Immunotherapy in pancreatic cancer—an emerging role: a narrative review

Introduction

Pancreatic cancer (PC) is one among very few cancer types for which the prognosis has not improved much over the past decades (1). While the 5-year survival for all cancers altogether is above 60%, the survival of all-stage PC remains below 10% (1,2). Three major features of PC make it particularly difficult to treat and roadmap its dismal prognosis. The tricky anatomic location not only predefines the limitation to extend surgical resection margins, resulting in about 80% R1 resections, but is also the reason why about 30% of patients present with locally advanced disease with tumor advancement along major abdominal vessels and propagation along the rich neural routes in the area (2-4). Second, PC is prone to give early rise of metastases that can occur even before the primary tumor becomes visible to the clinician (5). This is one of the explanations why even smaller primary resectable tumors tend to recur in the majority of cases even following curative resection, leaving a 5-year chance of survival of only about 20% (2). These two major characteristics of PC are the reason why systemic oncologic treatment is making its way as the new standard in the neoadjuvant setting. Its purpose is to combat occult distant spread and/or consolidate the advanced tumor in order to select who would benefit the most from surgical resection. However, as potent and promising the new combination regimens like FOLFIRINOX or gemcitabine-nab-paclitaxel might be in prolonging life, used alone they basically never lead to cure due to the microenvironment architecture of PC.

The third unfortunate characteristic of PC is the abundant stroma that shields the tumors cells and defines its chemoresistance (6,7). The poor vascular tumor network is responsible for the ineffective drug delivery and is the driver of hypoxia which enhances endothelial-mesenchymal transformation and invasiveness of PC cells (8). The thick fibrotic stroma increases the distance between the vessels and the tumor cells and mechanically hampers the diffusion of the infused drugs, which cannot reach the cancer cells in therapeutic concentrations (9). Thus, theoretically any passively infused treatment would be doomed to failure.

The tumor microenvironment also plays an active role in carcinogenesis and tumor progression. The components of the immune system are part of this environment and depending on the immune cell composition and its balance, it can either tip over the response toward tumor antigen recognition and appropriate adoptive anti-tumoral response or aid in escaping effective tumor recognition and elimination. Manipulating the immune response towards continuous activation and tumor recognition is the basis of immunotherapy—the fastest growing branch of oncology. Immunotherapy has already revolutionized the treatment of some dismal cancer types, such as malignant melanoma or lung cancer (10,11). In particular, treatment with check point inhibitors has led to long-term survival in patients with melanoma and renal cancer (10,12,13). Inevitably, there is hope that immunotherapy may have similar significant impact on the prognosis of PC. The theoretical advantage of immunotherapy compared to cytotoxic drugs is that it will not only “work” during the treatment occasion but can perpetuate itself and be able to augment and persist during cancer recognition and elimination.

The purpose of this review is to give a comprehensive overview of the role and current attempts of immunotherapy for PC from the clinician’s perspective of possible integration in treatment, to map the problematic areas and to highlight what might be opportunities for successful implementation. We present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-21-174/rc).

Methods

A search in PubMed was performed to identify clinical trials in humans, published in English between January 2000 and June 2021 and using components of the immune system for immunomodulation in patients with PC. Search was performed using a combination of the search terms “immunotherapy”, “pancreatic cancer”, “pancreatic adenocarcinoma”, “check-point inhibitors”, “vaccine”, “peptide vaccine”, “antibody”, “dendritic cells”, “tumor infiltrating lymphocytes”, and the bibliography of the revised literature cross-checked for additional references as the dublettes have been removed. Trials in which other products were tested, targeting signaling pathways not directly and specifically targeting the immune system were excluded.

