pancreatic cancer is increased by long-term conditions of excess gastric/ duodenal acidity[ 162 ]. Gastric acid drives pancreatic bicarbonate secretion and, a consequence of hyperchlorhydria and suppressed somatostatin increases bicarbonate output from the pancreas in H. pylori carriers[ 162 ]. Low-level, prolonged generating of secretin or pancreatic bicarbonate increases the activity and turnover rate of ductular epithelial cell to sufficiently enhance the carcinogenic effect of environmental or endogenous N-nitroso carcinogens[ 162 ]. Asymptomatic H. pylori colonization, non-ulcer dyspepsia, or duodenal ulcers, and exposure to N-nitroso carcinogens via dietary or other routes in individuals would increase the risk of developing pancreatic cancer by increasing basal secretors or pancreatic bicarbonate[ 162 ]. CagA injected into gastric parietal cells through the interaction of H. pylori with integrin results in the activation of extracellular regulated protein kinases (ERK1/2) to further mobilize NF-κB p50 homodimers into the nucleus, leading to the inhibition of gastric H,K-adenosine triphosphatase (H,K-ATPase) α subunit transcription and the repression of gastric acid secretion[ 163 ]. Seropositivity of CagA-positive H. pylori was shown to protect against pancreatic cancer when compared to CagA-negative H. pylori , suggesting that differential modification of CagA-negative vs CagA-positive strains of H. pylori on chronic gastric acidity may be involved in modulating the risk of pancreatic cancer[ 160 ].

Socioeconomic status and insurance

In contrast with the traditional biomedical model, the bio-psycho-social-medical model highlights the significant role of socioeconomic status in health care services, including insurance status, marital status, and poverty level[ 164 ]. A study suggested that African-Americans, and in some cases Hispanics, had lower rates of surgery, less accessed to aggressive stage specific treatment, and underwent surgery at low volume hospitals and/or by lower volume surgeons, which might contribute to the differences in outcomes[ 165 ]. In addition, underinsured or uninsured patients also tended to receive less aggressive treatment[ 165 ]. A study of a total of 83902 patients with pancreatic cancer showed that patients with lower socioeconomic status were less likely to undergo surgical resection among patients with localized/regional pancreatic cancer[ 166 ]. Among patients with localized/regional pancreatic cancer who underwent surgical resection, patients with higher socioeconomic status have better overall survival, and patients with lower socioeconomic status have worse pancreatic cancer-specific survival compared with patients with higher socioeconomic status[ 166 ]. These findings suggest that racial differences in treatment and outcomes might be attributable to socioeconomic, insurance, and geographic factors[ 165 ]. The study of pancreatic cancer cases from the National Cancer Database from 2004 to 2015 showed that private insurance was associated with more treatment and better survival, higher education was associated with earlier treatment, and treatment was less and delayed among African-Americans despite later diagnosis[ 167 ]. After adjusting for socioeconomic status, African-Americans had about the same rate of survival overall at integrated facilities and the survival was improved, suggesting that higher socioeconomic status was associated with better treatment and survival[ 167 ]. A pan-cancer analysis showed that socioeconomic status was strongly associated with 1-mo postoperative mortality in primary solid tumors, and the risk of dying was high within 1-mo after surgery in socioeconomically disadvantaged people[ 164 ]. And underserved populations around the world often face similar barriers to cancer treatment, largely reflecting inequalities in social factors[ 165 ]. Therefore, socioeconomic status plays an extremely important role in the prevention and prognosis of pancreatic cancer, and the formulation of policies targeting low socioeconomic status patients may improve the low 5-year survival rate of pancreatic cancer.

Over the next 10 years to 20 years, an increase in pancreatic cancer is inevitable. At the same time, in the face of the characteristics of high mortality and difficult early diagnosis of pancreatic cancer, early prevention of pancreatic cancer through understanding the risk factors for pancreatic cancer is an economical and effective means, which is to prevent pancreatic cancer in advance. In view of the non-modifiable factors affecting pancreatic cancer, we may screen the susceptible population to pancreatic cancer, and provide reliable screening strategies and reasonable diagnostic ideas for the early diagnosis of pancreatic cancer. By studying the modifiable risk factors that affect pancreatic cancer, we may provide earlier interventions to prevent pancreatic cancer so that it can be possibly blocked in its early stages of canceration, thus significantly reducing the incidence of pancreatic cancer. Globally, a comprehensive prevention and control strategy for pancreatic cancer should include effective tobacco-control policy, recommendations for healthier lifestyles, and enlarging coverage of screening, education and vaccination programmes to better improve public awareness of the need to take precautions.

ACKNOWLEDGEMENTS

We sincerely thank International Agency for Research on Cancer for granting us permission to use Figure ​ Figure1 1 in this paper.

Conflict-of-interest statement: All the authors of this paper declare that there is no conflict of interest to declare.

Manuscript source: Invited manuscript

Peer-review started: February 8, 2021

First decision: March 6, 2021

Article in press: June 15, 2021

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: China

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P-Reviewer: Sperti C, Takemura N S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Wang LL

Contributor Information

Jian-Xiong Hu, Intensive Care Unit (ICU), Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China.

Cheng-Fei Zhao, School of Pharmacy and Medical Technology, Putian University, Putian 351100, Fujian Province, China. Key Laboratory of Pharmaceutical Analysis and Laboratory Medicine in University of Fujian Province, Putian University, Putian 351100, Fujian Province, China. moc.361@902iefgnehcoahz .

Wen-Biao Chen, Department of Basic Medicine, Quanzhou Medical College, Quanzhou 362011, Fujian Province, China.

Qi-Cai Liu, Department of Reproductive Medicine Centre, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, China.

Qu-Wen Li, Department of Priority Laboratory for Zoonoses Research, Fujian Center for Disease Control and Prevention, Fuzhou 350001, Fujian Province, China.

Yan-Ya Lin, Intensive Care Unit (ICU), Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China.

Feng Gao, Department of Pathology, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, China.

New MD Anderson Research Uncovers Drug Combo That Could Eliminate Pancreatic Cancer Tumors

Researchers at the University of Texas MD Anderson Cancer Center published two studies this week on a new approach that could improve treatment for patients with pancreatic cancer. The preclinical studies showed that combining immunotherapy with a KRAS inhibitor can lead to long-lasting tumor elimination.

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Researchers at the University of Texas MD Anderson Cancer Center published two studies this week on a new approach that could improve treatment for patients with pancreatic cancer — a disease that an estimated 64,050 U.S. adults will be diagnosed with in 2023.

The preclinical studies showed that combining immunotherapy with a KRAS inhibitor can lead to  long-lasting tumor elimination in pancreatic cancer.

A Deep-dive Into Specialty Pharma

A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.

The research explored the functional role of KRAS mutations in pancreatic cancer. KRAS belongs to a family of genes that encode proteins that participate in cell signaling, activating or deactivating to regulate the growth of cells. When KRAS are mutated, they cause the uncontrolled cell growth that occurs in cancer. The oncology community has known “for a while now” that KRAS mutations drive pancreatic cancer, but it has had a hard time figuring out a way to effectively drug these mutated genes, explained Dr. Raghu Kalluri, an author for both studies. 

In the study published in Developmental Cell , the research team tested the functional role of KRAS by generating mouse models with a variety of genetic alterations known to go along with KRAS mutations. By thoroughly examining KRAS’ functional role, the research team gained key insights about how to prepare the tumor microenvironment in advanced pancreatic cancer, Dr. Kalluri pointed out.

The research team then genetically suppressed KRAS in the mice, which led to cancer cell death. In some cases, the number of myeloid cells in the tumor decreased significantly, and in others, the tumor was completely eradicated, Dr. Kalluri said.

In his view, prior models didn’t do a great job of replicating the constantly changing tumor microenvironment found in advanced pancreatic cancer. However, the models generated by his team more accurately reflected the tumor microenvironment present in patients with metastatic pancreatic cancer, and this helped them identify immune activation as a vital element for sustained tumor suppression and elimination, he declared.

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In the study published in Cancer Cell , the researchers tested the effects of a KRAS G12D inhibitor known as MRTX1133 in 16 different lab models. They found that the drug reversed both early- and late-stage tumor growth — but not for good. The tumors grew back after some time, letting the research team know that KRAS G12D inhibition will only be successful in the long term if immune cells are activated.

In other words, KRAS inhibitors do a good job of suppressing pancreatic tumors, but these drugs cannot sustain those effects over a long period of time unless they are combined with various immune checkpoint inhibitors, Dr. Kalluri explained.

These preclinical studies have already led to a Phase I clinical trial at MD Anderson, which is testing the use of MRTX1133 in combination with immune checkpoint inhibitors in patients with pancreatic cancer.

Photo: The National Cancer Institute

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• Published: 04 June 2024

Current and future immunotherapeutic approaches in pancreatic cancer treatment

• Pooya Farhangnia 1 , 2 , 3 , 4 ,
• Hossein Khorramdelazad 5 ,
• Hamid Nickho 2 , 3 &
• Ali-Akbar Delbandi 1 , 2 , 3  

Journal of Hematology & Oncology volume  17 , Article number:  40 ( 2024 ) Cite this article

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Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.

Introduction

Pancreatic cancer comprises mostly pancreatic ductal adenocarcinoma (PDAC), a persistent and recalcitrant disease [ 1 ], and is responsible for an estimated 50,550 deaths in the United States of America in 2023 [ 2 ]. Diagnosis in the early stages of metastasis or late-stage is common since symptoms are often vague. The current approach for treating PDAC is standard cytotoxic chemotherapy, but it only extends overall survival (OS) by a few months [ 3 , 4 , 5 ].

PDAC carcinogenesis like all the solid tumors is mediated by the gradual build-up of driver mutations, such as the oncogene KRAS (G12D mutation) [ 6 , 7 , 8 , 9 ] and the tumor suppressor gene TP53 [ 10 , 11 ]. These molecular modifications are accompanied by corresponding histological alterations during different stages of PDAC development [ 12 ]. The morphological progression initiates with the formation of precursor lesions known as pancreatic intraepithelial neoplasia (PanIN) [ 13 ], which then advance to invasive adenocarcinoma. Changes in the surrounding tissue stroma occur as cancer continues to advance. The non-transformed tissue stroma, composed of components such as immunological, vascular, and connective tissue, plays a vital role in maintaining homeostasis in response to damage. However, cancer exploits these physiological responses to create a favorable tumor microenvironment (TME) for its efficient growth [ 12 , 14 ]. Indeed, cancer resembles "persistent wounds", and alterations in the stroma are the outcome of "abnormal wound healing" [ 15 ].

Immunotherapeutic strategies possess a significant capability in inducing strong immune responses against tumors. Immunomodulators, immune checkpoint blockade (ICB), and adoptive cell transfer therapy could potentially offer hopeful strategies [ 16 , 17 , 18 ]. Remarkable outcomes have been achieved from 2010 to the present through clinical research that utilizes various immunotherapeutic approaches to treat patients with different types of cancer [ 19 , 20 , 21 , 22 ]. The immune responses specifically targeting cancer cells, triggered by immunotherapy, differ from those stimulated by tumor-directed therapies. Furthermore, these responses can endure for a prolonged period even after the treatment is discontinued [ 23 , 24 ]. However, the application of immunotherapy yields insufficient results for the vast majority of PDACs. This is predominantly attributed to the characteristics of its TME, which is deficient in effector T cells that have previously been exposed to antigens [ 25 ].

Tumor immunotherapy has revolutionized the treatment of various solid tumors. Nevertheless, current immunotherapies have had limited success in improving survival for patients with PDAC [ 26 , 27 ]. The immunological resistance of PDAC to immunotherapies can be attributed to its low mutational burden and the hostile TME characterized by fibrosis, hypoxia, and immunosuppression [ 28 , 29 , 30 ]. However, a meta-analysis suggested that targeted immunotherapy is more effective than standard treatments in increasing survival and enhancing immune responses in pancreatic cancer patients [ 31 ]. Moreover, combining chemotherapy and surgery with other immunotherapies may synergistically improve outcomes. Various cytotoxic drugs and adjuvant therapies have been shown to sensitize the TME to immunotherapy by inducing immunogenic cell death, modifying evasive immune processes, and reducing immune suppression [ 32 , 33 ].

Immunotherapy is presently emerging as a focal point in the treatment of pancreatic cancer. This persistent tumor primarily escapes immune detection through various means, including the secretion of immunosuppressive factors like transforming growth factor-beta (TGF-β), the creation of an immunosuppressive environment lacking T lymphocytes, and the expression of immune checkpoints such as programmed death-ligand 1 (PD-L1) and PD-L2 [ 4 , 34 ]. Furthermore, research is being conducted on ICB to activate T-cell function in pancreatic cancer [ 35 , 36 , 37 ]. The pancreatic cancer microenvironment is characterized by extensive desmoplasia, a scarcity of effector T lymphocytes, and an immunophenotype dominated by T helper 2 (TH2) cells, all of which facilitate the evasion of cancer cells from immune surveillance [ 38 , 39 , 40 ]. Consequently, monoclonal antibodies (mAbs) targeting programmed cell death protein 1 (PD-1) and PD-L1 have shown limited efficacy [ 4 ]. Moreover, immunotherapies like PD-1 inhibition may benefit only a small percentage of cancer patients (3%) who have hyper-mutation and microsatellite instability [ 41 ].

This article delves headfirst into a comprehensive analysis of the immunosuppressive microenvironment in pancreatic cancer. In the context of contemporary knowledge and future trends, the article elaborates on a wide range of immunotherapies, such as oncolytic virus therapy (OVT), adoptive cell transfer therapy including T-cell receptor (TCR)-engineered T cells therapy, chimeric antigen receptor (CAR) T-cell therapy, CAR natural killer (NK) cell therapy, and cytokine-induced killer cells. Additionally, it examines immune checkpoint inhibitors (ICIs) and immunomodulators, cancer vaccines, and immunotherapeutic approaches that target myeloid cells. Lastly, the article highlights the effects of the gut microbiome in modulating response to ICIs and the emerging role of CRISPR/Cas9 gene-editing technology in pancreatic cancer immunotherapy. Finally, it discusses the main challenges ahead of pancreatic cancer immunotherapy.

Exploring the tumor microenvironment (TME) of pancreatic cancer

The complicated interaction between tumor cells and their adjacent microenvironment significantly impacts the development of solid tumors. Determining the outcome of cancer, whether it progresses or regresses, heavily relies on the immune environment present in tumors. This environment is made up of various cell types such as adaptive immune cells, macrophages, dendritic cells (DCs), NK cells, and other innate immune cells [ 42 ]. PDAC serves as a prime example of the various types of communication that can occur between tumors and surrounding tissue. PDAC demonstrates strong resistance to new immunotherapies due to the exclusive collaboration between different immune cells, resulting in the creation of a highly immunosuppressive setting that aids tumor advancement [ 12 , 43 , 44 , 45 , 46 ]. The "cold" TME is a distinct feature of a pancreatic tumor wherein a considerable infiltration of myeloid cells is observed, and CD8 + T cells are usually absent, resulting in immunological characteristics [ 47 ]. Given the heterogeneous nature of pancreatic TME, components may have dual, contradicting roles (Table  1 ). In this section, we outline the involvement of immune cells and non-immune cells in the TME of pancreatic cancer and cross-talk between these cells (Figs.  1 and 2 ).

Tumor microenvironment (TME) in pancreatic cancer. ADCC: Antibody-dependent cellular cytotoxicity; APC: Antigen-presenting cell; CAF: Cancer-associated fibroblast; CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; DLL: Delta like canonical notch ligand; ECM: Extracellular matrix; GM-CSF: Granulocyte–macrophage colony-stimulating factor; HGF: Hepatocyte growth factor; IDO: Indoleamine 2,3-dioxygenase; IFNs-I: Type I interferons; IFN-γ: Interferon-gamma; IL-2: Interleukin 2; MDSC: Myeloid-derived suppressor cell; MMP: Matrix metalloproteinase; MQ: Macrophage; MSC: Mesenchymal stromal cell; NK: Natural killer; NO: Nitric oxide; PCSC: Pancreatic cancer stem cell; PDAC: Pancreatic ductal adenocarcinoma; PDGF: Platelet-derived growth factor; PSC: Pancreatic stellate cell; STING: Stimulator of interferon genes; TAM: Tumor-associated macrophage; TAN: Tumor-associated neutrophil; TGF-β: Transforming growth factor beta; Th1: Type 1 T helper; TNF-α: Tumor necrosis factor alpha; Treg: Regulatory T cell; VEGF: Vascular endothelial growth factor

Crosstalk between pancreatic ductal adenocarcinoma (PDAC) cells and key components of tumor microenvironment (TME). Arg1: Arginase 1; BMPs: Bone morphogenetic proteins; Breg: Regulatory B cell; BTK: Bruton's tyrosine kinase; CAFs: Cancer-associated fibroblast; CSF1: Colony stimulating factor 1; CTGF: Connective tissue growth factor; DC: Dendritic cell; FAP: Fibroblast activation protein; HIF: Hypoxia-inducible factor; IDO: Indoleamine 2,3-dioxygenase; iNOS: Inducible nitric oxide synthase; LIF: Leukemia inhibitory factor; M-CSF: Macrophage colony-stimulating factor; MDSC: Myeloid-derived suppressor cell; MHC: Major histocompatibility complex; MSCs: Mesenchymal stem/stromal cells; NK: Natural killer; Pin1: Peptidylpropyl isomerase; ROS: Reactive oxygen species; SPP-1: Osteopontin/secreted phosphoprotein 1; TAM: Tumor-associated macrophage; TAN: Tumor-associated neutrophil; TCR: T cell receptor; TGF-β: Transforming growth factor beta; TIGIT: T cell immunoreceptor with Ig and ITIM domains; TNF: Tumor necrosis factor; Treg: Regulatory T cell; VEGF: Vascular endothelial growth factor

The role of immune cells

The TME comprises various immune cells, each with distinct roles and significance. This section will elucidate the functions of these immune cells within the TME.

Role of T lymphocytes in TME

The immunological diversity among tumors in patients with PDAC is wide-ranging, characterized by varying densities of infiltrating T-cells and the composition of T-cell subpopulations [ 48 , 49 , 50 , 51 ]. The presence of desmoplastic elements might not influence the accumulation of T cells, thus revealing a separate spatial arrangement of T cells in PDAC [ 50 ]. This challenges the idea that the inhibitory environment shaped by fibroblasts and desmoplastic stroma suppresses the infiltration of T cells [ 52 , 53 ]. In pancreatic tumors, the extravasation of T cells is constrained by the desmoplastic stroma [ 54 ], leading to immune exclusion, the induction of immunosuppression, and the inefficacy of anti-cancer therapies [ 55 ].

The presence of more CD8 + cytotoxic T lymphocytes (CTLs) encircling cancerous cells is associated with a boost in the survival rates of patients [ 50 ]. According to the study, in patients who had a better survival, tumor samples exhibited a greater percentage of CD8 + T cells, but a lesser percentage of CD4 + T cells compared to tumor samples from patients with a short survival [ 51 ]. These results highlight the complexity of the immune response in PDAC and raise questions about the role of the TME in shaping immune profiles. Further investigation is needed to fully understand these findings and their implications for future treatments. In the subsequent discourse, we explicate the pivotal contribution of T cells in the TME according to distinct T cell phenotypes.

Cytotoxic T lymphocytes (CTLs)

The principal participants in the battle against cancer cells are the CTLs that produce IFN-γ, TNF, perforin, and granzymes. These CTLs are responsible for generating durable memory cells that grant protection against cancer cells in the times to come. CTLs can recognize and kill tumor cells that express cognate tumor antigens. This specific recognition is achieved through the interaction between the TCR on CTLs and the peptide-major histocompatibility complex (MHC) on the tumor cell surface. Once the recognition occurs, CTLs induce the death of the target cell through apoptosis [ 56 ].