The role of the immune system in PC

The immune system plays an active part in PC tumorigenesis throughout the stages of cancer immunoediting, from elimination, through equilibrium to the escape phase (14,15). The immune cell populations and immune mediators increase and change progressively as precursor lesions of PC evolve to invasive cancers, aiding the tumor to progress and increase its aggressiveness (16-18). The initial “good” local inflammation is represented by players with better effector function such as CD8⁺ and Th1 CD4⁺ T-lymphocytes, natural killer (NK) cells, mature dendritic cells (DC), type 1 macrophages, IL-1, TNF-α, IFN-γ. It gradually becomes replaced by “bad” inflammation, sustaining cancer growth. The latter is described by regulatory (Tregs) and ineffective CD8⁺ T-lymphocytes, immature DCs, myeloid derived suppressor cells (MDSCs), type 2 macrophages, IL-10, TGF-β (18,19). Interestingly, PC cells can mimic suppressive immune features that allow them to modulate the immune response against them. PC cells secrete inhibitory signals such as TGF-β, IL-10 and IL-6, VEGF, and express PD-L1, Fas-L, co-stimulatory molecules (B7-H3, CD40, CD40L) and can down-regulate the expression of antigens that could reveal their presence (19-21).

The typical for PC stromal reaction arises already during the early PanIN stages of tumor development (8). It not only traps and segregates immune cells from their target cancer cells, but also plays an active part in immunomodulation. PC-associated fibroblasts (CAFs), which represent the major cellular component in the desmoplastic stroma, can reduce T cell function in the stroma by receptor-mediated mechanism and promote expression of co-inhibitory markers on T cells (22,23). The stroma also recruits immunosuppressive Foxp3⁺ CD4⁺ T_reg lymphocytes and tumor-associated macrophages (TAMs) (24-26).

Extensive presence of tumor infiltrating lymphocytes (TILs) in cancerous lesions has been associated with improved survival in different cancer types (26-33). T cells are practically lacking in normal pancreas but increase in precancerous lesions and invasive cancer with grossly varying density of infiltration. A few studies point out that higher tumoral infiltration with TILs in resected pancreatic specimen, particularly by CD8⁺ TILs, is associated with 5-survival as high as 42% (31). Co-infiltration by various populations of CD8⁺, CD4⁺ TILs and DCs, perhaps reflecting better crosstalk in antigen-presentation and immune recognition resulted in a survival of 48% in 5 years (31).

In contrast to for instance colorectal cancer, TILs in PC do not have a distinct distribution to center and periphery of the tumor but have a more patchy appearance (26,27,29). Whether stromal or intraepithelial TILs are more important is also uncertain (29,30,32). CD4⁺ and CD8⁺ TILs have been observed captured in the stromal tissue, far away from cancer cells and lacking the expression marker of memory cells, CD45RO (34). While some of the CD8⁺ TILs population may still be naïve (CD45RB^high, CD44^low) as shown in mice models (17), others would have recognized a tumor antigen (35), meaning that under favorable conditions these are likely to be reacting against the cancer components that express them.

Better patient survival has been reported when high infiltration of CD8⁺ PD-1⁺ TILs was present, suggesting that PD-1, besides being an inhibitory marker, could also represent experienced and activated TILs recognizing a tumor target (26,36). PD-1 expression is also a possible predictive marker for success for eventual check-point inhibitor (CPI) therapy (26).

Immunotherapy for PC

Immunotherapy has been particularly successful in tumors with high-mutational load, such as malignant melanoma (37). This phenomenon provides plenty of epitopes for the immune system to target and is associated with the presence effector immune cells. Thus, the probability that any of the tumor antigens will be crucial for the cancer propagation and may induce a strong response is higher. PC is a cancer with low mutational load—in the range of 30–60 mutations compared to over 500 in melanoma (37,38). Also, with its poorer infiltration with effector T lymphocytes there are fewer potential “responders” to any immune-modulating signals. The addition of the abundant tumoral stromal reaction may hamper the delivery of any immune-stimulating drugs and the premises for success of immunotherapy in PC applied by the principles of standard oncologic treatment delivery are limited (38).

Immunotherapy runs better chances for success whenever lower tumor load is present and thus the counteractive effect of the tumor environment is lesser. Phase I and II clinical trials, just like for other types of oncologic therapy, are usually designed for patients with advanced disease who failed previous therapy attempts or are running out of therapeutic options. For cancers like PC, having already worse premises for response to immunotherapy, starting therapy too late may be particularly unlucky and predetermined to failure. Immunotherapy may also need some time to “work”, since it targets the mediator (the immune system) rather than the cancer cells directly. An example for this phenomenon is the observation of pseudoprogression in some patients with melanoma treated with CPIs (39). While increase in tumor size may occur during the first weeks of treatment as a result of the beneficial inflammation that takes place, the real effect becomes obvious within a few months (40). The life expectancy of patients with PC with no treatment option is hardly that long. Although 3 months of expected survival is generally the minimum required to enter a trial, for PC patients with spread disease that is generally an overestimation (41). Fast and sudden deterioration towards lethal outcome is not unusual and may further compromise the planned delivery of treatment cycles.

Immunotherapy trials in PC

Immunotherapy may provide a variety of different options for treatment based on the parts of the immune response that are being modulated. Loaning principles from the pharmaceutical treatment, the best cost-effective result would be achieved by standardized industrially produced medication, designed to address a certain cancer target. Cancer biology, though, is characterized by complex network of mutations (not unusually private) and changes in signaling pathways that evolve during cancer progression (42). Thus, defining the target that has a central role in the particular person’s tumor might be tricky and hitting only one target would mostly probably not be enough to combat the tumor. Applying a combination of drugs is quite often used in immunotherapy trials to both hit a target and to amplify the provoked response.

In order to better summarize and make a more comprehensive evaluation of the different types of immunotherapy studies in PC, we subdivided them into groups, based on what parts of the immune system have been used (Figure 1): (I) passive products of the immune system (tumor antigens, antibodies, interleukins)—secreted products that rely on triggering the whole chain of the immune response; (II) enhanced antigen presentation via the mediators of the immune response—DC; (III) adoptive cell transfer—reinfusion of expanded and activated effector lymphocytes—T-cells, NK cells.

Figure 1 Type of immunotherapy trials in pancreatic cancer.

Passive products of the immune system

Peptides and antibodies are the cheapest the easiest to obtain of the immunotherapy products and they have been most widely tested. They are both readily available and not cumbersome to standardize as pharmacological products. Peptides represent epitopes of a known tumor-associated antigen intended to trigger and boost the immune response against malignant cells. Antibodies are intended for receptor-mediated modulation of a signaling pathway or directly addressing immune cells. What is relied on in both cases is to unlock an effective chain of reactions, which requires the presence and adequate behavior of the other components of the adoptive response—antigen-presenting cells and T lymphocytes. The latter, though, are heavily influenced by the tumor environment.

Antigen vaccines

Boosting the reactivity of the immune system to the tumor cells by repeated exposure to foreign (cancer) antigens is the oldest concept of immunotherapy. Since cancer is derived from the own tissues and therefore prone to induce immunotolerance, tumor-associated antigens that are not present on normal cells can potentially induce immune cell reactivity. Mutations that are obliquitous in PC are most often the target of interest, such as KRAS, MUC1, survivin (43-55). Completed studies on antigen-based vaccines are summarized in Table 1.