Previous research has demonstrated that the prognosis of individuals diagnosed with pancreatic cancer is influenced by the distribution of CD8 + TILs [ 57 ]. Increased survival in pancreatic cancer is associated with an elevation in the quantity of CD8 + T lymphocytes found within the tumor tissue [ 35 , 50 , 51 ]. Furthermore, in prior investigations involving surgically removed samples from pancreatic cancer cases, it has been observed that the quantity of CD8 + T cells located in the TME exhibited a positive association with the survival rate of patients [ 57 , 58 , 59 , 60 ]. Early mortality related to pancreatic cancer was correlated with the percentage of CD8 + T cells in the peripheral region [ 61 ].

The dysfunction and exhaustion of CD8 + CTLs within tumors is characterized by both a decline in their ability to perform their intended functions and the presence of inhibitory receptors like PD-1, T-cell immunoglobulin and mucin domain 3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3), which hinder their activity. Additionally, there are changes to their gene expression patterns. According to a model studying pancreatic cancer, the signaling of the IL-18 receptor is responsible for regulating the exhaustion of tumor-targeting CD8 + T lymphocytes. This occurs by activating the IL-2/STAT5/mTOR pathway [ 62 ]. Neo-adjuvant chemotherapy exhibits a reduction in the population of CD8 + T cells with functional exhaustion in patients affected by PDAC [ 63 ].

T helper (TH) cells: TH1, TH2, and TH17

Type 1 T helper (TH1) TH1 cells, designated as a subgroup among TH cells, emerge from the activation of naïve CD4 + T cells by antigen-presenting cells (APCs) under the influence of IL-12. TH1 cells strengthen the immune response of type I immune cells by promoting the activation, proliferation, and mobilization of CTLs, M1 macrophages, and NK cells. This immune reaction aids in defending the body against intracellular infections and tumor cells. These cells express the T-box transcription factor TBX21 (T-bet) and are responsible for generating anti-cancer elements such as IFN-γ, IL-2, and TNF-α [ 64 ]. Nonetheless, in the case of PDAC patients, the impact of TH1 cells remains uncertain due to the possibility that IFN-γ could induce pro-tumorigenic consequences [ 65 ]. This is because IFN-γ has the potential to elevate the expression of PD-L1 in cancer cells, thereby hindering the effectiveness of anti-tumor immunity [ 66 ]. Murine models of PDAC demonstrate that TH1 cells play a crucial role in providing defense against tumors, while in human cases, these cells are linked with extended survival [ 67 ].

Microbial dysbiosis and the disruption of epithelial barrier function are considered inducing factors in the neoplastic transformation [ 68 , 69 ]. In this regard, the contribution of the microbiome to the development of pancreatic cancer and drug resistance of PDAC has been recognized [ 70 , 71 ]. Bacterial ablation is associated with immunogenic reprogramming of the TME, promoting TH1 differentiation of CD4 + T cells [ 70 ].

Type 2 T helper (TH2) GATA binding protein 3 (GATA3) is responsible for defining specialized TH2 cells, known for their proficiency in combating helminths and their involvement in allergies and asthma. These differentiated cells secrete interleukin IL-4, IL-5, and IL-13. Interestingly, the differentiation of TH1 cells is hindered by TH2 cells, and vice versa. There has been an association made between the activation of DCs and the induction of TH2 responses, and it is specifically linked to the thymic stromal lymphopoietin (TSLP), which is classified as a cytokine similar to IL-7 [ 64 ]. The prevalence of GATA3 + TH2 cell infiltration surpasses the occurrence of T-bet + TH1 cell infiltration in pancreatic cancer. The development of the disease is associated with a higher ratio of GATA3 + /T-bet + tumor-infiltrating lymphocytes (TILs) [ 72 , 73 ]. IL-4 enhances the growth of pancreatic cancer cells in humans [ 74 ]. Additionally, a worse OS rate is observed in patients suffering from PDAC characterized by a higher concentration of TH2 cytokines in their bloodstream [ 74 ]. Likewise, poor survival is linked with TH2-induced inflammation in individuals suffering from pancreatic cancer [ 75 ]. However, a study reported that the inhibition of pancreas cancer growth occurs when TH2 cells enhance the anti-tumorigenic responses of macrophages and eosinophils [ 76 ].

Given the fact that ligation of Toll-like receptor 4 (TLR4) could potentially heighten inflammation in the pancreas, it can be postulated that the activation of TLR4 may play a pivotal role in the onset of pancreatic cancer. An investigation demonstrated that DCs evoke CD4 + TH2 cells for pancreatic antigens, thereby advancing the transition from pancreatitis to cancer. Moreover, the restraint of MyD88 is accountable for inducing these outcomes [ 77 ].

Type 17 T helper (TH17) The commitment to the TH17 cell lineage begins with the action of TGF-β and IL-6, and this lineage is sustained by IL-23 while being strengthened by the autocrine production of IL-21. The crucial factors RORγt and STAT3 are necessary for the development of TH17 cells and the expression of IL-17 cytokines. TH17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces [ 64 ]. Elevated quantities of TH17 lymphocytes have been observed in multiple types of human malignancies, such as ovarian, pancreatic, kidney, and gastric cancer [ 78 , 79 , 80 ]. According to several investigations, the existence of augmented levels of TH17 cells in tumor tissues or peripheral blood is linked to the progression of cancer [ 81 , 82 ]. The aggressive form of the disease was found to be associated with a significant increase in the quantity of IL-17 produced by CD4 + TILs [ 83 ]. Conversely, alternative studies propose contrasting results and indicate that TH17 cells might possess a strong anti-tumor impact, as they are present in individuals with restricted disease or those who have survived for an extensive period of time [ 84 , 85 ]. Indeed, there is an ongoing debate regarding the involvement of CD4 + TH17 cells in cancer [ 86 ].

IL-17A plays a significant role in PDAC by assisting in the early stages of cancer development [ 87 , 88 ], controlling the characteristics of PDAC cancer stem cells (CSCs) [ 89 ], advancing tumor growth [ 83 , 88 , 90 ], and causing resistance to checkpoint inhibitors through the formation of NETs [ 91 ]. Additionally, recent studies have revealed that IL-17A affects the transcriptome of cancer-associated fibroblasts (CAFs) [ 92 ]. Prominently, the induction of CAFs that are inflammatory is promoted by T cells that produce IL-17A, thus contributing to the progression of PDAC [ 93 ]. The promotion of tumorigenesis is facilitated by the upregulation of B7-H4 through IL-17/IL-17 receptor signaling in the pancreatic epithelium [ 94 ]. These findings accentuate the role of TH17 cells in favor of pancreatic cancer progression.

Contrary to the aforementioned findings, there exist findings demonstrating that TH17 cells act against tumor cells. Enhancing survival in a murine model of pancreatic cancer is observed through the promotion of TH17 cell development within the TME [ 95 ]. All in all, the role of TH17 and IL-17A in pancreatic cancer is not yet fully understood, with evidence suggesting both pro-tumorigenic and anti-tumorigenic effects. Further research is needed to elucidate the mechanisms through which IL-17A influences pancreatic cancer progression and to determine the potential therapeutic implications of targeting IL-17A in this disease.

Regulatory T cells (Tregs)

Tregs express CD4, CD25, and a chief transcription factor, called forkhead box P3 (FOXP3). The prevention of autoimmune disorders, the limitation of chronic inflammatory diseases, and the maintenance of peripheral tolerance all hinge upon Tregs. Furthermore, Tregs play a crucial role in the tumor environment, influencing cancer progression and immune responses [ 96 ]. Tregs can exert their suppressive effects through various mechanisms, whether by direct contact or independently. These mechanisms include: The production of suppressive cytokines such as TGF-β, IL-10, and IL-35. The engagement of inhibitory immune checkpoints and enzymes, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), PD-1, LAG-3, TIM-3, T cell immunoreceptor with Ig and ITIM domains (TIGIT), CD39, CD73, and IDO. The induction of direct cytotoxicity through the release of perforin/granzyme. The disruption of T effector cell activity through metabolic alterations, specifically IL-2 consumption. The initiation of a tolerogenic environment by inducing tolerogenic DCs, which then facilitates T cell exhaustion [ 97 , 98 , 99 ].

In the peripheral blood and TME, individuals suffering from pancreatic cancer exhibit an increased frequency of Tregs [ 100 , 101 ]. Tregs play a part in controlling the immune response as PDAC advances from a premalignant state to a cancerous stage. The presence of elevated Tregs is linked to a more unfavorable prognosis in PDAC [ 102 ]. Tregs possess the ability to restrict the proliferation and immunogenicity of DCs in pancreatic cancer. Additionally, the stimulation of anti-tumor immunity in pancreatic cancer is achieved by diminishing Tregs in a manner that relies on CD8 + -activated T-cells [ 103 ]. Contrariwise, the depletion of Tregs shapes the TME, leading to an acceleration of pancreatic carcinogenesis [ 104 ]. There is an expansion of pro-inflammatory and immunosuppressive Tregs which simultaneously express RORγt and FOXP3 [ 105 ]. The underlying rationale for this dual functionality can be elucidated as follows: the presence of plasticity within the pancreatic cancer microenvironment enables the Tregs to exhibit the characteristic phenotype of TH17 cells.

Role of NK cells in TME

NK cells, which are a distinct type of immune cell found in the innate immune system, are believed to play a role in monitoring and controlling tumor growth and tumor immunosurveillance [ 106 , 107 ]. Both preclinical and clinical studies have demonstrated a link between decreased NK cell activity and an increased susceptibility to cancer as well as a higher chance of cancer spread and metastasis [ 108 , 109 , 110 ]. Researchers have identified several mediators, including indoleamine 2, 3-dioxygenase (IDO), matrix metalloproteinases (MMPs), TGF-β, and IL-10, that contribute to immune suppression in pancreatic cancer, impeding the ability of NK cells to recognize and eliminate tumor cells [ 28 ].

The survival of individuals with PDAC was found to be positively correlated with the relative frequency of NK cells in their blood. However, PDAC-associated NK cells demonstrated lower cytotoxicity compared to those of healthy participants [ 111 ]. Patients with PDAC were observed to have diminished expression of NKG2D, NKp46, and NKp30 on their peripheral NK cells, which was connected to the patient’s stage and histological grade [ 112 ]. Furthermore, the decreased expression of CD96 and CD226 (key regulators of NK cell function) on NK cells was linked to the development of cancer in PDAC patients [ 113 ]. Additionally, the evasion of NK cells in human pancreatic cancer is associated with the expression of Igγ-1 chain C region (IGHG1). Mechanistically, the presence of IGHG1 suppressed the cytotoxic activity of NK cells by inhibiting antibody-dependent cellular cytotoxicity (ADCC) [ 114 ]. Moreover, impaired localization resulting from the absence of CXCR2 and impaired tumor cytotoxicity contributed to NK cell immune evasion in patients with pancreatic cancer [ 115 ]. The function of NK cells is inhibited in the microenvironment of human PDAC by activated pancreatic stellate cells [ 116 ]. In pancreatic cancer, the orchestration of anti-tumor immune responses through CXCL8 (IL-8) by radiotherapy is reliant on NK cells. In xenografted mice, the use of high-dose radiotherapy in conjunction with adoptive NK cell transfer resulted in enhanced tumor control compared to using either treatment alone, indicating that combining NK cells with radiotherapy is a logical approach for cancer therapy [ 117 ]. Inhibiting the protein growth arrest specific 6 (Gas6), which is generated by tumor-associated macrophages (TAMs) and CAFs within the TME of PDAC, reverses the process of epithelial-mesenchymal transition (EMT) and enhances the activation of NK cells [ 118 ].

Role of DCs in TME

DCs, which are crucial for effective anti-tumor T cell responses, are scarce in the pancreatic tumor environment and are usually found at the tumor edges [ 119 ]. An increased presence of type-1 conventional DCs (cDC1s) within the entire tumor area and the tumor stroma was notably linked to improved disease-free survival (DFS). Furthermore, a rise in the number of cDC2s infiltrating the tumor’s epithelial layer was associated with enhanced DFS and OS [ 120 ]. Furthermore, patients with pancreatic cancer have been shown to have lower levels of DCs in their blood [ 121 ]. Interestingly, higher levels of circulating DCs are linked to better survival rates in these patients [ 121 , 122 ]. Additionally, the surgical removal of the pancreatic tumor has been found to enhance the function of blood DCs, suggesting that the tumor itself may influence immune function [ 123 , 124 ].

Cytokines originating from tumors, including TGF-β, IL-10, and IL-6, have been identified as factors that inhibit the survival and growth of DCs [ 125 ]. MDSCs generate nitric oxide (NO) and obstruct the activation of DCs [ 126 ]. In pancreatic tumors, T-cell dysfunction is common, and improving DC-mediated T-cell activation could be key for treatment. Dysfunction of cDC1s in PDACs leads to unresponsiveness to checkpoint immunotherapy. A study of 106 samples from PDAC patients showed decreased levels of circulating cDC2s, which was linked to poor prognosis. Elevated levels of IL-6 in PDAC patients were found to negatively impact DC numbers and differentiation. This suggests that inflammatory cytokines suppress DCs, impairing antitumor immunity [ 127 ].

DCs control T cells via cross-priming (cross-presentation). It is an open question in PDAC whether boosting the cross-priming capacity of DCs can enhance the T cells’ anti-tumor activity and remodel the TME. In the process of cross-priming, foreign antigens are absorbed by APCs, processed, and then displayed on MHC-I. This sequence of events ultimately triggers the activation of CD8 + T-cell responses [ 128 ]. Research has shown that the cross-priming of cDC1 is not only necessary for starting CD8 + T-cell responses as tumors progress, but it also has a pivotal role in the reactivation of tumor-specific CD8 + T cells through immunotherapy, leading to tumor shrinkage [ 129 ]. However, during the development of pancreatic cancer, the maturation of cDC1 is increasingly and universally hindered [ 130 ], impairing cross-presentation machinery. As a first proof of concept, a study tested whether cross-presentation by DCs could activate pancreatic tumor-specific CD8 + T cells in vaccinated pancreatic cancer patients. The process of in vivo cross-priming leads to the activation of mesothelin (MSLN)-specific CD8 + T cells in patients who received a vaccine for allogeneic pancreatic tumors. Also, the vaccine recruits DCs that cross-prime and generate MSLN-specific CD8 + T cells, which are capable of destroying tumor cells expressing MSLN [ 131 ]. All in all, the immunosuppressive pancreatic TME leads to the disruption of the cross-priming ability of DCs. Thus, finding solutions to reinvigorate the DCs to cross-prime tumor antigens paves the way for developing novel therapies that boost the anti-tumor immune response mediated by CD8 + T cells.

Role of macrophages in TME

Monocytes in circulation are drawn towards the TME and transform into macrophages, called TAMs, when exposed to cytokines, chemokines, and various stimuli, including high levels of concentration of hypoxia and lactic acid [ 132 , 133 , 134 ]. Several studies revealed that the CCL2/CCR2 and CXCL17/CXCR8 axes are involved in recruiting monocytes into the site of inflammation and tumor [ 135 , 136 ]. TAMs display diverse polarization states called functional states. A wide range of TAM subpopulations has been discovered and is continuously growing. They are commonly classified as “M1” and “M2” macrophages. M1 macrophages, as typically described, generate pro-inflammatory cytokines with mainly anti-neoplastic impacts, whereas M2 macrophages produce anti-inflammatory signals that potentially accelerate tumor development [ 137 , 138 , 139 , 140 ]. The presence of tissue-resident macrophages in PDAC is a result of their origin from embryonic hematopoiesis, and these macrophages play a crucial role in advancing the progression of tumors [ 141 ].

A range of scientific investigations on various tumor types, including pancreatic cancer, have demonstrated a contrary association between the invasion of TAMs and the prognosis of patients [ 133 , 142 , 143 , 144 ]. Multiple research groups have confirmed that TAMs are responsible for fostering immunosuppression, angiogenesis, and the growth of tumors in mouse models of PDAC. Their mechanism involves the release of growth factors like vascular endothelial growth factor (VEGF), cytokines, and proteases [ 145 , 146 , 147 , 148 , 149 ]. Within the PDAC microenvironment, the presence of granulocyte–macrophage colony-stimulating factor (GM-CSF) and lactate plays a crucial function in the polarization of TAMs, which are molecules discharged from cancer cells in a manner reliant on a mutant KRAS. A study has shown that TAM gene expression and metabolism are adversely affected by GM-CSF, disrupting their regulation through PI3K-AKT pathway signaling [ 150 ]. Collagen turnover in pancreatic cancer causes metabolic reprogramming of TAMs, leading to the promotion of fibrosis and extracellular matrix (ECM) remodeling [ 151 ].

The effectiveness of treatment in PDAC can be significantly reduced by TAMs. TAMs impact the function of cytidine deaminase, which is a critical enzyme in the metabolism of gemcitabine. This, in turn, leads to resistance to gemcitabine-based treatments in animal models of PDAC [ 152 ]. In mice models of PDAC, the suppression of C–C chemokine receptor type 2 (CCR2) promotes T-cell infiltration, enhances the efficacy of radiotherapy and chemotherapy, and diminishes metastasis by preventing the migration of monocytes to the TME [ 153 , 154 , 155 ]. Also, the combination of CCR2 and CXCR2 inhibitors can interrupt the accumulation of CCR2 + TAMs and CXCR2 + tumor-associated neutrophils (TANs) in the TME and enhance the effectiveness of chemotherapy in treating PDAC [ 147 ]. Moreover, the expression of CXCR2 is also reported on TAMs [ 156 , 157 ]. For example, in Pten-null prostate tumors, CXCR2 + TAMs are abundant. Activating CXCR2 shifts these macrophages to an anti-inflammatory state, but blocking CXCR2 with a selective antagonist reprograms them to a pro-inflammatory state [ 156 ]. Also, in pancreatic cancer mouse models, CXCR2 + CD68 + macrophages (M2 phenotype) are recruited to the TME by tumor-derived CXCL8, where they contribute to local immunosuppression, thereby reducing the effectiveness of PD-1 blockade therapy [ 157 ]. Thus, blocking the CXCR2 pathway offers a therapeutic option for enhancing cancer immunotherapy in PDAC. In a study, the tumor burden, M2 macrophage polarization, and migration are reduced, and the response to immunotherapy with anti-PD-1 is enhanced by ladarixin, a CXCR1/2 dual-inhibitor [ 158 ]. In pancreatic cancer models, the reprogramming of TAMs through colony-stimulating factor 1 (CSF1)/colony-stimulating factor 1 receptor (CSF-1R) blockade enhances the response to T-cell checkpoint immunotherapy [ 159 ].

Role of myeloid-derived suppressor cells (MDSCs) in TME

MDSCs, a diverse group of immature myeloid cells, are commonly categorized into two types: monocytic (M-MDSC) and granulocytic (polymorphonuclear [PMN]-MDSC). M-MDSCs closely resemble monocytes in terms of their phenotype and physical characteristics, while PMN-MDSCs are equivalent to neutrophils. MDSCs play a paramount role in cancer progression by promoting immunosuppression, shaping the TME, and facilitating the formation of pre-metastatic niches. Within the microenvironment of human tumors, MDSCs are abundant, and typically, PMN-MDSCs make up more than 80% of all MDSCs associated with tumors [ 160 , 161 ]. Furthermore, in the circulation of the portal vein, the survival and immunoresistance of PDAC circulating tumor cells are supported by influencing the differentiation of MDSCs [ 162 ].

The levels of MDSCs in human PDAC are associated with the stage of cancer [ 143 , 163 , 164 ]. GM-CSF, produced by tumor cells at the early stages of cancer, plays a crucial role in the recruitment and differentiation of MDSCs, as confirmed by studies on genetically modified mice [ 165 , 166 ]. CD73 causes the acceleration of pancreatic cancer pathogenesis by inducing T cell suppression through GM-CSF/MDSC [ 167 ]. Additionally, the receptor for advanced glycation end products (RAGE) facilitates the accumulation of MDSCs and promotes pancreatic carcinogenesis [ 168 ]. High expression levels of Yes-associated protein (YAP) or MDSC-associated genes indicate poor survival in PDAC patients. YAP expression levels are significantly correlated with a gene signature associated with MDSCs in primary human PDAC [ 169 ]. Following the mutation of KRAS, the transcription regulator YAP, as a downstream molecule of the oncogenic KRAS, plays a crucial role in the neoplastic development leading to PDAC [ 170 ]. The interaction between YAP/TAZ (downstream effectors of the Hippo pathway) and TEAD proteins facilitates the cancer-promoting functions of YAP. Thus, small-molecule inhibitors like GNE-7883 and IAG933, which block the interactions between YAP/TAZ and TEAD, can disrupt oncogenic YAP/TAZ signaling in RAS-altered tumors like PDAC [ 171 , 172 ]. Within the PDAC microenvironment, CD200, a regulator of myeloid cell function, is upregulated. Moreover, MDSCs from PDAC patients show increased expression of the CD200 receptor. CD200 expression may regulate the development of MDSCs in the microenvironment of PDAC [ 173 ].

MDSCs control the inhibition of tumor activity in CD4 + and CD8 + T lymphocytes. T-cell activation is repressed by PD-L1, which is upregulated by MDSCs through the PD-L1/PD-1 interaction [ 174 ]. Furthermore, in an interleukin-10 (IL-10)-dependent manner, MDSCs can limit T-cell activity by promoting the growth of immune-suppressive regulatory T cells (Tregs) through the release of TGF-β and interferon-gamma (IFN-γ) [ 175 , 176 ]. MDSCs play a significant role in both primary and acquired resistance to cancer immunotherapy [ 177 ]. In PDAC, reducing MDSCs enhances the accumulation of stimulated CD8 + T lymphocytes within the tumor, leading to cell death in tumor epithelial cells and remodeling of the tumor stroma [ 178 ]. Strategic MDSC targeting has been observed to effectively revitalize cytotoxic anti-tumor responses in PDAC cases. This mechanism induces the repolarization of TAMs and instigates the activation of the inflammasome machinery, thereby leading to the production of IL-18. The subsequent upregulation of IL-18 notably amplifies the functional capabilities of T-cells and NK cells within the TME [ 179 ]. In conclusion, targeting MDSCs presents a promising approach to the treatment of PDAC, and it has shown positive effects in revitalizing cytotoxic anti-tumor responses and enhancing the functional capabilities of T cells and NK cells. Therefore, further research into MDSC targeting could potentially lead to more effective therapeutic strategies for PDAC.

Role of neutrophils in TME

Neutrophils act as the first line of protection in the body against infection and respond to a broad range of pro-inflammatory signals and alarmins, such as cancer cells. These cells possess adaptability or plasticity, allowing them to adjust their actions when faced with different inflammatory triggers [ 180 ]. Because of the inflammatory state of the TME in PDAC, tumor cells secrete pro-inflammatory substances like tumor necrosis factor-alpha (TNF-α) and IL-12, causing the recruitment of neutrophils to the location of the tumor [ 181 ]. Factors secreted by tumor cells can attract neutrophils. Neutrophils can be drawn in by IL-1, CD200, CXCR2 ligands (like CXCL1 [in human and mouse], CXCL2 [in human and mouse], CXCL5 [in human], and CXCL8 [in human]) [ 182 ], GM-CSF (in human), granulocyte colony-stimulating factor (G-CSF; in human and mouse), and various other substances. These factors are released by tumor cells to attract neutrophils [ 182 , 183 , 184 ]. There exists a notable correlation between shortened survival and worse prognosis in patients with PDAC and increased quantities of neutrophils infiltrating the TME [ 60 , 185 ].

The roles of neutrophils in the TME vary depending on their polarization states, either promoting or suppressing cancer growth. TME attracts TANs through the action of cytokines and chemokines. TANs can be categorized based on their activation and cytokine profile, which determines their impact on the growth of tumor cells. N1 TANs exhibit a beneficial effect on tumor suppression either through direct cytotoxicity or indirect means. N2 TANs, on the other hand, promote immunosuppression, tumor expansion, angiogenesis, and metastasis by causing DNA instability and releasing cytokines and chemokines [ 186 ]. Recently, a new type of TANs called T3 neutrophils has been discovered. These T3 neutrophils stimulate angiogenesis, thus improving the ability of pancreatic tumors to survive in low-oxygen and nutrient-deficient environments [ 187 ]. Identifying the plasticity of N1/N2 neutrophils has been deemed a critical prognostic marker, potentially demonstrating TME and immune evasion in PDAC patients [ 188 ]. Neutrophils with anti-tumor properties can directly eliminate tumor cells through the production of reactive oxygen and nitrogen species. Additionally, they have the ability to activate T cells and attract pro-inflammatory M1 macrophages. Conversely, neutrophils that aid tumor development secrete MMP-9, facilitating the growth of new blood vessels and the dissemination of tumor cells. These neutrophils can also hinder the function of NK cells while recruiting anti-inflammatory M2 macrophages and Tregs. Further, suppressor neutrophils, referred to as PMN-MDSCs, as well as other pro-tumoral neutrophils, impede the activity of CD8 + T cells [ 24 , 180 ]. The growth of pancreatic cancer is reduced and the effectiveness of ICB treatment with anti-PD-1 is enhanced through the inhibition of TANs by lorlatinib [ 189 ]. The metastasis of pancreatic cancer is facilitated by neutrophils that infiltrate as a result of chemotherapy. This is achieved through the activation of the Gas6/AXL signaling pathway [ 184 ].

Neutrophils differentiate themselves from other immune cells by producing neutrophil extracellular traps (NETs), consisting of DNA fibers and proteolytic enzymes released to counteract infections [ 190 ]. Nevertheless, recent studies have suggested that NETs might contribute to cancer metastasis. By examining a PDAC mouse model, researchers investigated the effects of DNase I, a NET inhibitor, and observed a reduction in liver metastasis [ 191 ]. In the PDAC milieu, neutrophil recruitment and NETosis are triggered by IL-17 [ 91 ]. The activation of the IL-1β/epidermal growth factor receptor (EGFR)/extracellular-signal-regulated kinase (ERK) pathway is prompted by NETs, resulting in the promotion of migration, invasion, and EMT of pancreatic cancer cells [ 192 ].

Role of B lymphocytes in TME

A study found that a high density of B cells within tertiary lymphoid tissues of human PDAC is associated with longer survival rates, germinal center immune signature, and CD8 + TILs infiltration [ 193 ]. In the TME of PDAC, the predominant B cells are plasma cells and memory B cells, which exhibit high levels of CD27 expression. However, numerous studies have discovered that the upregulation of CXCL13, triggered by IL-1β and type I interferons (IFNs-I), leads to an increased influx of regulatory B cells (Bregs) that perform immunosuppressive activities [ 194 , 195 , 196 ]. Bregs can activate STAT3 signaling within themselves and CD8 + T cells via IL-35. This activation leads to two distinct effects: firstly, the transcriptional regulator BCL-6 experiences an increase in naive B cells, which interferes with the transformation of B cells into plasma cells; secondly, the operational capacity of CTLs is suppressed [ 197 , 198 ]. Recent research discovered that the resistance to the stimulator of interferon genes (STING) agonists in PDAC is attributed to the induction of IL-35 + B cell proliferation. The systemic application of anti-IL-35 and STING agonist (cyclic guanosine monophosphate-adenosine monophosphate [cGAMP]) can work together to suppress the amplification of Bregs and boost the effectiveness of NK cells [ 199 ]. A clinical trial showed that ibrutinib (a Bruton tyrosine kinase inhibitor) plus nab-paclitaxel/gemcitabine did not improve OS or progression-free survival (PFS) for patients with PDAC [ 200 ].

The role of non-immune cells

Within the microenvironment of pancreatic tumors, there exists a variety of non-immune cells. This section delves into a discussion about the most significant among them.

Pancreatic cancer stem cells (PCSCs)

PCSCs are a subset of cancer cells that exhibit stem cell-like characteristics, including the ability to self-renew and initiate tumorigenesis. They are believed to contribute to the initiation, metastasis, and recurrence of PDAC, and are also responsible for resistance to chemotherapy and radiation. PCSCs express several markers, including CD133, CD24, CD44, microtubule-associated doublecortin-like kinase 1 (DCLK1), CXCR4, epithelial-specific antigen (ESA), OCT4, nestin, and ABCB1 [ 201 , 202 ]. In PDAC, stem cells display unusual activation of multiple signaling pathways that are generally active in embryonic growth. This irregular signaling via mechanisms such as Hedgehog, Wnt, Notch, JAK-STAT, Nodal/Activin, and Hippo enables PCSCs to preserve their self-renewal ability, develop resistance to chemotherapy and radiation, enhance their capacity to induce tumors, and spread to other parts of the body [ 202 ]. A specific subpopulation of CSCs, identified by CD133 and CXCR4 markers, is crucial for tumor metastasis in human pancreatic cancer. Depleting this subpopulation can significantly reduce metastasis. Modulating the CXCL12/CXCR4 axis could be a potential strategy to inhibit CSC metastasis [ 203 ]. The E2F1/4-pRb/RBL2 axis, which undergoes deregulation following a KRAS mutation, is instrumental in maintaining equilibrium among signaling pathways controlling stem cell-like characteristics of CSCs. This axis governs the production of Wnt ligands, thereby managing the self-renewal, resistance to chemotherapy, and invasive nature of PCSCs, along with the proliferation of fibroblasts [ 204 ]. This axis might be a therapeutic target for eradicating PCSCs.

Mesenchymal stem/stromal cells (MSCs)

MSCs are a heterogeneous group of progenitor cells that transform into tumor-associated mesenchymal stem cells (TA-MSCs) within TME, influencing tumor growth, metastasis, angiogenesis, and treatment responses through the secretion of various factors, and their immunosuppressive properties could be targeted to enhance anti-tumor immunity [ 205 ]. First of all, TA-MSCs can release CCL2, CCl7, and CCL12 to recruit monocytes, macrophages, MDSCs, and neutrophils [ 206 ]. They also produce CXCL9 [ 207 ], CXCL10 [ 207 ], CXCL11 [ 207 ], inducible nitric oxide synthase (iNOS) [ 207 ], and IDO [ 208 ], resulting in the inhibition of effector T cells. Mechanistically, TA-MSCs produce large amounts of pro-metastatic and pro-tumor factors such as neuregulin-1 [ 209 ], VEGF [ 210 ], bone morphogenetic proteins [ 211 ], TGF-β [ 212 ], CCL5 [ 213 ], CXCL10 [ 214 ], CXCL12 [ 215 ], CD81-positive exosomes [ 216 ], and MMPs [ 217 ]. Also, they can adjust tumor cell’s response to chemotherapy by generating factors like polyunsaturated fatty acids [ 218 ], PDGF [ 219 ], hepatocyte growth factor [ 220 ], NO [ 221 ], and exosomes carrying these factors and microRNAs [ 222 , 223 ]. In patients with pancreatic cancer, the presence of MSCs in the peripheral blood is notable as they are thought to migrate to the tumor mass [ 224 ]. Evidence suggests that a significant portion of CAFs may originate from MSCs, which can differentiate and express CAF markers, such as vimentin and FAP when exposed to conditioned media from various human cancer cell cultures like pancreatic cancer [ 225 ]. In a pancreatic cancer tumor model, VEGF is secreted by bone marrow mesenchymal stem cells (BM-MSCs) that are co-injected with tumor cells, which aids in the promotion of tumor angiogenesis [ 210 ]. TA-MSCs can produce NO, which induces resistance to etoposide in pancreatic tumor cells and forms a positive feedback loop with IL-1β, contributing to chemotherapy resistance [ 221 ].

Cancer-associated fibroblasts (CAFs)

CAFs are a hodgepodge and heterogeneous group of stromal cells that produce ECM proteins. These cells, typically spindle-shaped, express activated fibroblast markers like fibroblast activation protein (FAP) and α-smooth muscle actin. They are associated with various tumor-promoting activities, including tumorigenesis, angiogenesis, immunosuppression, and metastasis [ 226 , 227 ]. CAFs in PDAC can originate from diverse cells like adipocytes, pericytes, bone marrow-derived macrophages, endothelial/epithelial cells, mesothelial cells, MSCs, resident tissue fibroblasts, and pancreatic stellate cells (PSCs) [ 228 ]. In PDAC stroma, CAFs interact with cancer cells through both direct cell-to-cell and paracrine mechanisms. CAFs are heterogeneous and include three subtypes: myofibroblastic, inflammatory, and antigen-presenting. Myofibroblastic CAFs are induced by cancer cells through TGF-β, and they create a mechanical barrier that can both promote and inhibit tumor growth. Inflammatory CAFs, located away from the tumor cells, are reprogrammed by IL-1 to generate cytokines and chemokines (like IL-6), which further stimulate cancer growth. Lastly, antigen-presenting CAFs express MHC class II molecules and modulate the immune cells in the stroma. These diverse interactions contribute to the complex dynamics of the PDAC stroma [ 12 ]. In the pancreatic environment, CAFs play a significant role in creating an immune-suppressive milieu by releasing substances like prostaglandin E2 (PGE2), IL-1, IL-6, CXCL2, CXCL12, and CXCL8 [ 35 , 229 , 230 , 231 ]. Not only do these fibroblasts attract and control immune-suppressing cells, but they also hinder the anti-cancer activities of CD8 + T cells by increasing the expression of inhibitory immune checkpoints [ 230 ]. Recently, a study identified three distinct metastasis-associated fibroblasts (MAFs) populations, with the generation of pro-metastatic myofibroblastic-MAFs (myMAFs) being critically dependent on macrophages. These myMAFs are induced through a STAT3-dependent mechanism and in turn promote an immunosuppressive macrophage phenotype, inhibiting cytotoxic T-cell functions. Blocking STAT3 pharmacologically or depleting it in myMAFs restores an anti-tumor immune response and reduces metastasis, providing potential targets to inhibit PDAC liver metastasis [ 232 ].

Pancreatic stellate cells (PSCs)

Approximately 7% of pancreatic cells are made up of PSCs, which are located in both the exocrine and endocrine regions of the pancreatic tissue. The interaction between PSCs and pancreatic cancer cells promotes tumor progression. Mechanistically, PSCs release several growth factors/mediators (such as insulin-like growth factor 1 [IGF-1], basal fibroblast growth factor [bFGF], platelet-derived growth factor [PDGF], stromal cell-derived factor 1 [SDF-1], and ECM proteins) and MMPs, which provoke the proliferation, migration, and invasion of pancreatic tumor cells. In response, pancreatic cancer cells produce TGF-β1, PDGF, and VEGF, which in turn stimulate PSCs to increase the migration and proliferation of CAFs and the production of ECM [ 233 , 234 ]. Indeed, a key characteristic of PDAC is a desmoplastic reaction, seen in both primary and metastatic tumors. This reaction is caused by the activation of PSCs, by cancer cells, leading to fibrosis around the tumor [ 235 , 236 ]. This fibrosis (also known as desmoplasia) forms a mechanical barrier around the tumor cells, hindering proper vascularization, limiting the effectiveness of chemotherapy, and resulting in poor immune cell infiltration [ 237 ]. PSCs serve as a significant source of MMP-2 and they hasten the advancement of the tumor in a murine xenograft model [ 238 ]. Also, TGF-β1 secreted by PSCs promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation [ 239 ]. Overall, PSCs are linked to ECM production and remodeling, intra-tumoral hypoxia, resistance/barrier to chemotherapy, proliferation, invasion, migration, reduced apoptosis, angiogenesis, immune suppression, and pain factors [ 234 ].

Endothelial cells

PDAC often has abnormal blood and lymphatic vessels, leading to a hostile microenvironment characterized by high acidity, hypoxia, aberrant metabolism, and immune evasion. In response, tumors stimulate angiogenesis, promoting tumor growth and metastasis [ 46 , 240 ]. Studies reveal that high expression of the endothelial cell marker CD31 and genes involved in vascular stability correlate with better prognosis and improved survival in PDAC [ 241 , 242 ]. This suggests that a subset of patients with highly vascular PDAC may benefit from antiangiogenic therapies [ 242 ].

Inadequate vasculature in tumors restricts nutrient, oxygen, and leukocyte delivery, leading to hypoxia in PDAC. Hypoxia-inducible factor 1α (HIF-1α) is stabilized in poorly vascularized PDAC tumors [ 243 ], activating genes crucial for metabolism, angiogenesis, cell survival, and inflammation [ 244 ]. Elevated HIF-1α levels are linked to poor prognosis in many cancers [ 244 ]. However, in PDAC, HIF-1α deletion accelerates tumor growth, facilitated by infiltrating B cells, demonstrating PDAC’s resilience and complex redundancies that support disease progression [ 245 ].

Lymphatics, in addition to blood vessels, play a crucial role in the progression of PDAC. They serve as a major pathway for leukocytes to transport tumor antigens to lymph nodes and for cancer cells to spread, often resulting in worse survival outcomes [ 46 , 246 , 247 ]. Chemokines play a role in lymphangiogenesis and cell migration, with lymphatic endothelial cells secreting CCL21 to attract DCs and tumor cells expressing CCR7 potentially using this mechanism for dissemination [ 248 ]. Likewise, CXCL12 produced in lymph nodes may attract cancer cells or leukocytes expressing CXCR4 [ 249 ].

Immunotherapeutic approaches in pancreatic cancer treatment

Pancreatic cancer is classified as non-immunogenic and immunologically cold since it does not effectively react to commonly employed ICIs such as anti-PD-1 and anti-CTLA-4. This resistance is partly caused by the immunosuppressive circumstances within the TME. In other words, although ICB has achieved explosive success, PDAC has shown limited response to ICB treatment alone. Research on using ICB alone or in combination with anti-PD-1 and anti-CTLA-4 antibodies has yielded overall response rates (ORRs) of 0% and 3%, respectively [ 250 ]. In this part, we will delineate immunotherapeutic strategies such as OVT, adoptive cell transfer therapy, ICB, cancer vaccine, and immunotherapies targeting myeloid cells (Fig.  3 ).

Immunotherapeutic strategies in pancreatic cancer treatment. The immune response to pancreatic ductal adenocarcinoma (PDAC) is guided by antigen-presenting machinery involving dendritic cells (DCs), inflammatory macrophages, and CD4 + helper T cells, leading to the activation of CD8 + cytotoxic T cells to eliminate the cancer. However, regulatory T cells (Tregs) and suppressor cells can inhibit this response, creating an immunosuppressive tumor microenvironment. Various strategies have been suggested to counteract these inhibitory pathways. CAF: Cancer-associated fibroblast; CAR: Chimeric antigen receptor; CSF-1R: Colony-stimulating factor 1 receptor; CTLA4: Cytotoxic T-lymphocyte associated protein 4; DLL: Delta-like ligand; MDSC: Myeloid-derived suppressor cell; MHC: Major histocompatibility complex; MQ: Macrophage; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; TCR: T cell receptor

Oncolytic virus therapy (OVT)

OVT represents an innovative form of immunotherapy where an oncolytic virus, upon infiltrating and lysing a cancerous cell, initiates an immune reaction within the patient by discharging tumor antigens into the circulatory system [ 251 ]. Oncolytic viruses possess desirable qualities and specificity that make them an attractive strategy for treatment. Research is currently underway, exploring and utilizing diverse oncolytic DNA and RNA viruses for the treatment of different cancer forms. Their ability to invade cancer cells is made possible by the genetic composition of these viruses [ 252 ].