Peptide vaccines

Peptide vaccines are usually administered with an adjuvant to help enhance their efficacy. They have the advantages of being easy to apply, unexpensive, and can be combined uncomplicatedly with other treatments. They are also usually well tolerated and with few side effects, usually limited to local reaction at the application site. Measurable immunologic reactions as response to their application have been registered in pretty much all trials. However, their effectiveness is limited. Clinical benefit has been observed in single cases and a near complete response has been presented in a case report (49). The exceptionally few trials making it to phase III, however, show no survival benefit from the peptide vaccination (56,58,64,67). For this reason, the interest towards peptide vaccines has been declining over the past years to being almost abandoned. Even in the adjuvant setting after resection, no impressive effect has been observed. Palmer et al. reported survival after resection and vaccination with seven KRAS peptides comparable to that of the patients receiving adjuvant gemcitabine, yet no control arm was present in this study (43). Also, the new current standards for adjuvant treatment with combination chemotherapy give superior results. As a proof of principle, though, immunologic response towards the vaccination agent has been induced in at least part of the patients. Some of the studies also reported a tendency for improved survival in the patients with well-developed immunologic responses (45,55-57,59,71).

Whole tumor vaccines

Another way of providing antigen stimuli is whole-tumor vaccines. They have the advantages over peptide vaccines that the cells express multiple relevant antigens. Also, the specific antigens do not have to be identified. Particularly the allogenic tumor cell lines are readily available.

Most of the trials have used GVAX, consisting of two allogenic tumor cell lines, tested both in resected and metastatic patients with evidence of immunoreactivity (Table 1). Le et al. reported that when mesothelin-expressing Listeria monocytogenes was added to a combination of GVAX with the immunomodulating chemotherapeutic cyclophosphamide, it almost doubled the survival of patients with metastatic PC after previous treatment failure—9.7 versus 4.6 months if treated per protocol (P=0.02) (77). Particularly, enhanced mesothelin-specific CD8⁺ T cell responses have been linked to longer survival. In a following phase IIb RCT, however, the triple combination did not show advantage over physician’s choice of single-agent chemotherapy (79). Improved survival after resection for PC have also been observed with GVAX, with a one-year survival of 93% (73). Another trial tested autologous PC stem cells in phase I but did not report survival data (78). Injection was even attempted towards lymph node groups following resection, with a median survival of 24.8 months—comparable to standard treatment (75). So far, there are no phase III trials with this type of vaccines.

Vector vaccines

A few studies aimed to enhance the antigen presentation through vector delivery—virus or attenuated bacteria (77,80-85). The vector may lead to better engagement of innate immune signals by co-stimulation and providing “danger signals” that could more effectively trigger DCs and the following cascade of T cell activation by the chosen targets such as CEA, KRAS MUC-1, etc. (80,81,84). A couple of studies have aimed at introducing oncolytic viruses locally. Although some trends towards improved survival among the responders in phase I trials (80,81) no benefit has been confirmed in phase II (84,85).

Antibody trials

Trials using antibodies have marked a peak of publication over the most recent years. Antibodies are a ready product of the immune system that can be industrially produced. The treatment protocols can be standardized as for any other pharmaceutical drug and that translates correspondingly into more straight-forward safety regulation and mass production. In this way clinical trials with antibodies are easier to convey, which explains their domination among the immunotherapy studies for PC for the last couple of years.

The most aimed targets by antibodies in PC are EGFR and VEGF-A, which is likely due to that these antibody drugs have already been registered for treatment of other cancer types (Table S1). Whether administered alone or in combination with other targeted drugs or chemotherapy in advanced PC, so far, no improved survival has been seen in phase II and III antibody trials targeting EGFR and VEGF-A, even if applied as first-line therapy (86-91). The few combination trials with more than one of these target agents show some potential survival benefit, but have limited application due to increased toxicity (92,93). No benefit has been seen if antibody treatment has been used in conjunction to surgical resection, either (94-96). Phase II and III trials using different antibodies such as ganitumab, selumetinib, ibrutinib, tarextumab towards IGF1R, MEK, BTK, Notch2/3R (97-100) have failed to show improved survival, as well. Even targeting components of the tumor stroma, such as matrix metalloproteinase-9, have shown no convincing benefit (101).

As earlier studies have shown no benefit of solely antibody therapy, the more recent trials have focused on combination of antibody and chemotherapy. Gemcitabine has been almost exceptionally used, sometimes in combination with nab-paclitaxel (100-102). Gemcitabine has been by far surpassed by FOLFIRINOX in improving survival of patients with advanced PC, yet it is the most tolerable chemotherapeutic available. The toxicity profile of the antibody treatment, however, might restrict its co-application with the potent chemotherapy and it will be difficult to outrun its efficacy.

Checkpoint inhibitors

CPIs are a particular group of drugs, mostly antibodies, that deserve special attention. CPI treatment has become the label of practical immunotherapy as they have drastically improved the prognosis of cancers like malignant melanoma where standard treatment has failed (12). CPI block the inhibitory signals on effector T cells, such as PD-1 and CTLA-4, which are upregulated on T cells to avoid destructive immune overreaction and as a result of exhaustion in the tumor microenvironment. PD-L1 is often expressed on tumor cells and can via ligation with PD-1 on T cells directly inhibit T cell function. CTLA-4 provides an inhibitory signal to T cells after binding to the B7-1 and B7-2 on APC which hence prevents efficient T cell priming and activation.

Unlike the fantastic results that have been achieved in other cancer types, so far CPI have not proved to be particularly effective in trials with patients having advanced PC, with or without concomitant chemotherapy (Table 2). The reported survival has generally been no better than using single gemcitabine (121). One study reported acceptable tolerability of pembrolizumab used in the neoadjuvant setting for resectable and borderline resectable PC, but provided no survival data (110). The resectability rate was slightly higher in the CPI group—71% versus 50%, however, the groups were too small to allow for any conclusions. A study from China in cases with only local recurrence found improved survival by 2 months if CPI was used instead of gemcitabine in conjunction to radiation therapy (128).

Interestingly, a link has been reported between defective mismatch repair genes (dMMR) and response to PD-1 and PD-L1 inhibitors (117,129). In a retrospective cohort, one complete and one partial response have been seen in 7 patients receiving CPI and having dMMR, which is considerably better response rate than what all other studies have reported (117). Unfortunately, the presence of dMMR is a very rare event in patients with PC—only in 0.8% (129). Generally, CPI do not seem to have any ground-breaking effect in patients with advanced PC.

DC vaccines

The idea of using DCs in cancer vaccines follows the initial trials of antigen vaccination in an attempt to improve the immunoreactivity by correct major histocompatibility complex (MHC)-restricted antigen presentation to the effector lymphocytes and providing additional co-stimulation. This type of antigen presentation is a potent inductor of effector CD4⁺ and CD8⁺ lymphocytes.

In PC, DC vaccination is in many cases combined with cellular therapy—lymphokine-activated killer cells (LAK) or cytokine-induced killer cells (CIK) (Table 3). In the trials with vaccination with DCs only, the latter have been pulsed with peptides (130,132,136,139-141) or mRNA (135). In patients with advanced cancer, no objective responses have generally been observed (130,136,139,140). Some authors report isolated cases where partial (131) or no tumor activity was observed after longer follow up (135). Inducing specific delayed-type hypersensitivity responses by DC vaccines has been associated with improved survival (139). Interestingly, when DCs have been applied in the adjuvant setting after resection for PC, 100% of the patients survived the first year (132).

The studies combining DC vaccination with LAK cells or CIK have all been conducted in Asian population (133,134,137,142). Unlike the isolated DC vaccination, in these trials some objective responses were observed. Kimura et al. reported objective responses in 34% of the treated patients out of which two were complete responses (137). Hirooka et al. reported a median survival of 16 months and a 1-year survival of 80% in five patients with LAPC where DC were injected in the tumor while LAK were given intravenously—a result that can hardly be explained by the gemcitabine monotherapy that was used (134). However, larger studies are lacking.