Talimogene laherparepvec (T-VEC or OncoVEXGM-CSF), a Herpes simplex virus (HSV), has become the inaugural oncolytic virus approved by the US Food and Drug Administration (FDA) for the treatment of melanoma. The T-VEC virus harbors the genetic integration of the GM-CSF gene. T-VEC exhibited remarkable lytic properties when tested against various tumor cell lines, encompassing pancreatic cancer cells [ 253 , 254 ]. Furthermore, both NV1020 (r7020) and G207, two distinct herpes simplex oncolytic viruses, effectively invade and annihilate human pancreatic cancer cells in vitro and in vivo [ 255 ]. HF10 is a virus that has originated from HSV-1 and has experienced an unexpected mutation. This particular virus has the ability to substantially combat tumors without causing any damage to healthy tissue. The treatment of locally advanced pancreatic cancer involves the secure administration of HF10 through direct injection, alongside erlotinib and gemcitabine [ 256 ]. The anti-tumor response and apoptosis are enhanced in pancreatic cancer when an H-1 oncolytic parvovirus is combined with a hypoxia-inducible factor (HIF)-1α inhibitor, resulting in increased effectiveness [ 257 ].

VCN-01, a type of oncolytic adenovirus, has been specifically designed to reproduce within cancer cells that possess a faulty RB1 pathway. Moreover, it has the ability to generate hyaluronidase, which serves to expedite the spread of the virus within the tumor. Additionally, it facilitates the migration of both chemotherapy medications and immune cells into the tumor. VCN-01 exhibited augmented anti-cancer properties when administered in conjunction with chemotherapy to animals with PDAC. Remarkably, the hyaluronidase produced by VCN-01 effectively obliterated the tumor stroma, thereby bolstering the transport of various therapeutic drugs such as chemotherapy and therapeutic antibodies [ 258 ]. A clinical experiment exhibited that it is feasible to administer VCN-01 through an intravenous route for the treatment of patients suffering from PDAC and this administration method is associated with adverse events (AEs) that can be predicted and controlled. Intravenous VCN-01 has exhibited a positive tolerability profile [ 259 ]. These results establish a helpful bedrock for the future use of OVT in pancreatic cancer immunotherapy. Furthermore, several clinical trials are underway to evaluate the efficacy of various oncolytic virus-oriented therapies in pancreatic cancer. A phase I/II trial demonstrated that the combination of intratumoral injections of LOAd703, an oncolytic adenovirus with transgenes encoding trimerized, membrane-bound (TMZ)-CD40L and 4-1BB ligand, with standard nab-paclitaxel/gemcitabine chemotherapy was both safe and feasible for patients with unresectable or metastatic PDAC. The treatment met the target response rate at the highest dose level, with an ORR of 44% and a disease control rate of 94% (NCT02705196) [ 260 ]. Moreover, a study found that the combination of pelareorep and pembrolizumab showed modest efficacy in unselected patients, with a clinical benefit rate of 42% among the 12 patients. Notably, the treatment led to significant immunological changes, including a decrease in VDAC1 expression in peripheral CD8 + T cells and on-treatment peripheral CD4 + Treg levels in patients who responded to the treatment (NCT03723915) [ 261 ]. The efficacy of talimogene laherparepvec (T-VEC), administered endoscopically, will be assessed in a clinical trial for the treatment of locally advanced or metastatic pancreatic cancer that is refractory to at least one chemotherapy regimen (NCT03086642).

A study demonstrates promising findings for a new technology called ONCOTECH, which combines oncolytic adenoviruses (OAs) with T cells to enhance the delivery of viruses to tumors. The engineered OAs target the immune checkpoint protein PD-L1. In mouse models of PDAC, ONCOTECH displayed a notable increase in OAs within tumor cells, resulting in a significant decrease in PD-L1 expression and better survival rates. In summary, ONCOTECH has the potential to be a successful approach in combining virotherapy and cell therapy for cancer treatment [ 262 ].

Adoptive cell transfer therapy

Adoptive cellular therapy, which is a type of immunotherapy, holds promise for cancer patients. By utilizing the patient's immune cells, such as T cells, this technique endeavors to combat the disease. These immune cells are frequently obtained, replicated, and altered to augment their efficiency in directing their focus on cancer. The progress made by the FDA in granting approval to CAR T-cell therapy for certain blood cancers has greatly propelled this area of medical research. Modified T cells possess the ability to discern tumor cells through their unique molecular features [ 263 ]. In the subsequent discussion, we shall elucidate and analyze these various immunotherapeutic approaches.

Tumor-infiltrating lymphocyte (TIL) therapy

TILs, which are mononuclear cells naturally infiltrating the TME, can also be known as immune cells present at the tumor site. TIL therapy remains a hopeful treatment approach whereby the patient's TILs are utilized following the surgical extraction of the cancerous growth, followed by the cultivation of these cells outside the body and subsequent reinfusion back into the patient [ 264 , 265 , 266 ]. Successful techniques for increasing the production and reactivity of TILs encompass inhibiting the PD-1 receptor, stimulating the CD137 receptor (4-1BB), and augmenting CD8 + T cell levels [ 267 ]. According to a study, it was found that functional expanded TILs from tumors in the pancreas possess the capability to identify antigens associated with pancreatic cancer [ 267 ]. Based on a meta-analysis, the long-term oncological prognosis of patients with PDAC is significantly associated with specific categories of TILs, specifically CD8 + T cells [ 57 ]. At the present moment, two ongoing clinical trials are currently in the process of recruiting participants. These trials will aim to implement TIL therapy on individuals who are affected by metastatic PDAC (NCT03935893 and NCT01174121). The former trial will assess the efficacy of the adoptive transfer of autologous TILs in combination with fludarabine and cyclophosphamide, while the latter trial will investigate the efficacy of young TILs in combination with aldesleukin (a recombinant analog of IL-2), pembrolizumab, cyclophosphamide, and fludarabine. To further explain, the young-TIL approach involves minimal in vitro culturing of TILs and does not select for tumor recognition before they are rapidly expanded and infused into the patients. This method has achieved objective response rates similar to those of used TILs screened for tumor recognition, without introducing any additional toxicities [ 268 ].

Genetically modified T cells therapy

Tcr-engineered t-cell therapy.

The production of TCR-engineered T cells involves modifying T cells outside the body to express TCRs that recognize tumor antigens. TCRs have the capacity to detect peptides displayed by both MHC class I and II [ 269 ]. Investigating the safety and effectiveness of autologous MSLN-specific TCR T cells in patients with stage IV pancreatic cancer is the objective of a phase I clinical trial (NCT04809766). In this trial, autologous MSLN-specific TCR-T Cells were used in combination with bendamustine, cyclophosphamide, and fludarabine. Patients received three infusions of TCR-TMSLN cells every 21 days following leukapheresis. The main focus was on safety and dose-limiting toxicities, but the study also looked at ORR, PFS, and OS. The goal is to achieve a significant ORR of 20% among the 15 participants [ 270 ].

The patient with metastatic PDAC received autologous TCR-engineered T cells as treatment. These modified T cells express two allogeneic human leukocyte antigen (HLA)-C*08:02-restricted KRAS G12D in a clonal manner. Remarkably, the patient's visceral metastasis showed regression, with an overall partial response of 72%. Furthermore, the therapeutic effect persisted for a duration of 6 months. Moreover, after six months of the T-cell transfer, the modified T cells accounted for more than 2% of all circulating T cells in the peripheral circulation [ 271 ].

• CAR T-cell therapy

CAR T cells can be compared to the administration of a living drug to patients. At, the CAR T-cell therapies that are accessible are tailored according to each patient's needs. These therapies are created by gathering T cells from the patient and modifying them in the lab to generate CARs on the cell surface. The specific CARs possess the ability to detect and attach themselves to particular proteins, known as tumor antigens, located on the outer surface of cancer cells. Despite its impressive clinical outcomes in the treatment of specific subgroups of B-cell leukemia or lymphoma, CAR T-cell therapy encounters numerous impediments that impede its widespread application in the treatment of solid tumors and hematological malignancies. Impediments such as life-threatening toxicities, cytokine release syndrome (CRS), inadequate anti-tumor efficacy, antigen escape, and limited trafficking all pose obstacles to the successful implementation of CAR T-cell treatment [ 272 , 273 ]. Tables 2 and 3 provide a comprehensive overview of data regarding CAR T-cell therapy in both preclinical and clinical trial settings.

A crucial obstacle to the effective use of cellular immunotherapy for treating PDAC, specifically CAR T-cell therapy, is the lack of suitable tumor-specific antigens. In their research, Schäfer et al. pinpointed CD318, TSPAN8, and CD66c as potential target molecules for CAR T-cell-based immunotherapy in PDAC, among a pool of 371 antigens [ 274 ]. Highlighted in the subsequent text are the appropriate therapeutic targets for the CAR T-cell therapy of pancreatic cancer (Fig.  4 ).

An overview of chimeric antigen receptor (CAR) T cell therapy concept. CAR T cell therapy is a treatment approach, whereby T cells from an individual are modified in a laboratory setting to possess the ability to identify specific antigens found on cancer cells, leading to their elimination. (1) This process involves removing autologous T cells from the patient's blood. (2) Subsequently, the T cells are manipulated by introducing a gene encoding a specialized receptor, known as a CAR, into their genetic makeup through viral vectors. (3) This genetic alteration results in the expression of the CAR protein on the surface of the patient's T cells, thereby creating CAR T cells. These CAR T cells are then multiplied and expanded in laboratory conditions, producing millions of them. (4) Eventually, these CAR T cells are administered to the patient through intravenous infusion. (5) The CAR T cells attach themselves to the cancer cells by binding to the antigens present on their surface and proceed to eradicate the cancer cells. EGFR: Epidermal growth factor receptor; FAP: Fibroblast activation protein; MSLN: Mesothelin; PDAC: Pancreatic ductal adenocarcinoma; ScFv: Single-chain variable fragment; TAA: Tumor-associated antigen; TSA: Tumor-specific antigen

B7H3 (CD276) B7H3, a molecule found on the surface of cells, acts as an immune checkpoint and hinders the activation of T-cells and the ability of NK cells to kill. The promise of targeting B7H3 for CAR T-cell therapy arises from its high expression in numerous cancer types while being minimally expressed in healthy tissues [ 275 ]. Survival was achieved in mice following treatment with B7H3 CAR T cells, and there were no observed AEs [ 276 ]. The outcome of studies conducted in vitro revealed that these cells exhibited a potent ability to suppress the growth of cancer cells in the pancreas [ 276 , 277 ].

Fibroblast activation protein (FAP) FAP is a type-II transmembrane serine protease expressed almost exclusively on CAFs. In mouse models of solid tumors, the growth of tumors can be effectively suppressed by FAP-expressing stromal cells being targeted by CAR T cells designed specifically for FAP [ 278 , 279 ]. When FAP-specific CAR T cells are administered along with anti-PD-1 treatment, the combination leads to a synergistic reduction in pancreatic tumor growth and significantly elongated survival in mouse models compared to alternative treatment combinations [ 54 ].

Human epidermal growth factor receptor 2 (HER2) HER2, a glycoprotein located on the cell membrane, performs a function in promoting cell division and distinction during various stages, including embryonic and adult periods. HER2 contributes to tumor progression, growth, and spread by obstructing cell death, triggering the formation of new blood vessels, and boosting cell movement [ 275 ]. The expression of the HER2 in pancreatic cancer is controversial [ 280 ]. However, it has been detected in 20–60% of PDACs according to certain research studies [ 281 , 282 ]. Also, HER2 might be a potential target in immunotherapy for a small subset of patients with pancreatic cancer, since a report explains nearly 50% of PDAC cases have a total HER2 expression of 2 + or above [ 283 , 284 ].

The combination treatment of oncolytic adeno-immunotherapy and HER2-specific CAR-T cells shows promising results in eradicating metastatic PDAC. This combinational therapy enhances the migration of CAR-T cells to the tumor site, while also stimulating systemic host immune responses that improve the overall anti-tumor activity [ 285 ]. The clinical effect of anti-HER2 CAR T cells was assessed in a study involving 11 patients, two of whom had metastatic pancreatic cancer. The optimal overall outcome for both patients was disease stability, with a PFS of 5.3 and 8.3 months, respectively [ 286 ]. The potential clinical outcomes of the treatment should be proven in clinical trials with a larger sample size including patients with PDAC.

All in all, in different studies, the expression of HER2 in pancreatic cancer is controversial and varies from high-level expression [ 287 ] to low-level expression [ 288 ], making it a potential target for personalized immunotherapy of PDAC. Thus, it is reasonable that HER2 should not be ignored in such a heterogeneous disease with limited treatment options.

Epidermal growth factor receptor (EGFR) The EGFR protein, which spans across the membrane, has the capability of binding to various proteins from the EGF family that are located outside the cell. Around 90% of patients diagnosed with PDAC exhibit an identifiable amount of EGFR [ 289 ]. For individuals diagnosed with metastatic pancreatic cancer, the safety and effectiveness of the treatment were demonstrated by a median overall survival (mOS) of 4.9 months among the entire group of 14 patients who received anti-EGFR CAR T cells [ 290 ].

Sialic acid-binding immunoglobulin-type lectin (Siglec) Cell-surface proteins known as Siglecs exhibit the ability to attach themselves to sialic acid. These proteins are predominantly present in immune cells, belonging to a specific group within the I-type lectins. Targeting sialic acids on tumor cells can be accomplished through direct means as well. A new advancement comprises the development of CAR T cells based on Siglec-7/9, which specifically target tumor cells that express sialic acid, causing a delay in the growth of tumors within a melanoma model [ 291 ]. According to a study, Siglec-7 and Siglec-9 ligands are specifically expressed by PDAC cells, indicating the potential effectiveness of CAR T cells in combating PDAC [ 292 ]. Furthermore, enhancing the effectiveness of solid tumor cellular immunotherapy is greatly facilitated by the cancer cell desialylation approach that reverses the state of immune evasion. By eliminating the Siglec-5 and Siglec-10 genes, it became possible to make a CAR macrophage that exhibits enhanced anti-cancer activity as a result of blocking the glycoimmune checkpoint [ 293 ].

Carcinoembryonic antigen (CEA) In order to evaluate the efficacy of CEA-specific CAR T cells in combination with recombinant human IL-12 for the treatment of various solid tumors, an experiment was conducted. The findings illustrated that the incorporation of rhIL-12 alongside anti-CEA CAR T cells notably augmented their capacity to suppress the proliferation of pancreatic tumor cells when compared to solely utilizing CEA CAR T-cell treatment [ 294 ]. Regarding the central role of IL-12 in CAR T cells, a study has proven that membrane-bound IL-12 in CAR T cells targeting TAG72 promotes anti-tumor responses against human ovarian cancer xenograft models [ 295 ]. However, there is a need to apply this approach in PDAC that has not been met.

Additionally, CEACAM7 (CGM2), which is a part of the CEA protein family, may serve as a potential target for PDAC and is specifically present exclusively in the colon and the pancreas. The remission of xenograft tumors occurs as a result of the targeted destruction of pancreatic cancer cells expressing the specific antigen by CAR T cells designed to recognize CEACAM7 [ 296 ].

Mesothelin (MSLN) CAR T cells have the ability to be altered in a way that enables them to identify a cell surface antigen called MSLN. This antigen is associated with the invasion of tumors and is present in mesothelial tissues, albeit in small amounts. However, it is highly expressed in PDAC [ 275 ]. A potent anti-MSLN hYP218 CAR T cells possess improved abilities to infiltrate and remain in tumors, enhancing their effectiveness in combating pancreatic cancer in vitro and in vivo [ 297 ]. CAR T cell therapy, which targets both MSLN and CD19 simultaneously, proved to be a safe and well-tolerated approach in treating individuals suffering from metastatic PDAC [ 298 ]. In orthotopic animal models of human pancreatic cancer, it was demonstrated that MSLN-specific CAR T cells are efficient [ 299 ]. Mice with extremely aggressive PDAC experience tumor shrinkage when subjected to a mixture of MSLN-redirected CAR T cells and TNF-α/IL-2-armed oncolytic adenoviruses [ 300 ]. In a phase 1 trial, T cells engineered to express a CAR specific for MSLN were tested in six patients with chemotherapy-refractory metastatic PDAC. The treatment was well tolerated, with no serious toxicities. Disease stabilized in two patients, and one patient showed a significant reduction in tumor metabolic activity, providing evidence of the potential anti-tumor activity of these engineered T cells [ 301 ].

Disialoganglioside (GD2) GD2, present on the external cellular membrane, is integral to the immunological characteristics of mammalian cells; however, it rarely elicits an immune reaction. Due to the prevalence of GD2 in embryonal malignancies such as brain tumors and its infrequent manifestation in healthy cells, it is viable to target GD2 molecules using CAR T cells specific to this molecule [ 275 ].

Natural killer group 2D (NKG2D) The NKG2D receptor shows potential as a target for immunotherapy of malignant neoplasms. CAR T cells specific to NKG2D have been employed in the treatment of patients with hematologic and solid tumors. An evaluation was conducted by researchers to determine the practicality and safety of NKG2D-specific CAR T cells, resulting in the discovery that their capacity to multiply and endure within the body was restricted. Gao and colleagues have successfully suppressed the 4.1R gene in NKG2D-specific CAR T cells, thereby augmenting the efficacy of CAR T cells in combatting pancreatic carcinoma [ 302 ].

Epithelial cell adhesion molecule (EpCAM) EpCAM is a transmembrane glycoprotein of type I that is excessively expressed in various carcinomas, for instance, colon, stomach, PDAC, and endometrial malignancies. Its connection to the Wnt/β-catenin signaling pathway has been observed, which is believed to trigger inadequate infiltration of T-cells in different human malignancies [ 275 ]. A number of clinical trials have been registered to utilize EpCAM-specific CAR T cells in individuals suffering from pancreatic cancer (NCT04151186 and NCT03013712). In these trials, outcomes like toxicity profile, survival time and persistence of CAR T cells in vivo, and anti-tumor efficacy will be measured.

Mucin-1 (MUC-1; CD227) At the apical surface of epithelial cells, the transmembrane mucin glycoprotein MUC-1 shows a high level of expression. In more than 80% of human PDAC, MUC-1 is excessively expressed. This excessive expression of MUC-1 is associated with a grim prognosis and increased metastasis. Moreover, through the upregulation of multidrug resistance genes, MUC-1 boosts chemo-resistance in pancreatic cancer cells [ 303 ]. In xenograft models of pancreatic cancer, there was successful inhibition of tumor growth by anti-MUC-1 CAR T cells, which exhibited effective targeting capabilities and induced cytotoxicity [ 304 ]. To investigate the effectiveness of MUC-1-specific CAR T cells on individuals suffering from pancreatic cancer, two clinical trials have been officially registered under the codes NCT05239143 and NCT04025216. The former clinical trials demonstrated three patients with different types of cancer have been treated with anti-MUC-1 CAR T cells, showing good tolerance and no observed toxicities [ 305 ]. Latter clinical trial showed safety and preliminary efficacy in treating various solid tumors, with no dose-limiting toxicities observed in the six treated patients and preliminary results indicating stable disease in all patients [ 306 ].