Cellular therapy

The most efficient form of immunotherapy reported to date is adoptive cell transfer therapy using TILs (144,145). In patients with metastatic malignant melanoma, objective responses have been observed in 72% when TILs were administered after pre-conditioning chemotherapy with cyclophosphamide and fludarabine and whole-body radiation (144,146). In the patients who were found to be complete responders (impressive 22% of patients), the 3- and 5-year survival was 100% and 93%, respectively. A later randomized trial showed that these results can be achieved without radiation (147). Such results have not been achieved by any other type of oncologic therapy. The isolation of TILs, however, is a cumbersome process and has for long been impossible in PC. It was first reported by our group in 2016 that TILs from PC can be isolated using a cytokine cocktail of IL-2, IL-15, and IL-21 and expanded in sufficient amount to be sufficient for therapy (148). Another group also reported the isolation of TILs (149). So far, the data is only preclinical, but clinical trials are ongoing (150,151).

The most used immune cells for therapy are LAK cells and CIK and in combination with DC vaccination, as descried in the previous section (Table 3). Qiu et al. used autologous CIK together with pulsed DCs and reported a median survival of 24.7 months among the four responders with advanced PC (Table 3) (138). Chung et al reported that 60% of patients with metastatic PC were alive after 6 months after treatment with autologous CIK and not receiving any other oncologic treatment (Table 4) (154).

T cell therapy has also been attempted in PC, with cells derived from peripheral blood mononuclear cells (PBMCs) but without any overwhelming efficacy. Both allogeneic and autologous T lymphocytes from PBMCs sensitized to MUC-1 have been tested in resected and advanced PC (152,153). The combination of T cell and DCs has resulted in one out of 20 patients with advanced cancer with complete response, alive after 6 years (153). γδT cells retrieved and applied after resection have not proved to be of survival advantage (155). CAR-T cells for mesothelin have been tested in metastatic PC and two out of six patients have shown stable disease for 3.8 and 5.4 months without any other ongoing therapy (157). A common feature of all T cell trials is that, unlike the experience from TIL therapy, no preceding lymphodepleting treatment have been administered.

An interesting study has reported the use of allogeneic hematopoietic stem cell transplantation from HLA-identical siblings in patients with PC, analogical to its use in hematologic disease (158). Two patients receiving the treatment after radical resection for PC were both still alive after 9 years. Both cellular and humoral reactivity against two novel tumoral antigens has been observed as evidence for immunologically mediated treatment effect against cancer. Of course, larger trials are necessary before any conclusions can be drawn.

Discussion

As PC is constantly the one that fails to respond to any treatment attempts by standard oncologic means, inevitably lots of hope is brought onto immunotherapy to stop this closed cycle of desperation. The immunotherapy trials in PC have so far not shown a large-scale impact on prognosis in a broad patient cohort. Even though the clinical effects of immunotherapy have been limited, the immunological changes induced in response to treatment indicate a proof of concept—immunotherapy works. The premises for success, though, need to be diligently reevaluated.

Apparently, immunotherapy planned and delivered just like chemotherapy does not work in PC. Yet, the vast majority of the most recent trials seek to evaluate the potential efficacy of the mass-produced standardized antibody medication to an unselected cohort of patients. While CPI treatment would work in melanoma where the premises with mobilizing the infiltrating TILs, which recognize a large number of mutations, are already present in the tumors, in PC with its much fewer, scattered, and often naïve, TILs, that strategy as a single treatment option seems to be meaningless. If CPI might work in combination, for example with a stroma-targeting drug in order to aid accessibility of CPI to cancer cells in PC is unknown. However, it is the cheapest and most profitable type of treatment. But what could be the roadmap to immunotherapy’s success in PC?