CD133 Both hematopoietic cells and epithelial cells exhibit the pentaspan transmembrane glycoprotein CD133. CD133 has been identified not only in pancreatic cancer CSCs but also in different tumors like hepatocellular and gastric carcinomas, emphasizing its widespread presence in malignancies. In 50% of cases involving pancreatic cancer, the expression of CD133 was observed to be significantly high [ 289 ]. CD133-specific CAR T cells were administered to 7 individuals who suffer from PDAC during a phase 1 clinical trial. Before the infusion of CAR T cells, the patients were treated with cyclophosphamide and nab-paclitaxel. The outcomes of the trial exhibited 3 instances of disease stabilization, 2 instances of partial remission, and 2 instances of disease progression [ 307 ].

Prostate stem cell antigen (PSCA) Initially, PSCA was identified as a surface glycoprotein that consists of 123 amino acids and is linked to glycophosphatidylinositol. Its function remained unknown, although it showed significant presence in prostate cancers while exhibiting minimal levels in the prostate epithelium, urinary bladder, kidney, esophagus, stomach, and placenta. Further investigations confirmed its amplified expression in various human cancers, such as pancreatic cancer, while being absent in a healthy pancreas. By employing a humanized mouse model for pancreatic cancer, it was observed that CAR T cells specifically targeting PSCA were able to prompt the eradication of tumors [ 308 ].

CD47 CD47, an immunoglobulin superfamily member, frequently exhibits heightened expression in various hematological and solid cancer tumors. Its crucial function involves the inhibition of phagocytosis, leading to enhanced tumor survival, metastasis, and angiogenesis. CD47 is recognized as a "don’t eat me" since it bonds with signaling regulatory protein alpha (SIRP-α) and obstructs the phagocytosis of cancer cells [ 309 ]. The blocking of pancreatic xenograft tumor growth is efficiently accomplished and cancer cells are effectively killed by CD47-specific CAR-T cells [ 310 ]. A significant challenge in using CD47-CAR-T cells could be the potential detrimental effects on red blood cells and platelets due to the expression of CD47 on these cells. However, in this study, CD47-CAR-T cells were administered intratumorally, which may prevent the induction of toxic effects on other cells. Therefore, the clearing of blood cells during systemic injection of this treatment should be considered as a potential AE.

Claudin18.2 (CLDN18.2) The protein known as CLDN18.2 is an isoform-specific to the stomach of the CLDN18 tight junction protein. This protein is found in high levels in various types of cancer, particularly those affecting the digestive system like pancreatic cancer. Therefore, it could be a promising candidate for cancer treatment strategies [ 311 , 312 , 313 ]. Studies indicated a positive response rate for CT041, which are autologous T cells that have been genetically modified to express a CAR targeting CLDN18.2, in cases of digestive system malignancies [ 311 , 314 , 315 , 316 ]. Two patients with metastatic pancreatic cancer were treated with anti-CLDN18.2 CAR T cell therapy (CT041) after standard treatments failed. Both patients experienced CRS, which was managed with tocilizumab. The first patient showed a partial response with a significant reduction in lung metastasis, while the second patient achieved a complete response. Both cases experienced an increase in CD8 + T cells and Treg cells, a decrease in CD4 + T cells and B cells, an increase in IL-8, and a decrease in TGF-β1. The tumors were well-controlled at the last follow-up [ 312 ].

CAR -NK cell therapy

CAR NK cell therapy is a promising strategy in cancer treatment that seeks to enhance the cancer-fighting power of NK cells. CAR-NK cells are engineered to express CARs that recognize specific antigens in cancer cells, which allows them to target and kill cancer cells more effectively [ 106 , 317 ]. Table 4 provides a comprehensive comparison between CAR T cells and CAR NK cells. Compared to CAR T cells, CAR NK cells possess multiple benefits. Their limited lifespan implies a decreased likelihood of unintended harm to healthy cells (referred to as on-target/off-tumor toxicity). The unique set of cytokines they release signifies a reduced potential for CRS and neurotoxicity. Furthermore, their lower propensity for alloreactivity facilitates the production of off-the-shelf allogeneic CAR NK cells derived from NK cell lines [ 318 ]. However, they may have several negative points, which restrict their broad application in clinical contexts. First of all, difficulties in proper antigen selection, antigen heterogeneity, donor selection, challenges in designing an effective CAR, and difficulties in producing and storing CAR NK cells are fundamental hurdles in this type of treatment modality [ 106 , 319 ]. Secondly, issues such as NK cell infiltration into tumor sites and the short half-life of NK cells must be considered [ 319 ]. This short lifespan can necessitate repeated administrations to achieve a durable response. Furthermore, the need for continuous immune surveillance and prevention of cancer recurrence requires the reprogramming of CAR NK cells with memory cell properties and long-term survival in vivo [ 320 , 321 ]. Lastly, NK cells have several inhibitory killer-cell immunoglobulin-like receptors (KIRs) on their surface, which are cognate with their ligands, HLA molecules. Thus, the universally expressed HLA molecules on nucleated cells can inhibit CAR NK cell function [ 318 ]. Thus, the translation of CAR NK cell therapy from bench to bedside requires addressing the aforementioned challenges properly.

When ROBO1 is targeted, CAR-NK immunotherapy accompanied by radiation therapy proves to be more effective in treating human PDAC in an orthotopic mouse model [ 322 ]. A study demonstrates the effectiveness of a novel human NK cell-based immunotherapy targeting PSCA. It found that these cells effectively suppressed PSCA + pancreatic cancer in vitro and in vivo. The therapy showed promising results without causing systemic toxicity [ 323 ]. Furthermore, the inhibition of tumor growth and enhancement of survival were observed in a mouse model of pancreatic cancer when utilizing a fusion of CAR-NK cells that targeted MSLN, along with cGAMP, an agonist for STING [ 324 ]. There are two clinical trials that have been registered for the implementation of ROBO1 and MUC-1-specific CAR NK cells in the existing clinical scenario of immunotherapeutic methods, specifically for patients diagnosed with pancreatic cancer (NCT03941457 and NCT02839954). Outcome measurements include an examination of the safety profile and ORR.

In the realm of immunotherapy for pancreatic cancer, PSCA has recently gained acclaim as a promising contender. Research findings highlight that CAR-NK cells designed to target PSCA demonstrate notable efficacy in combating advanced PDAC in humans, all while ensuring the absence of any harmful effects at a systemic level [ 323 ]. These positive outcomes provide a rigorous rationale for the future progression of clinical trials.

Induced pluripotent stem cells (iPSCs) provide a convenient supply of lymphocytes for immunotherapy. These NK cells, derived from iPSCs, express essential NK-defining markers such as CD56 and CD16. They demonstrate cytotoxicity through cytokine secretion and ADCC, showing potential for cancer treatment [ 325 , 326 ]. The first-in-class, off-the-shelf iPSC-derived NK cell therapy called FT500 is currently being evaluated in a phase I clinical trial. This trial aims to treat advanced solid tumors, including pancreatic cancer. FT500 is administered both as a monotherapy and in combination with checkpoint inhibitor therapy (nivolumab, pembrolizumab, Atezolizumab), IL-2, cyclophosphamide, and fludarabine (NCT03841110).

Cytokine-induced killer (CIK) cell therapy

CIK cells form a diverse group of CD8 + T cells that were produced from lymphocytes extracted from human peripheral blood and simply expanded ex vivo through incubation with an anti-CD3 antibody, IFN-γ, and IL-2. Through FasL and perforin, they have the ability to eliminate cancer cells. Depending on the existence of the cell surface molecule CD56, CIK cells are additionally categorized into two primary subsets: T cells that are positive for CD3 and CD56, and T cells that are positive for CD3 but negative for CD56 [ 327 ]. Adopting CIK cells and transferring them has proven to be highly effective and safe in cancer treatment, as demonstrated by the increased survival of individuals affected by different types of tumors. When utilized alongside chemotherapy, CIK cell therapy exhibits enhanced efficiency in thwarting cancer relapse and enhancing patients' prognosis [ 24 ].

Researchers have investigated the application of CIK cells as a potential second-line treatment for advanced pancreatic cancer, which has yielded encouraging outcomes in both standalone usage and when combined with other therapeutic methods. In a phase II clinical investigation, the inclusion of CIK cells alongside gemcitabine-refractory advanced pancreatic cancer demonstrated a mOS of 6.2 months among patients [ 328 ]. In advanced pancreatic cancer, gemcitabine-resistant patients who underwent CIK cell therapy in combination with S-1, an oral fluoropyrimidine derivative, demonstrated a mOS of 6.6 months, surpassing the mOS of patients solely treated with S-1 alone (6.1 months) [ 329 ]. Following CIK cell therapy, individuals diagnosed with advanced pancreatic cancer exhibit notable enhancements in the OS [ 330 ].

Immune checkpoint-oriented immunotherapy

Immunotherapy has become a leading pillar of cancer treatment, thanks to the triumph of an effective ICB method, mainly exemplified by the approval of ipilimumab in 2011. By inhibiting specific inhibitory immune checkpoints like CTLA-4, PD-1, and PD-L1, ICB actively halts or reverses the development of acquired peripheral tolerance to cancer antigens, consequently restoring T-cell activation [ 331 ]. Table 5 presents a comprehensive overview of clinical trials investigating the potential of ICIs and immunomodulatory agents in the treatment of pancreatic cancer. In the subsequent discourse, we elucidate the pivotal significance of immune checkpoints in the therapeutic intervention of pancreatic cancer.

Inhibitory immune checkpoints

Pd-1/pd-l1 axis.

The PD-1/PD-L1 axis has been studied in relation to immune checkpoint molecules in pancreatic cancer following the successful use of anti-PD-1/PD-L1 treatment in melanoma. PD-1 is a member of the B7-CD28 protein family and its expression is associated with T-cell exhaustion. PD-1 ligands (PD-L1 and PD-L2) are expressed by tumor cells, MDSCs, TAMs, and tumor-infiltrating DCs. Engagement between PD-1 and PD-L1 leads to T-cell exhaustion by blocking T-cell activation [ 332 , 333 ]. Certain malignancies have demonstrated promising results when treated solely with PD-1/PD-L1 inhibitors [ 334 , 335 ]. PD-L1 inhibitors elicit different reactions in individuals, as evidenced by some PD-L1 positive patients exhibiting unfavorable responses while some PD-L1 negative patients responding favorably. This implies the potential involvement of other PD-1 ligands, like PD-L2, in impacting the efficacy of PD-1 axis immunotherapy in specific cancers. A body of research accentuates the notion that PD-L2 influences the anti-PD-1 axis immunotherapy, particularly in PDAC [ 336 , 337 ]. Chemotherapy-induced senescent cancer cells modify the TME, promoting immunosuppression and pancreatic tumor growth. PD-L2 is highly upregulated in senescent cancer cells, helping them evade the immune system and persist within tumors. Blocking PD-L2 in combination with chemotherapy leads to tumor regression and remission in mice [ 338 ], offering a promising therapeutic strategy targeting senescence-induced vulnerabilities.

Combination immunotherapy targeting PD-L1 and CCL5 has shown benefits in PDAC by decreasing Treg and TAM infiltration, inducing CD8 + T-cell activation, promoting tumor regression, and improving OS [ 339 ]. Tumor regression, improved OS, and the generation of anti-tumor memory cells were achieved by the joint action of anti-tumor necrosis factor receptor 2 (TNFR2) and PD-L1 monoclonal antibodies, by reducing the infiltration of Tregs and TAMs while activating CD8 + T-cells in PDAC microenvironment [ 340 ]. ADH-503, an agonist of CD11b, exerts an agonistic influence on innate immune responses, leading to a reprogramming effect. This reprogramming enhances the response of innate immune responses towards immunotherapies, specifically anti-PD-L1 antagonists and anti-4-1BB agonists, thereby facilitating a more effective therapeutic outcome in the treatment of pancreatic cancer [ 341 ]. A bispecific immunocytokine (PD-1/IL-2 complex) targeting of PD-1 and IL-2Rβγ enhances tumor-antigen-specific T-cell activation while reducing Treg-mediated suppression. The use of this immunocytokine, combined with radiotherapy, attenuates the progression of pancreatic cancer and impedes its metastatic potential [ 342 ].

CTLA-4 (CD152)

CTLA-4 is predominantly found in Tregs and its expression increases when T-cells are activated. CTLA-4 works intrinsically by suppressing the co-stimulatory signal within the cell, inhibiting T-cell activation. It also acts externally by removing CD80 and CD86 from APCs, which reduces the response of effector T cells [ 332 ]. Controlling the pathway of CTLA-4/CD80 regulates the entry of T cells into the microenvironment of pancreatic cancer. By interrupting the interaction between CTLA-4 and CD80, one can induce the infiltration of CD4 + and CD8 + T-cells into the microenvironment of PDAC [ 343 ]. Pancreatic tumors can be regressed by inhibiting both IL-6 and CTLA-4, and this regression occurs through a T cell and CXCR3-dependent mechanism [ 344 ].

Cancer cells utilize the LAG-3 signaling pathway to escape the immune system's detection. Through interaction with Galectin-3, activated T cells experience decreased functionality. Moreover, the activity of plasmacytoid DCs, responsible for initiating the growth of naïve T cells, is hindered by LAG-3. Additionally, LAG-3 has the capacity to regulate T-cell proliferation, reduce memory and effector T-cell immune responses, and heighten immunosuppression through the suppression mediated by Tregs [ 332 ]. Pancreatic cancer patients with TILs that express LAG-3 exhibit lower rates of DFS [ 345 ]. Anti-tumor immunity and enduring response in pancreatic cancer can be achieved by directing attention towards T cell checkpoints 4-1BB and LAG-3, alongside myeloid cell CXCR1/CXCR2 [ 346 ].

The expression of TIGIT occurs on the surface of immune cells and results in the inhibition of T-cell stimulation. By attaching to CD155 and CD112, TIGIT generates signals that suppress the activation of T-cells. Additionally, TIGIT can competitively bind to CD226 or CD96 along with CD155 and CD112 in order to suppress the active signal received by T-cells [ 347 ]. Increased PD-1 and TIGIT expression were evident in intratumoral T cells [ 348 ]. Thus, to optimize the responses of CD8 + T cells against tumors, it is necessary to co-block the TIGIT and PD-1 inhibitory pathways due to their mechanistic convergence [ 349 ]. The co-blockade of PD-1 and TIGIT on tissue-resident memory T cells in PDAC revitalizes them [ 350 ]. In pancreatic cancer, the CD155/TIGIT axis plays a significant role in boosting and sustaining immune evasion [ 351 ]. Combining TIGIT and PD-1 blockade enhances the efficacy of vaccinations in a model of pancreatic cancer [ 352 ]. The reinvigoration of T lymphocytes specific to pancreatic tumor cells occurred as a result of the co-blockade of TIGIT/PD-1 and the stimulation of CD40 agonist [ 351 ]. A research study uncovered that interactions in samples of human PDAC decrease following chemotherapy, specifically between TIGIT on CD8 +  T cells and its receptor on cancer cells. TIGIT was identified as the primary inhibitory checkpoint molecule of CD8 +  T cells, revealing that chemotherapy greatly affects the PDAC TME and potentially enhances resistance to immunotherapy [ 353 ].

V-domain Ig-containing suppressor of T-cell activation (VISTA)

VISTA is an original member of the B7 family checkpoint molecules. It exerts a distinctive influence on cancer immune evasion through its distinct expression patterns and functions. In contrast to checkpoints that mainly control T-cell effector function and exhaustion, VISTA has various roles. It aids in the functioning of MDSCs, governs the activation of NK cells, promotes the survival of Tregs, restricts antigen presentation on APCs, and also maintains T cells in a state of rest [ 354 , 355 , 356 ]. The expression of VISTA is associated with a more favorable prognosis in cases of pancreatic cancer [ 357 ]. Pancreatic cancer exhibits an increased expression of the immunological checkpoint VISTA. It has been shown that the activation of VISTA hinders the production of cytokines by T cells that are obtained from metastatic pancreatic cancers [ 358 ]. Given this, monoclonal antibodies against VISTA could potentially function as a beneficial immunotherapeutic approach for individuals diagnosed with pancreatic cancer [ 357 , 358 ].

CD39/CD73 axis

Extracellular adenosine is a metabolite that suppresses the immune system and affects adversely both innate and adaptive immune responses. It is accumulated through the actions of two ectonucleotidases, CD39 and CD73. Adenosine exerts its immunosuppressive effects by binding to A2A receptors on lymphoid and myeloid cells, as well as A2B receptors on myeloid cells. These A2B receptors are frequently overexpressed in cancer cells and have been found to promote tumor growth, spread, and resistance to chemotherapy [ 359 , 360 ]. In PDAC, the levels of CD73 are notably elevated compared to other types of cancer. This correlation is associated with negative clinical results [ 361 ]. The findings of a study highlight the significant role of CD39 and CD73 in promoting PDAC progression. The expression of these ectonucleotidases was associated with worse survival outcomes in human PDAC samples and disrupted the positive impact of tumor-infiltrating CD8 + T cells. Furthermore, targeting both CD39 and CD73 demonstrated superior anti-tumor activity compared to individual inhibition, emphasizing the potential of these molecules as therapeutic targets in PDAC [ 362 ]. Several anti-CD73/CD39 antibody-oriented clinical trials are underway, which will assess the effectiveness of agents like oleclumab or MEDI9447 (anti-CD73; NCT02503774), TTX-030 (anti-CD39; NCT03884556), and CPI-006 or mupadolimab (anti-CD73; NCT03454451) [ 363 ] alone or in combination with other ICIs. Regarding NCT02503774, the study involved the treatment of 192 patients with oleclumab and durvalumab (anti-PD-L1), with no instances of dose-limiting toxicities during the escalation phase. The most frequently observed side effects were fatigue, diarrhea, and rash. While the escalation phase showed no objective response, the expansion cohorts demonstrated some positive response rates [ 364 ].

Bispecific antibodies (BsAbs)

BsAbs have been engineered to effectively engage two specific antigens at the same time. These specialized antibodies effectively modulate the immune response by redirecting and stimulating immune cells, blocking the co-inhibitory receptors on these cells, activating molecules that enhance the immune response, interfering with specific signaling pathways, and employing a strategy of simultaneously targeting multiple cancer antigens [ 365 ]. BsAbs have been developed for pancreatic cancer treatment, with examples such as anti-EGFR × HER2 [ 366 ], anti-CD3 × CEA [ 367 ], MCLA-128 (anti-HER2 × HER3 BsAb; zenocutuzumab) [ 368 ], anti-CD3 × EGFR BsAb [ 369 ], anti-CD3 (Vγ9TCR) × HER2/Neu [ 370 ], XmAb22841 (anti-LAG-3 × CTLA-4; NCT03849469), XmAb23104 (anti-PD-1 × inducible co-stimulatory molecule [ICOS]) [ 371 ], ATOR-1015 (anti-CTLA-4 × OX40) [ 372 ], and KN046 (anti-CTLA-4 × PD-L1) [ 373 ]. BsAb targeting CD3 and EGFR-armed activated T cells have the ability to target and kill drug-resistant pancreatic cancer cells. Furthermore, the "priming" of these resistant cells with BsAb-armed activated T cells enhances their responsiveness to chemotherapeutic drugs through modulation of ABC transporter expression [ 369 ]. These findings provide insight into the use of BsAbs for immunotherapy against PDAC. A trial tests XmAb23104’s efficacy and safety in treating advanced solid tumors, both alone and with ipilimumab (NCT03752398). The study showed that XmAb23104 was generally well tolerated at doses up to 15 mg/kg in subjects with advanced solid tumors. Clinical activity was observed, including partial responses in three subjects and stable disease for over 12 months in two subjects [ 371 ].

Cancer vaccines

There are several types of cancer vaccines, including whole tumor cell vaccines, DC vaccines, peptide vaccines, DNA vaccines, and mRNA vaccines. While conventional immunotherapies may demonstrate efficacy against cancers featuring identifiable surface antigens specific to tumors, cancer vaccines possess the capability to also encompass a wider range of intracellular antigens for targeting purposes. Up to this point, the FDA has granted approval to a solitary therapeutic vaccine for cancer treatment, namely sipuleucel-T (PROVENGE). This particular vaccine solely enhances patient survival in prostate cancer cases by a mere 4 months [ 374 ].

Vaccination is being examined to activate or enhance pre-existing immune responses using agents like GVAX (pancreatic cell lines modified with GM-CSF) or CRS207 (live attenuated Listeria monocytogenes expressing MSLN), either alone or in combination with a mAb targeting the CD40 molecule to activate APCs [ 41 ]. In this section, we provide an overview of various types of cancer vaccines and underscore the significant studies conducted with these vaccines (Tables 6 , 7 ).

Whole tumor cell vaccines

Utilizing a tumor cell vaccination is a simple and straightforward approach to tumor immunotherapy. The tumor cell vaccination contains both CD4 + helper T-cell and CTL epitopes. Algenpantucel-L (NLG0205) is an example of such a vaccine. Results from a phase II study demonstrated that the combination of Algenpantucel-L with the adjuvants gemcitabine and 5-fluoruracil yielded an 86% survival rate at one year, a 51% survival rate at two years, and a 42% survival rate at three years [ 375 ]. Nevertheless, a study demonstrated that Algenpantucel immunotherapy did not yield advantages for patients suffering from advanced PDAC, despite following the standard of care, neo-adjuvant chemotherapy, and chemoradiation [ 376 ].

To elicit T-cell immune responses against various tumor antigens, scientists manufactured a pancreatic cancer vaccine called GVAX. This particular vaccine, classified as allogeneic, consists of human GM-CSF-secreting whole tumor cells [ 377 , 378 , 379 , 380 ]. A study's findings reveal that neo-adjuvant and adjuvant GVAX, with or without nivolumab (an anti-PD-1 monoclonal antibody) and urelumab (an anti-CD137 agonist), are safe. Furthermore, treating with GVAX alongside nivolumab and urelumab leads to a remarkable increase in tumor-infiltrating activated effector T cells. This combination also demonstrates efficacy by substantially enhancing DFS in comparison to GVAX with or without nivolumab [ 381 ].

DC vaccines

DCs that were isolated from the patient's peripheral blood were loaded with tumor-associated antigens (TAAs) or tumor-derived mRNA. After the administration of these vaccines, the modified DCs proceed to the lymph nodes, where they transmit antigens to T lymphocytes and concurrently induce co-stimulatory signals [ 382 ]. In a study, DCs were gathered from 7 patients who had stage III/IV pancreatic cancer through the employment of apheresis. Afterwards, these collected DCs underwent the process of being pulsed with MUC-1 peptide. The injection of MUC-1-pulsed DCs in these patients exhibited both safety and efficacy, successfully triggering an immune response towards the MUC-1 [ 383 ].

Many pancreatic cancer cells exhibit overexpression of the Wilms’ tumor 1 (WT1). Several studies assessed the effectiveness of using DCs pulsed with WT1 peptides and chemotherapy in treating advanced pancreatic cancer [ 384 , 385 , 386 , 387 , 388 ]. A retrospective multicenter analysis was conducted on 255 patients with pancreatic cancer. These patients were receiving standard chemotherapy and a DC vaccine. This study showed that in patients with pancreatic cancer who received a DC vaccine, a positive erythema reaction at the site of DC vaccine injection was linked to better survival [ 389 ].

The impact of using mesothelioma lysate-loaded DCs in combination with FGK45 (a CD40 agonist) was examined in PDAC mice models. This innovative technique provoked a remarkable alteration in the transcriptome of the tumor, involving the suppressive indicators on CD8 + T cells, and resulted in a considerable improvement in survival [ 390 ]. The administration of lymphokine-activated killer (LAK) cell therapy significantly extended the survival of patients with advanced pancreatic cancer who underwent DC vaccine-based immunotherapy along with gemcitabine. Nevertheless, the use of immunotherapy on its own enhanced the quantity of cancer antigen–targeting CTLs while decreasing the presence of Tregs [ 391 ]. In vivo, the induction of anti-tumor immunity against pancreatic cancer is achieved through DC vaccines that have been pulsed with alpha-galactosylceramide [ 392 ].

Peptide vaccines

The peptide vaccine candidate GV1001 possesses certain noteworthy cell-penetrating peptide characteristics. GV1001 is generated from a peptide derived from a reverse-transcriptase portion of telomerase, or hTERT. In a phase II study, a significant immune response was observed in a majority of patients with advanced pancreatic cancer who received GV1001, and these immune responders had a notably improved median survival compared to non-responders [ 393 ]. However, a subsequent phase III clinical trial combining chemotherapy with the GV1001 vaccine did not yield a significant improvement in OS [ 394 ]. Another peptide cancer vaccine, KIF20A-66, was also examined in a phase I/II trial and found to be well-tolerated. The mOS and median progression-free survival (mPFS) were reported as 142 days and 56 days, respectively [ 395 ]. Recently, the phase 1 study of ELI-002 2P in patients with KRAS-mutated pancreatic cancer demonstrated promising results. ELI-002 2P is a cancer vaccine that specifically targets lymph nodes and consists of three components. These components include modified G12D and G12R mKRAS long peptides, which have been modified with amphiphiles, and an amphiphile-modified TLR9 agonistic CpG-7909 DNA. The therapy was well-tolerated, induced significant T-cell responses, and resulted in biomarker clearance and improved relapse-free survival. These findings suggest that ELI-002 2P has the potential to be an effective treatment option for patients with immunotherapy-recalcitrant KRAS-mutated tumors [ 396 ].

DNA vaccines

Several studies have shown that DNA vaccines targeting TAAs can effectively prolong survival in mice with PDAC. Targeting α-Enolase (ENO1) with a DNA vaccine has been particularly effective [ 397 ]. In addition, combining this DNA vaccine with chemotherapy using gemcitabine has shown improved efficacy against multiple TAAs, including ENO1, glyceraldeheyde-3-phosphate dehydrogenase (G3P), keratin, type II cytoskeletal 8 (K2C8), and far upstream binding protein 1 (FUBP1) [ 398 ]. Another DNA vaccine targeting mucin 1-variable number tandem repeat (MUC1-VNTRn) has demonstrated strong cytotoxic effects in both in vivo and in vitro experiments [ 399 ]. Furthermore, a chimeric DNA vaccine that targets human fibroblast activation protein alpha (FAPα) and survivin has been shown to reduce immunosuppressive cells and increase TILs, thereby creating a more favorable TME for immune responses against pancreatic tumors [ 400 ].

RNA vaccines

Personalized cancer vaccines made of mRNA include mRNA that encodes specific tumor-specific antigens (TSAs) and TAAs. Subsequently, APCs take in the mRNA and exhibit the matching peptide antigens, which prompts immune responses encompassing CTLs and memory T cells. RO7198457, also known as BNT122, represents an mRNA-based cancer vaccine that aims to elicit T-cell-triggered immune reactions against tumor neo-antigens. Various clinical studies are scheduled to be conducted among individuals diagnosed with diverse types of cancer, such as pancreatic cancer (NCT04161755 and NCT05968326), solid tumors (NCT03289962), melanoma (NCT03815058), and colon cancer (NCT04486378). However, many of these trials’ results have not been released yet. Next, the outcomes of the clinical trial NCT04161755 are explained.

An mRNA vaccine called autogene cevumeran was generated using uridine mRNA-lipoplex nanoparticles. After the surgical procedure, a combination therapy that included atezolizumab, the mRNA vaccine (with a maximum of 20 neo-antigens per patient), and chemotherapy was conducted. The results indicated that vaccine-enhanced T cells, which accounted for as much as 10% of the total T cells in the bloodstream, experienced re-expansion through a vaccine booster. These re-expanded cells consisted of durable, polyfunctional CD8 + T cells that targeted pancreatic cancer neo-antigens. After a median follow-up period of 18 months, patients who exhibited vaccine-enhanced T cells demonstrated a significantly prolonged median recurrence-free survival when compared to the control group [ 401 ].

Viral/bacterial vector-based vaccines

These cancer vaccines use modified viruses or bacteria as vectors to deliver genetic code for tumor antigens into human cells. The infected cells then produce tumor antigens, which trigger an immune response in the host. The bacterial vector can be used to treat castration-resistant prostate cancer, and the bacterial-based cancer vaccine has shown promising anti-tumor effects in clinical trials [ 402 ]. One of the widely recognized cancer vaccines of this kind is CRS207, which is a live attenuated strain of Listeria monocytogenes engineered to express MSLN. The utilization of the CRS207 vaccine in individuals diagnosed with metastatic pancreatic cancer has demonstrated promising outcomes in terms of prolonged survival rates while causing minimal detrimental effects to patients [ 41 ]. The utilization of an exogenous immunization antigen, administered via Salmonella bacteria acting as a vector, effectively redirects the attention of CD8 + T cells towards cancer cells within the cytoplasm of tumor cells. Consequently, this approach leads to the complete eradication of pancreatic tumors, the enhancement of anti-tumor immunity, and a significant extension in survival duration, as demonstrated in PDAC mouse models [ 403 ]. Moreover, VEGFR-2, a target for anti-angiogenic intervention, is expressed on tumor vasculature. VXM01, an oral tumor vaccine using attenuated Salmonella with a VEGFR-2 expression plasmid, was tested in a phase I trial with advanced pancreatic cancer patients. The study found that VXM01 was well tolerated, with no dose-limiting toxicities and significant increases in VEGFR2-specific T effector responses. Vaccinated patients showed reduced tumor perfusion and elevated serum biomarkers indicative of anti-angiogenic activity, which correlated with preexisting VEGFR2-specific T-cell levels [ 404 ].

Stem cell-based vaccines

The fact that cancer cells and embryonic tissues have several similar cellular and molecular characteristics suggests that we can potentially utilize iPSCs to stimulate anti-tumor responses within cancer vaccines. Indeed, iPSCs share gene expression profiles with tumor cells. The prevention of tumor growth in murine breast cancer, mesothelioma, and melanoma models is achieved by iPSC vaccines. Acting as an adjuvant, the iPSC vaccine effectively hinders the reoccurrence of melanoma and decreases the spread of tumors [ 405 ]. Research demonstrates that a cancer vaccine derived from iPSCs stimulates a defensive immune response in a PDAC mouse model. Furthermore, this immune response is linked to heightened CD8 + effector and memory T cell reactions against tumor cells, the generation of antibodies specifically targeting cancer cells, and a reduction in immunosuppressive Tregs composed of CD4 + T cells [ 406 ].

Strategies based on targeting myeloid cells and CAFs

In this section, our primary objective is to elucidate the therapeutic potential associated with specifically targeting myeloid cells in the context of pancreatic cancer (Table  8 ).

Targeting macrophages

Therapies that retrain macrophages to engulf and destroy tumor cells may provide a new approach to treating cancer. Antibodies that stimulate the phagocytic program in macrophages were initially found in pancreatic cancer patients treated with anti-CD40 agonistic antibodies [ 407 ]. It was believed that these antibodies only affected macrophages, but further research showed they also improved the function of DCs and T-cell priming [ 408 , 409 ]. However, a phase II trial found that an anti-CD40 antibody called APX005M (sotigalimab) did not improve clinical outcomes in pancreatic cancer patients, suggesting that its mechanism of action may be different in humans [ 410 ]. As mentioned earlier, CD47 is a protein found on cancer cells that prevents them from being engulfed by macrophages. However, blocking CD47 alone does not have a significant effect on some types of solid tumors [ 411 ]. Macrophages can be stimulated to have anti-cancer properties, including engulfing cancer cells expressing CD47, by using a specific molecule, CpG oligodeoxynucleotide (an agonist for the TLR9) [ 412 ]. The utilization of a specific TLR9 ligand known as K3-SPG for in situ vaccination prompts a durable immune response and enhances the effects of both local and systemic immunotherapy in preclinical models [ 413 ], which may be associated with overcoming T-cell exhaustion [ 414 ]. Moreover, signal transduction by the CSF-1R in macrophages could be a useful target for improving the immune response in pancreatic tumors and enhancing the effectiveness of immunotherapy. Blocking the CSF1/CSF-1R pathway eliminates TAMs from tumors and reprograms remaining macrophages to enhance anti-tumor immunity. This blockage improves interferon responses, increases infiltration of CTLs, and prevents tumor growth [ 159 ]. In a trial investigating the safety and immunologic impact of GVAX in combination with cyclophosphamide, pembrolizumab, and IMC-CS4 (a CSF-1R inhibitor), nine patients were enrolled, with two experiencing severe immune-related side effects (diarrhea and rash). The study reported a median DFS of 12.6 months and OS of 20.4 months, with 78% achieving major pathological response post-surgery. The primary immunologic endpoint was met, with 75% of patients showing a significant increase in CD8 + T cells and granzyme B + CD8 + T cells following triple therapy. No significant change in myeloid cell density was observed, suggesting macrophages were reprogrammed rather than depleted (NCT03153410) [ 415 ].

PDAC is a type of cancer that spreads to the liver with the help of macrophages. The process of macrophages engulfing dead cells, known as efferocytosis, promotes liver metastasis by changing the macrophages. A protein called progranulin in macrophages affects their ability to break down cells, leading to a change in the macrophages and an increase in arginase 1 levels. Blocking efferocytosis or reducing progranulin levels can decrease liver metastasis and enhance the function of CD8 + T cells [ 416 ]. Targeting these mechanisms may prevent the spread of PDAC to the liver.

Targeting CAFs

Although previous attempts to target CAFs in PDAC have failed, there is renewed interest in targeting subgroups of fibroblasts or their secreted products. Schwann cells provoke CAFs in the microenvironment of PDAC [ 417 ]. Suppressing stromal TGF-βR2 leads to a decrease in IL-6 production from CAFs, which in turn results in diminished STAT3 activation in tumor cells and a reversal of the immunosuppressive environment [ 418 ]. Also, In vivo neutralization of TGF-β remodels CAF dynamics, reducing myofibroblasts and promoting interferon-responsive fibroblasts. This enhances anti-tumor immunity and the effectiveness of PD-1 immunotherapy [ 419 ].

It is suggested that vitamin D might play a role in inducing a state of rest or inactivity in fibroblasts. A study indicates that the stroma of human pancreatic tumors contains the vitamin D receptor (VDR). Using calcipotriol, a ligand of VDR, as a treatment significantly reduces inflammation and fibrosis in both pancreatitis and tumor stroma. The study demonstrates that VDR plays a crucial role as a transcriptional regulator of PSCs, aiding them to revert to a dormant state. This results in stromal alterations, enhanced intratumoral delivery of the chemotherapy drug gemcitabine, a decrease in tumor size, and a survival rate increase of 57% compared to chemotherapy alone [ 420 ]. In light of this finding, two phase II clinical trials are currently in progress for patients with PDAC. The first trial (NCT03520790) aims to combine paricalcitol with gemcitabine and nab-paclitaxel, while the second trial (NCT02754726) seeks to combine nivolumab with gemcitabine, paclitaxel, and cisplatin. These trials are actively recruiting participants to further investigate the potential benefits of these treatment approaches.

IL-1β has multiple effects on the TME, including promoting the development of CAFs. These CAFs, in turn, produce IL-6, which creates an environment that helps tumors evade the immune system and allows tumor cells to survive for longer [ 231 , 421 ]. Not only immune cells, but PDAC tumor cells themselves can also produce IL-1β. In preclinical studies, blocking IL-1β has shown promising results when combined with blocking PD-1 [ 422 ]. A phase I clinical trial (NCT04581343) evaluated the efficacy of combining gemcitabine and nab-paclitaxel with two antibodies—one that blocks IL-1β (canakinumab) and another that blocks PD-1 (spartalizumab). The most common severe AEs (Grade 3/4) included neutropenia (60%) and anemia (50%), with no fatalities. One patient discontinued spartalizumab due to grade 3 pneumonitis. There were 3 confirmed partial responses, 5 patients with stable disease, and 2 patients with disease progression as their best response (n = 10), and a 1-year OS rate of 60% was reported. Both patients who responded and those who did not showed CD8 + T cell activation in peripheral blood and increased serum levels of IFN-induced chemokines CXCL9/10 [ 423 ].

CAFs have elevated levels of the protein PIN1. PIN1 promotes several cancer-related pathways by affecting the structure of phosphorylated proteins. Blocking PIN1 with drugs has shown promise in treating cancer. Several small molecule drugs, such as all-trans retinoic acid (ATRA), have been identified as PIN1 inhibitors and have been used to study their functions in cancer development [ 424 , 425 ]. Clinical trials have shown positive results when combining ATRA with chemotherapy in patients with advanced pancreatic cancer [ 426 ]. PIN1 inhibition also reduces the formation of fibrous tissue within tumors and increases sensitivity to chemotherapy drugs. In addition, PIN1 inhibition may enhance the effectiveness of immunotherapy [ 425 , 427 ]. Animal models have demonstrated reduced tumor growth when treated with a combination of a PIN1 inhibitor AG17724, an antibody against FAPα, and DNA aptamers that recruit specific immune cells [ 424 ].

Placental growth factor (PlGF) is a protein expressed mainly in the placenta. Blocking PlGF in animal models of intrahepatic cholangiocarcinoma led to improved survival by decreasing desmoplasia and enriching quiescent CAFs [ 428 ]. PlGF also promotes liver fibrosis, tumor angiogenesis, and cancer cell metastasis [ 429 ]. In pancreatic cancer, PlGF is upregulated by chemotherapy, leading to the generation of extracellular matrix by CAFs. Combining atezolizumab (an anti-PD-L1 mAb) with PlGF/VEGF inhibition targeting CD141 + CAFs enhances the efficacy of chemotherapy [ 429 ].

Reprogramming DCs

The restoration of the expression of peptide-MHC complexes and co-stimulatory molecules is achieved through DC reprogramming. This reprogramming enabled the display of tumor antigens originating within the context of MHC-I, ultimately enhancing the targeted elimination by CD8 + CTLs [ 430 ]. Studies in mice have demonstrated that cDCs play a crucial role in initiating immune responses specific to tumors by CD8 + T lymphocytes. However, pancreatic cancer lacks an adequate presence of these cDCs [ 130 , 431 ]. In comparison to lung adenocarcinoma mouse models, models of PDAC displayed a notable scarcity of CD103 + cDCs. Following treatment with FMS-like tyrosine kinase 3 ligand (FLT3L), which augments the number of intratumoral cDCs, mouse models of PDAC showed renewed sensitivity to CD40 agonist antibody and radiation therapy [ 431 ]. Currently, a trial is being conducted to investigate the potential of combining CDX-1140, a CD40 agonist antibody, with FLT3L (CDX-301) in patients with PDAC (NCT03329950).