PC has from baseline a lower probability of success with immunotherapy. Theoretically, adoptive transfer therapy with ex vivo expanded effector T lymphocytes would be the most appropriate choice to address the problem of having fewer mutations and fewer TILs. This means that the mutational profile of the individual patients’ tumors, carrying quite often private mutations, needs to be outlined - by genetic sequencing and typing of the T-cell receptors of the TILs. Apparently, this is a very costly undertaking that universities must cover, since for the industry that option is unattractive. This is a major limitation of this type of treatment. Using cellular therapy against preselected tumor associated antigen (TAAs), that has been tried so far, is not even nearly effective.

Immunotherapy by itself is among the most precise and strictly targeted treatments.

Cancers have evolved in a variety of molecular mechanisms to evade the recognition by the immune system. A combined strategy, by addressing a few of these mechanisms rather than picking a single target, should result in better efficacy. For example, an autopsy investigation after a vaccine trial revealed that the tumors of patients have been largely infiltrated by lymphocytes (159). Yet, this has not been enough to change the outcome, since the tumors have been overexpressing PD-L1. Supposedly, combination with a CPI might have improved the outcome. Combination strategies are, though, much more difficult to plan, since there are a variety of parameters to control for—choice and sequence of administration of the components, dosages, timing during treatment, etc.

The right timing and route of administration during the individual treatment algorithm of each patient is another point of concern. Complementation to surgical resection would hypothetically be the best scenario as the tumor burden has been reduced the most and the mutational landscape of the whole tumor can be assessed. The generation of a good product for adoptive transfer therapy, is a time-restricted process in order to generate the most efficient young TILs (160-162). This means that reinfusion would need to be two to three weeks after surgery, but this is perhaps the most inconvenient period in terms of healing and complications. Pancreatic surgery is inevitably associated with up to 40–50% complications rate and the development of pancreatic fistula or deconditioning may hamper the process. Longer culture of the TILs may drive them to exhaustion and decrease their effectiveness. On the contrary, a patient with metastatic PC who have progressed upon previous treatment, may deteriorate fast before the immune product has been generated and thus become unsuitable for the protocol. Therefore, adaptation of the planned studies to the clinical scenarios with earlier introduction of immunotherapy, as combination in first-line palliative or neoadjuvant therapy might be worth considering.

Another critical point is the preparation of the patient before treatment. As the autopsy studies after vaccination and the earlier trials in TIL therapy in melanoma revealed, the immunosuppressive environment created and maintained by the tumor rapidly deactivates the administered boosting immune product (146,159). The key to success has been the proper preconditioning by lymphodepletion using cyclophosphamide and fludarabine in order to “create space” for the activated product to settle (146,147). None of the finished trials in PC has used this principle, except for a couple of them relying on the mild and largely insufficient effect of cyclophosphamide or gemcitabine (141,155). Furthermore, chemotherapy that is used in parallel in the prevailing number of immunotherapy studies in PC, often goes with the administration of potent corticosteroids to counteract adverse events (43,69,163). That might theoretically completely deactivate the “good” inflammation that immunotherapy pursues. The route of administration should also be carefully considered. The usual intravenous infusion (apart from DC vaccination) may lead to that a large part of the product is sequestrated when bypassing the pulmonary circulation and does not reach a more distant target in significant amount.

Despite the difficult start, immunotherapy is slowly making its way in the treatment of PC. With careful consideration of the clinical premises, choice of the immune agents and preconditioning, immunotherapy could make a treatment breakthrough in PC.

Summary

Current studies, mostly using passive immunotherapy with antibodies (including checkpoint inhibitors) and antigen vaccines, have so far not marked a major breakthrough in the treatment of patients with advanced PC. The induced immunologic responses and individual cases of success among responders show a proof of concept—that immunotherapy is an emerging option for the treatment of patients with PC. Careful planning of the studies considering the particular characteristics and premises in patients with PC might be the key to better outcome in the near future.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Savio George Barreto) for the series “Unresolved Issues in Pancreatic Cancer” published in Chinese Clinical Oncology. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-21-174/rc

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-21-174/coif). The series “Unresolved Issues in Pancreatic Cancer” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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