The activation of DCs can be provoked by the death of tumor cells, and the subsequent ingestion of fragments from these tumor cells also triggers regulatory processes in DCs that hinder their interaction with T cells. By subjecting DCs to microbial products that stimulate TLR signaling, such as pIpC or CpG DNA, which imitate viral nucleic acid, this regulatory function can be bypassed. Hence, innate immune adjuvants are incorporated into vaccination strategies. Additionally, targeted medications that affect the pathways of DNA replication and repair can activate the STING pathway, which subsequently stimulates the production of IFN-I and enhances the activation of DCs [ 432 , 433 ]. As a result, in animal models of pancreatic cancer, the administration of STING agonists boosts inflammation in the surrounding immune environment and reduces tumor load [ 434 ]. Moreover, using Pt IV -MSA-2 conjugates containing cisplatin and a STING agonist is effective against pancreatic cancer, leading to increased immune cell infiltration and activation in tumor tissues [ 435 ].

The enforcement of expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) is adequate to trigger the cDC1 phenotype. By this reprogramming through PIB, cancer cells are transformed into capable APCs, offering an approach to counteract the strategies employed by tumors to evade immune surveillance. These reprogrammed DCs were capable of presenting endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8 + T cells [ 430 ].

Targeting immunosuppressive MDSCs

There is significant synergy between PD-1 blockade and the CD11b agonist as it substantially decreases the accumulation of the majority of myeloid cell types in PDAC mice models [ 436 ]. Furthermore, CD11b agonists like GB1275 cause reprogramming of the innate immune system, leading to an enhanced response of pancreatic cancer to immunotherapies [ 341 ]. Mice that were administered CCR2 inhibitors specifically aimed at circulating monocytes experienced a reduction in the PDAC tumor load [ 153 ]. A study found the ideal dose of the CCR2 inhibitor PF-04136309 to be used alongside chemotherapy in a clinical trial for pancreatic cancer patients. The combination therapy was found to be safe and well-tolerated by the patients. The study also discovered that the inhibitor caused monocytes to accumulate in the bone marrow of patients, leading to a decrease in circulating monocytes and M-MDSCs in the TME. This resulted in significant reductions in the size of the primary tumors [ 437 ]. Nevertheless, the combination of nab-paclitaxel/gemcitabine along with PF-04136309 resulted in notable pulmonary toxicity and failed to demonstrate a favorable indication [ 438 ]. The signaling of CXCR2 is found to be increased in myeloid cells. The absence of CXCR2 leads to a decrease in metastasis and its inhibition extends the period of survival without tumors in mice. Also, the suppression of CXCR2 improves the infiltration of T cells and makes them more responsive to anti-PD-1 therapy [ 439 ].

Gut microbiome in modulating immune checkpoint blockade

Preclinical research on mice with sarcoma, melanoma, and colon cancer revealed that the most effective responses to anti-CTLA-4 and anti-PD-L1 treatments were reliant on the existence of certain species of gut bacteria. This underscores the connection between the gut microbiome and the success of immune checkpoint therapy [ 440 , 441 , 442 , 443 , 444 ]. The connection between certain gut bacteria and the immune response has also been noted in individuals with cancer. These bacteria impact the operation and maturation of immune cells in lymph nodes or within the TME, thus dictating the success of ICB [ 445 ]. Specific gut bacteria have been identified to affect immune responses in cancer. For instance, Bacteroides fragilis can trigger TH1 responses and assist in the development of DCs in tumors, enhancing the effectiveness of anti-CTLA-4 treatment. Bifidobacterium can modify the activation of DCs and amplify the activity of CD8 + T cells that are specific to the tumor. Akkermansia muciniphila can augment the penetration of particular CD4 + T cells into tumors and elevate the proportion of effector to regulatory CCR9 + CXCR3 + CD4 + T cells [ 22 , 440 , 441 , 446 ].

The fact that pancreatic cancer tissues contain a unique microbial fingerprint that aids in acquiring cancer characteristics and influences the long-term survival of patients has now been widely accepted and acknowledged [ 447 , 448 , 449 ]. Pancreatic cancer progression and the effect of particular treatments have been linked to separated alterations observable in the microbiome of the gut and tumor [ 442 , 450 , 451 ]. For instance, a tryptophan metabolite derived from tryptophan by gut microbiota, known as indole-3-acetic acid (3-IAA), is linked to improved responses to treatment. Alterations in diet or the administration of 3-IAA enhanced the effectiveness of chemotherapy in mouse models of PDAC. This effectiveness is associated with myeloperoxidase, which oxidizes 3-IAA, resulting in an increase in ROS and a decrease in autophagy in cancer cells, thereby inhibiting their proliferation [ 452 ]. In another study, the oncogenic mutation KRAS G12D boosts IL-33 production, promoting type 2 immunity in PDAC. The tumor’s mycobiome further increases IL-33 secretion. This IL-33 then recruits and activates TH2 cells and innate lymphoid cells 2 (ILC2s) in the PDAC TME. Remarkably, either deleting IL-33 genetically or administering anti-fungal treatment leads to PDAC tumor regression [ 453 ]. This highlights the crucial roles of IL-33 and the tumor’s mycobiome in PDAC progression and potential treatment strategies.

Multiple studies conducted on murine models of PDAC have demonstrated that eliminating the gut microbiome with antimicrobial agents could potentially amplify the susceptibility of tumors to ICIs and diminish the overall burden of tumors [ 70 , 454 , 455 ]. While the majority of the literature concentrates on the potential employment of microbiota-centered interventions together with chemotherapy and ICB, it emerges as plausible that microbiome modulation may also be employed concurrently with CAR T cells, antibody–drug conjugates, and immunotherapies that are yet to be established [ 456 ]. A multitude of current research and clinical trials are exploring the possibility of modifying the microbiome to boost the efficacy of ICB. It has been demonstrated that fecal microbial transplantation can enhance ICB outcomes and reduce associated AEs in patients [ 457 , 458 , 459 ]. Furthermore, altering the diet is a potential approach to adjust the gut microbiome, and an increasing number of preclinical studies indicate its potential to enhance the response to ICB [ 460 ].

A study suggests that the composition of the tumor microbiome in resected pancreatic adenocarcinoma patients plays a significant role in long-term survival. The higher alpha-diversity in the tumor microbiome of long-term survivors and the identified microbiome signature predictive of long-term survivorship highlight the importance of the tumor microbiota in influencing the natural history of the disease. Furthermore, the findings from fecal microbiota transplantation experiments demonstrate the ability to modulate the tumor microbiome and affect tumor growth and immune infiltration, indicating the potential for targeted interventions to improve patient outcomes [ 459 ]. Moreover, in individuals with pancreatic cancers, a higher presence of Megasphaera within the tumor has been linked to improved survival rates following anti-PD-1 therapy [ 461 ]. Additionally, bacterial elimination in PDAC leads to immune changes, reducing MDSCs, promoting CD8 + T-cell activation, and increasing differentiation of TH1 cells and M1 macrophages. This also enhances immunotherapy effectiveness by increasing PD-1 expression. The PDAC microbiome induces TLRs driven-T cell anergy, suggesting the microbiome’s role in immune suppression and its potential as a therapeutic target [ 70 ].

All in all, the association of pancreatic cancer with gut and tumor microbiome in the context of cancer immunotherapy is an interesting research area in treatment, prognosis, and predicting response to immunotherapy. Approaches like modulating the gut microbiome, fecal microbial transplantation, and dietary regimen-oriented interventions might improve the clinical outcome in patients undergoing cancer immunotherapy.

CRISPR/Cas9 and pancreatic cancer immunotherapy

CRISPR/Cas9, a precise gene editing tool, is revolutionizing cancer research and treatment. The combination of CRISPR/Cas9 and cancer immunotherapy may further broaden the application of immunotherapy to more cancer patients, and ongoing clinical trials are using the CRISPR/Cas9 system in immune cells to modify genomes in a target-specific manner. The CRISPR/Cas9 system's ability to create site-specific, highly efficient gene knockout makes it a desirable tool to address long-standing challenges in cancer treatment, such as T cell exhaustion and TME immunosuppression [ 462 , 463 ]. In the context of pancreatic cancer, there are numerous studies utilizing CRISPR/Cas9 for gene knockout (Fig.  5 ) [ 464 , 465 , 466 , 467 , 468 ]. The utilization of CRISPR/Cas9 methodology to disrupt the CD73 gene in both human and murine cellular models of pancreatic cancer demonstrated that CD73 inactivation impeded cellular proliferation and motility, leading to a halt in the G1 phase of the cell cycle. Additionally, it was observed that deletion of CD73 hindered the ERK/STAT3 signaling pathway while stimulating the E-cadherin pathway [ 469 ]. A study found that mesenchymal-like pancreatic cancer cells are more resistant to immune cell-mediated killing than the parental epithelial-like cells. In this study, the researchers used CRISPR-Cas9 knockout screens to identify the genes involved in this resistance. They discovered several mesenchymal-specific regulators, such as Egfr and Mfge8, that were responsible for inhibiting immune cell function [ 470 ]. The application of CRISPR/Cas9 technology to introduce targeted BRCA1/2 mutations enables the reinstatement of olaparib responsiveness in pancreatic cancer cells [ 471 ]. Apart from potential challenges and limitations of CRISPR/Cas9 such as off-target toxicity, Cas9-related immunogenicity, and off-target mutations, these studies highlight the useful application of this genome editing tool in the context of pancreatic cancer immunotherapy.

The emerging role of genome editing technology CRISPR/Cas9 in pancreatic cancer treatment. Utilizing CRISPR/Cas9 technology, autologous T cells are genetically modified to eliminate or alter genes that contribute to T cell exhaustion or resistance to immunotherapy. Once modified, these cells are reinfused into the patient, effectively improving the eradication of pancreatic ductal adenocarcinoma (PDAC) cells. TAA: Tumor-associated antigen; TCR: T cell receptor; TSA: Tumor-specific antigen

Potential strategies improving efficacy of pancreatic cancer immunotherapies

Combination therapy.

Pancreatic cancer presents a range of mechanisms that resist immunotherapy. Therapies that target only one mechanism have not yielded successful results. The research proposes the optimization of the benefits of current agents through logical combinations. The suggested approach for advanced immunotherapy for PDAC involves combinations that amplify immune activation, inhibit immune checkpoints, improve the TME, and are compatible with conventional cytotoxic therapy [ 472 , 473 ]. There are a plethora of combination therapies for cancer immunotherapy of PDAC (Tables 5 , 7 , 8 , 9 ). For example, BMS-687681, which acts as a dual antagonist for CCR2/5, was used in conjunction with anti-PD-1 and radiotherapy. The results indicated an increase in the infiltration of intratumoral effector and memory T cells, while simultaneously observing a decrease in the infiltration of Tregs, M2 TAMs, and MDSCs [ 474 ]. Overall, combination therapies could improve the efficacy of immunotherapies due to providing a potential for synergistic effects.

Costimulatory molecule agonists

CD40 activation and using CD40 agonists are a novel clinical opportunity for cancer immunotherapy [ 407 , 475 , 476 , 477 , 478 ]. There are several agonistic anti-CD40 antibodies, such as SGN-40, SEA-CD40, selicrelumab, APX005M, CDX-1140, and ADC1013, applicable in clinical trials [ 477 ]. In a phase I clinical trial, the combination of an agonistic anti-CD40 antibody and gemcitabine for treating PDAC was tested. The treatment showed only a slight effect, but its safety was confirmed [ 479 ]. The combination of the CD40 agonist and gemcitabine could potentially overcome resistance to anti-PD-1/CTLA-4 therapy by increasing the accumulation of CD8 + T cells that fight against tumors in PDAC [ 480 ]. A study found that selicrelumab (an agonist CD40 antibody) significantly altered the TME in PDAC patients. Selicrelumab-treated tumors were enriched with T cells (82%) compared to untreated (37%) and chemotherapy/chemoradiation-treated tumors (23%). Additionally, selicrelumab reduced tumor fibrosis, decreased M2-like tumor-associated macrophages, and matured intratumoral DCs. The treatment had an acceptable toxicity profile and resulted in an overall survival of 23.4 months [ 475 ]. Moreover, a study demonstrates that using a nanofluidic drug-eluting seed (NDES) for sustained, low-dose intratumoral delivery of CD40 monoclonal antibody can alter the TME and reduce tumor size in mouse models of PDAC [ 478 ]. These findings elucidate the therapeutic mechanisms of CD40 targeting and modification of the TME in pancreatic cancer, aiming to enhance the effectiveness of immunotherapies against cold tumors like PDAC.

Neutralizing tumor acidity

Acidosis plays a significant role as an immunosuppressive mechanism that contributes to the proliferation of PDAC and immune escape [ 481 ]. A study investigates the application of L-DOS47, a urease immuno-conjugate, for the purpose of neutralizing the acidity of tumors and enhancing the response to immunotherapy. L-DOS47 attaches to CEACAM6, a protein that is predominantly present in gastrointestinal cancers, and increases the local pH by breaking down urea into two NH4 + and one CO2. This was experimented on a model of pancreatic tumors in mice, and it was observed that L-DOS47 elevated the extracellular pH of the tumor. When L-DOS47 was used in conjunction with anti-PD-1, it significantly boosted the effectiveness of the monotherapy, leading to a reduction in tumor growth for a duration of up to 4 weeks [ 482 ]. This study paves the way for using L-DOS47 in future clinical trials.

Targeting desmoplastic barriers of TME

A significant obstacle to the effectiveness of cancer immunotherapies in PDAC is the presence of desmoplastic barriers within the stromal ECM, such as hyaluronan. These mechanical barriers encapsulate the tumor cells, thereby restricting their exposure to immunotherapeutic agents. The targeted removal of hyaluronan in a mouse model of PDAC resulted in better vascular permeability and enhanced drug delivery. This led to increased effectiveness of chemotherapy when combined with the cytotoxic chemotherapy drug, gemcitabine [ 483 ]. A study found that combining PEGPH20 (a PEGylated recombinant human hyaluronidase), focal adhesion kinase inhibitor, and anti-PD-1 antibody treatments improved survival in PDAC-bearing mice, increased T-cell infiltration, altered T-cell phenotype and metabolism, reduced granulocytes, and decreased CXCR4-expressing myeloid cells. Additionally, adding an anti-CXCR4 antibody significantly reduced metastatic rates in a PDAC liver metastasis model [ 484 ].

Innate immune activation

A useful strategy in combating pancreatic cancer involves the stimulation of the body’s innate immune system to bolster its anti-cancer defenses. This is accomplished by, for instance, utilizing a genetically altered version of Listeria monocytogenes , which is engineered to produce MSLN. Alongside this, a vaccine named GVAX is used. The synergistic effect of this combination has been shown to enhance the survival rates of patients [ 41 , 378 , 485 ]. This therapeutic approach transforms PDACs into a state that is more receptive to immune responses. This change is marked by a rise in T cell infiltration and the formation of tertiary lymphoid clusters within the tumors [ 380 ], likely converting the cold tumor into the hot tumor. Innate immune cells use cGAS to trigger inflammatory signals when they bind to the pathogen or damage-related molecular patterns (PAMPs/DAMPs). This process leads to the production of cGAMP and the activation of STING, a protein in the endoplasmic reticulum, which then promotes cellular gene programs resulting in the production of IFN-I [ 486 , 487 ]. IFNs-I (IFN-α and IFN-β) are essential for the development of CD8 + T cells that fight against tumors. Tumors that are inflamed with T cells, often referred to as “hot” tumors, have been linked to a transcriptional signature of type 1 interferon [ 488 , 489 ]. The activation of STING, either systemically or within the tumor, through STING agonists, has been shown to reverse immune-suppression and cause tumor shrinkage in various preclinical cancer studies [ 434 , 490 , 491 , 492 , 493 , 494 ]. IACS-8803 (a STING agonist) increases sensitivity to anti-PD-1 and anti-CTLA-4 immunotherapy in the orthotopic PDAC models [ 495 ]. Furthermore, a STING agonist called IMSA101 boosts CAR T cell function in a mouse pancreatic tumor model, which is facilitated through STING agonist-induced IL-18 secretion [ 496 ]. All in all, the STING innate immune sensing pathway, when activated, could potentially transform tumors lacking T cell infiltrates into tumors with infiltrating T cells, and thus offers a promising target in PDAC immunotherapy.

TME-modulating agents

A successful immunotherapy for PDAC usually requires combining different treatments to help T cells infiltrate and stay activated in the hostile TME. Current research is focused on developing strategies to improve the PDAC TME, boost the immune response, and enhance the effectiveness of T cell therapy [ 44 , 497 ].

ADH-503 is a small molecule that binds to CD11b and enhances the adhesion of myeloid cells, inhibiting their migration into tissues [ 498 ]. It also shifts TAM polarization to an anti-tumor phenotype, improves survival in PDAC-bearing mice, and sensitizes PDAC tumors to anti-PD-1/PD-L1 immunotherapy [ 341 ]. In clinical trials, ADH-503 was well tolerated with common side effects, but no clinical responses were observed in pancreatic cancer patients (NCT04060342) [ 499 ].

In PDAC, it is expected that targeting the CCL2/CCR2 pathway would help to reduce the accumulation of TAMs in the TME. A CCR2 inhibitor, PF-04136309, was tested in combination with chemotherapy in patients with pancreatic cancer. A manageable level of safety was observed. Early correlational studies indicated a decrease in TAMs and an increase in TILs (NCT01413022) [ 437 ]. Another trial combining PF-04136309 with chemotherapy in pancreatic cancer patients showed high rates of lung toxicity and no significant improvement in efficacy (NCT02732938) [ 438 ]. A study tested the CCR2 antagonist CCX872-B in combination with FOLFIRINOX for patients with advanced pancreatic cancer. Analysis showed an OS rate of 29% at 18 months with no safety concerns (NCT02345408) [ 500 ]. BMS-813160 is a dual antagonist for CCR2 and CCR5 that is being tested in combination with chemotherapy or immunotherapy in patients with advanced pancreatic or colorectal cancer, but no results from the study have been reported yet (NCT03184870) [ 501 ].

Several studies have shown that by inhibiting the CXCR4/CXCL12 axis, the PDAC TME can be modified. For example, when CXCR4 was knocked down, the invasion potential of pancreatic cancer cells in vitro was decreased. Treating fresh human PDAC slices with a combination of PD-1 and CXCR4 blockade resulted in enhanced tumor cell death and lymphocyte expansion into the juxtatumoral compartment [ 502 ]. In a mouse model of PDAC, administering the CXCR4 inhibitor AMD3100 (plerixafor) led to the accumulation of T cells among cancer cells, resulting in a synergistic tumoricidal effect when combined with anti-PD-L1 immunotherapy [ 35 ]. A trial tested AMD3100 in patients with colorectal and pancreatic cancer, resulting in decreased tumor markers (circulating tumor DNA and IL-8) and changes in immune cells (reduced number of CAFs and increased number of effector TILs/NK cells) [ 503 , 504 , 505 ]. Motixafortide (BL-8040; CXCR4 antagonist) is a synthetic peptide that is administered subcutaneously and has shown promising results in combination with pembrolizumab in treating metastatic PDAC, increasing CD8 + T cell infiltration and decreasing MDSCs and circulating Tregs (NCT02826486) [ 506 ]. NOX-A12 (olaptesed pegol) is a PEGylated drug that inhibits CXCL12 and enhances the activity of anti-PD-1 therapy in pre-clinical models [ 507 ]. In a phase 1/2 study with advanced PDAC patients, NOX-A12 in combination with pembrolizumab led to induced TH1 cytokines, prolonged stable disease, and increased effector immune cells in tumor biopsy tissue (NCT03168139) [ 508 ].

Pharmacologic inhibition of the A2A adenosine receptor enhances the effectiveness of anti-PD-1 therapy [ 509 ]. Several anti-CD73 therapeutics and adenosine receptor inhibitors have been developed [ 510 ]. Oleclumab (MEDI9447), a monoclonal antibody that targets CD73, demonstrated positive outcomes in inhibiting tumor progression and promoting immune cell infiltration in colon cancer models. When used in conjunction with anti-PD-1 treatment, it resulted in the elimination of tumors in 60% of animal subjects [ 511 ]. Clinical studies of oleclumab, either alone or in combination with durvalumab, in patients who did not respond to anti-PD-L1 therapies like advanced pancreatic cancer revealed good tolerability and some partial responses (22 and 28 months) in a small subset of patients (2/73; NCT02503774) [ 512 ]. A study evaluated the safety of quemliclustat (a small molecule inhibitor of CD73) in combination with standard treatment and zimberelimab in patients with metastatic PDAC. The safety profile is similar to single agents, with no new toxicities. Some patients showed partial responses with long-lasting effects (NCT04104672) [ 513 ].

Main challenges ahead of pancreatic cancer immunotherapy

Immunotherapy for pancreatic cancer is a significant therapeutic strategy. However, despite comprehensive studies, there are obstacles in translating research outcomes and determining the best therapeutic combinations. These challenges necessitate a joint effort from scientists and medical practitioners to deepen our comprehension of the interactions between cancer and the immune system and to enhance the treatment choices available to patients. In this part, we will explore in greater detail the chief hurdles facing immunotherapeutic strategies for pancreatic cancer.

Low antigenic strength and number of neo-antigens

During the process of tumor development, non-synonymous gene mutations occur, leading to the generation of neo-antigens that are exclusively expressed by tumor cells. Pancreatic cancers carry a moderate load of these non-synonymous neo-antigenic mutations [ 497 ]. In essence, PDACs show a low load of neo-epitopes; therefore, the tumors are more likely to adapt to immune pressure and escape T cell-mediated killing through cancer immunoediting. In a study, T cell immunity was assessed in a mouse model of pancreatic cancer, revealing a low level of mutations, no anticipated neo-epitopes resulting from these mutations, and resistance to respond to checkpoint immunotherapy [ 514 ]. Also, pancreatic tumors that have the greatest quantity of neo-antigens and the highest concentration of CD8 + T cell infiltrates are linked to the longest survival rates in patients. Moreover, enrichment of neo-antigens in the tumor antigen MUC16 (CA125) was observed in long-term survivors of pancreatic cancer [ 53 ]. Thus, the quality of neo-antigens as a biomarker for PDAC could potentially steer the use of immunotherapies [ 53 , 515 ]. Additionally, the BCL2A1 neo-epitope is presented as a potential target for personalized immunotherapy, which stimulates CTLs to combat pancreatic cancer cells [ 516 ]. All in all, neo-antigens might broaden the horizon towards personalized immunotherapy of pancreatic cancer. A major challenge restricting their applicability, however, is that a low number of neo-antigens is rarely shared among patients [ 497 ], making the use of relevant treatment approaches cumbersome and costly.

Primary, adaptive, and acquired resistance

In primary resistance, there can be instances where cancer does not respond to immunotherapy, potentially due to adaptive immune resistance mechanisms. Adaptive resistance pertains to a resistance strategy where the cancer, even though identified by the immune system, shields itself by adjusting to the immune attack. Lastly, acquired resistance refers to a situation where a cancer initially shows a response to immunotherapy, but after a certain period, it experiences a relapse and advances [ 517 ]. From a biological perspective, resistance to immunotherapy can be linked to both intrinsic factors in tumor cells and extrinsic factors associated with TME like ECM and stroma-derived factors, immune cells/factors, and intratumoral microbiota. Tumor cell-intrinsic factors include genetic/epigenetic defects, IFN-γ signaling, lack of neo-antigens, oncogenic signaling pathways, and epigenetic reprogramming [ 22 ]. FAP + CAFs hinder the anti-tumor activity of T cells in pancreatic cancer. However, directing therapies towards these FAP + subtypes improves the tumor’s response to anti-PD-L1 [ 35 ]. T-cell exclusion is a process that resists immune checkpoint therapy, and it’s particularly noticeable in ‘cold’ tumors like pancreatic cancer, which have a low presence of T cells in TME. Some cancer-causing pathways might allow tumors to use this method to avoid the immune system. For instance, the activation of Wnt/β-catenin within the tumor cells has been demonstrated to result in the exclusion of T cells from the TME [ 518 , 519 ]. Moreover, PTEN deficiency is linked to provoke PI3K-AKT pathway signaling and is connected to decreased presence of CD8 + T cells and unfavorable clinical outcomes from immunotherapy [ 520 ]. A recent study found that the loss of interferon regulatory factor 6 (Irf6) leads to resistance to immunotherapy, and its re-expression improves immunotherapy responses to PDAC [ 521 ]. All in all, the resistance to immunotherapy in pancreatic cancer is complex and influenced by both internal and external factors within the tumor. A sophisticated strategy of basic and translational/clinical research is needed to understand these mechanisms and identify tumor-specific resistance patterns.

Immune-related adverse events (irAEs)

The irAEs are diverse and can affect any organ. Different immunotherapy regimens have unique toxicity patterns like CRS and neurologic toxicities, making understanding their mechanisms crucial [ 522 , 523 , 524 , 525 ]. However, a positive association exists between the occurrence of non-lethal irAEs and the response to ICB [ 526 ]. Mild (Grade 1–2) effects are observed in over 90% of patients, whereas severe (Grades 3–5) effects can occur in 20–60% of patients [ 527 ]. Studies highlight the role of certain immune cells such as CD8 + tissue-resident memory T cells and neutrophils, and cytokines like IFN-γ and IL-6 in causing immunotherapy-induced colitis [ 528 , 529 , 530 ]. Other mechanisms like loss of self-tolerance, molecular mimicry, and inflammation also contribute to irAEs. For example, in myocarditis, autoreactive T cells targeting specific peptides are activated, a process worsened by the release of self-antigens from dying tumor cells [ 531 ]. This is known as epitope spreading. Glucocorticoids are the main treatment for non-endocrine irAEs, and hormonal therapy is used for endocrine disorders. Intravenous immunoglobulins, plasma exchange, and monoclonal antibodies such as infliximab are employed for neurological, hematological, and persistent irAEs [ 22 ]. For ICB-induced colitis, fecal microbiota transplantation is utilized [ 532 ]. All in all, irAEs are life-threatening reactions that deserve special attention. Thus, it is crucial to formulate personalized strategies for patient categorization and potential biomarkers to investigate the dynamics and resolution timing of irAEs to identify.

Scarcity of robust predictive biomarkers of response and toxicity

Individual biomarkers have been utilized to forecast responses to cancer immunotherapy. Both Microsatellite Instability-High (MSI-H) and Tumor Mutational Burden (TMB) have been associated with enhanced responses to ICB [ 533 , 534 ]. Nonetheless, the efficacy of TMB as the only biomarker is restricted, as a low TMB can still elicit effective responses, and a high TMB does not assure a response to ICB [ 22 ]. Although immune-related biomarkers such as PD-L1, interferon signature, and TIL density have been found to have restrictions when used as the only biomarkers, it is important to note that even though there is an association between PD-L1 expression and improved outcomes in certain types of tumors, substantial responses can still be observed in tumors that do not express PD-L1 [ 535 ]. It has been proposed that CAFs, microbiomes, and exosomes derived from tumors could serve as potential biomarkers for tracking the response to immunotherapy in pancreatic cancer [ 536 ]. Furthermore, a study on pancreatic cancer patients who received PD-1 inhibitor-based therapies showed that a lower neutrophil-to-lymphocyte ratio predicted better tumor response [ 537 ]. Collectively, the progression of predictive biomarkers has been obstructed by the intricate interplay within the pancreatic tumor microenvironment. The field must comprehend these interactions and establish suitable assays for successful biomarker development and codifying combinatorial biomarker strategies. These approaches should be confirmed in upcoming clinical trials.

Lack of integrated regulatory endpoints for cancer immunotherapy

Conventional methodologies for evaluating the efficacy of cancer immunotherapies, such as pembrolizumab and nivolumab, have demonstrated considerable utility [ 538 ]. These methodologies encompass metrics such as ORR, PFS, and OS, which have been instrumental in assessing therapeutic outcomes. Nevertheless, these conventional metrics exhibit limitations when applied to the evaluation of cancer immunotherapies. The primary objective of cancer immunotherapy is to induce a durable response and prolong survival, optimally quantified by examining the ‘tail’ of survival curves. However, the extant methodologies for this measurement are deficient [ 539 ]. In circumstances where an immunotherapy’s impact takes time to manifest and the rate of successful outcomes is not high, conventional benchmarks such as mPFS and median OS can provide deceptive early indications [ 473 ]. This becomes evident in the case of patients with MSI-H PDAC who underwent treatment with pembrolizumab. Despite a relatively low ORR of 18% and a mPFS of just 2.1 months, the responses proved to be quite durable, with a median response duration of 13.4 months [ 540 ]. All in all, continued collaboration and optimization of pancreatic cancer immunotherapy endpoints is needed to address the aforementioned issues.

Lack of proper preclinical animal models

Preclinical models are crucial in cancer drug discovery for prioritizing targets and studying various aspects of treatment. These models have contributed to significant discoveries in cancer treatment and immunotherapy, including the effects of CTLA-4 and PD-L1/PD-1 blockade [ 539 ]. Nevertheless, the models commonly utilized do not always accurately represent the immune biology of human cancers [ 541 ]. This can be attributed to inter-tumoral and intra-tumoral heterogeneity, recapitulation of TME, and serial passaging of tumor cells [ 542 ]. For instance, the intricate interplay between tumor and stroma, along with the diverse traits of stromal elements, present substantial obstacles in accurately reproducing the pancreatic cancer microenvironment. Furthermore, the weak immunogenicity and the immunosuppressive characteristics of PDAC complicate preclinical modeling [ 542 ]. A problem with frequently utilized preclinical models is their dependence on the inoculation of cancer cell lines. The tumors that develop following this insertion often fail to accurately reproduce the immune context of the tumor, which plays a crucial role in shaping the immune response in human cancers [ 543 ]. Moreover, cancer in humans is thought to have evolved over the years, shaping its interaction with the immune response. Genetically engineered mouse models, developed by altering genes and inducing mutations, best represent this disease [ 544 ]. However, these models do not mimic the gradual mutation accumulation seen in human cancers, resulting in stable cancers that do not respond well to cancer immunotherapy [ 539 ]. Also, a significant obstacle in current attempts to comprehend the occurrence of irAEs is the absence of suitable preclinical animal models. There is a pressing need for the generation of animal models that accurately mimic irAEs, which would facilitate the detailed study of irAEs associated with pancreatic cancer immunotherapy [ 545 ]. Thus, there is an unmet need to further develop pancreatic cancer animal models with high-throughput techniques for better mimicking the human pancreas cancer features. It can pave the way for a rapid translation of preclinical findings into clinical settings.

Conclusion and future directions

In summary, the paradigm shift brought about by immunotherapy is fundamentally altering our understanding of cancer treatment. This groundbreaking approach is now being implemented in clinical settings for a variety of solid cancers. Standard therapies have proven ineffective for patients with PDAC, but immunotherapy has demonstrated encouraging results in preclinical stages. Despite these promising results, immunotherapies still face fundamental challenges, which may limit their efficacy in clinical contexts. It is important to consider that each treatment modality has its advantages and disadvantages (Table  10 ). This article explored a wide range of immunotherapies, such as OVT, and adoptive cell transfer therapies including TCR-engineered T cells, CAR T-cell therapy, CAR NK cell therapy, and CIK cell therapy. Additionally, ICB, immunomodulators, cancer vaccines, and strategies targeting myeloid cells were discussed as potential avenues. Furthermore, this article provided the application of CRISPR/Cas9 technology and gut microbiome in pancreatic cancer immunotherapy. Lastly, strategies for enhancing the effectiveness of immunotherapy and the primary obstacles confronting pancreatic cancer immunotherapy were highlighted.

The complex nature and heterogeneous composition of cellular elements in the pancreatic tumor microenvironment are of significant importance. There is a complex transition of cell populations as PDAC advances. Employing advanced methods such as single-cell sequencing and multi-omics analysis allows us to delve deeper into the immune cell profile in PDAC, pinpoint cells with higher precision, and chart the single-cell trajectories [ 546 ]. This advancement lays a stronger groundwork for developing immunotherapies that target the various elements of the TME.

As we progress in developing immunotherapeutic strategies for the treatment and management of PDAC, it is crucial to prioritize efforts that enhance patients' quality of life. Numerous trials employing immunotherapy in PDAC have had disappointing outcomes, primarily due to the immunosuppressive TME. Therefore, it is imperative to refine and improve existing immunotherapies to effectively address this significant challenge. Furthermore, it is essential to conduct further research on the efficacy of novel immunotherapy targets identified in preclinical studies, thereby validating their potential through human clinical trials. Overall, the open-ended research question remains unanswered as to why many patients with pancreatic cancer do not respond to immunotherapies.

The identification of novel and appropriate molecular targets for targeted immunotherapies is crucial for the success of this immunotherapy in treating pancreatic cancer. While CAR-based therapies have achieved impressive clinical responses in targeting cancer antigens, the efficacy of these therapies in solid cancers has been disappointing, in part due to antigen escape. Targeting heterogeneous pancreatic tumors with immunotherapies will require the identification of novel tumor-specific targets. Therefore, identifying novel and appropriate molecular targets for CAR T cell therapy is essential for the development of effective cancer treatments.

As our understanding of the complex interplay between the immune system and pancreatic cancer continues to evolve, the field of pancreatic cancer immunotherapy is positioned at the forefront of cutting-edge research. These groundbreaking domains of research, such as machine learning and artificial intelligence [ 547 ], mutant KRAS peptide-driven vaccines and personalized RNA neo-antigen vaccines [ 401 , 548 ], single-cell multi-omics-oriented approaches [ 546 , 549 ], and CRISPR/Cas-based RNA editing [ 550 ], are of utmost importance as they define the active research areas of the future, paving the way for gaining better clinical outcomes. Given the role of artificial intelligence in cancer research, researchers used machine learning to analyze complex tumor molecular data from pancreatic cancer patients and found that anti-CD40 therapy reduced T-cell exhaustion in the TME. They identified specific T-cell populations that correlated with improved DFS following anti-CD40 therapy, demonstrating the potential of machine learning in pancreatic cancer immunology research [ 547 ]. The creation of multiplexed effector guide arrays (MEGA) has made it possible to effectively control and regulate the T cell transcriptome through the use of CRISPR-Cas13d. With MEGA, genes can be suppressed in primary human T cells without any changes to the DNA, leading to improved T cell function and stronger anti-tumor capabilities. MEGA also enables the regulation of CAR activation and disruption of immunoregulatory metabolic pathways [ 550 ], providing a flexible and powerful tool for use in pancreatic cancer immunotherapy.

Abbreviations

Adverse events

Antigen-presenting cell

All-trans retinoic acid

Regulatory B cell

Bispecific antibodies

Chimeric antigen receptor

Cancer-associated fibroblast

Conventional dendritic cells

Cytokine release syndrome

Cytotoxic T lymphocyte

Cytotoxic T-lymphocyte-associated protein 4

Colony-stimulating factor 1

Colony-stimulating factor 1 receptor

Dendritic cell

Disease-free survival

Extracellular matrix

Epidermal growth factor receptor

Epithelial-mesenchymal transition

Fibroblast activation protein alpha

Granulocyte–macrophage colony-stimulating factor

• Immune checkpoint blockade
• Immune checkpoint inhibitor

Indoleamine 2, 3-dioxygenase

Type I interferon

Interferon-gamma

Interleukin

Induced pluripotent stem cell

Lymphocyte-activation gene 3

Monoclonal antibody

Myeloid-derived suppressor cell

Major histocompatibility complex

Matrix metalloproteinase

Median overall survival

Mesenchymal stem cell

Microsatellite Instability-High

Natural killer

Overall response rate

Overall survival

• Oncolytic virus therapy

Programmed cell death protein 1

• Pancreatic ductal adenocarcinoma

Programmed death-ligand 1

Progression-free survival

Pancreatic stellate cell

Stimulator of interferon genes

Tumor-associated mesenchymal stem cells

Tumor-associated macrophage

T-cell receptor

Transforming growth factor-beta

T helper 17

T cell immunoreceptor with Ig and ITIM domains

T-cell immunoglobulin and mucin domain 3

Tumor-infiltrating lymphocyte

Toll-like receptor

Tumor Mutational Burden

Tumor microenvironment

Regulatory T cell

Talimogene laherparepvec

Vascular endothelial growth factor

V-domain Ig-containing suppressor of T-cell activation

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Pooya Farhangnia & Ali-Akbar Delbandi

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Farhangnia, P., Khorramdelazad, H., Nickho, H. et al. Current and future immunotherapeutic approaches in pancreatic cancer treatment. J Hematol Oncol 17 , 40 (2024). https://doi.org/10.1186/s13045-024-01561-6

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Advances in treating pancreatic cancer mean options and hope–2022

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November is  Pancreatic Cancer Awareness Month . A diagnosis of cancer may feel devastating. And pancreatic cancer is the least survivable cancer of all known cancers. That's because when it is diagnosed, it often has already spread.

Dr. Mark Truty , a surgical oncologist at Mayo Clinic , says the stigma around the diagnosis can leave people feeling hopeless. He wants people with pancreatic cancer to know that advance s in treatment mean more options are available than ever before.

Watch: Advances in treating pancreatic cancer mean options and hope

Journalists: Broadcast-quality video (1:32) is in the downloads at the end of this post. Please "Courtesy: Mayo Clinic News Network." Read the  script .

"If you think about it — breast cancer , prostate cancer , lung cancer , brain cancer — pancreas cancer continues to be the least survivable of all of those cancers," says Dr. Truty.

But it is more survivable now than it used to be. Dr. Truty says that’s due in part to advances in the approach to treating the cancer.

Patients that can have surgery for their pancreatic cancer live longer than those who cannot. Unfortunately, in the past, surgery wasn’t an option for most patients, but with better chemotherapy came dramatic changes. Now, more patients are considered candidates for curative surgery.

"Those patients that are able to undergo chemotherapy prior to the surgery tend to do much better than they historically have done," Dr. Truty says.

That includes patients who may have been considered inoperable elsewhere due to complex tumors involving blood vessels. Mayo Clinic is the first and only center that routinely uses  positron emission tomography, or PET , scans to help determine if that chemotherapy is effective.

"This is what we want to see at the beginning; we want to see a tumor lighting up really bright prior to chemotherapy. And then, after chemotherapy, we want to see it sort of disappear — the activity that would suggest that chemotherapy was effective. And then when we ultimately operate on these patients and we take the tumors out, the pathologist tells us that all the cancer is dead," explains Dr. Truty.

The primary goal for any patient with pancreatic cancer is to extend their life and maintain or improve their quality of life. Advances like this are offering patients hope.

"Oh, without question, they should have hope," Dr. Truty says.

• AI applied to prediagnostic CTs may help diagnose pancreatic cancer at earlier, more treatable stage .
• Identifying inherited gene mutations in pancreatic cancer can lead to targeted therapies, better survival.
• Consumer Health: Pancreatic cancer risks and prevention .

For the safety of its patients, staff and visitors, Mayo Clinic has strict masking policies in place. Anyone shown without a mask was either recorded prior to COVID-19 or recorded in a nonpatient care area where social distancing and other safety protocols were followed.

• High adopters of AI-enabled screening tool are more likely to diagnose left ventricular dysfunction than low adopters, Mayo Clinic study finds Lung cancer diagnosis innovation leads to higher survival rates

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