Recent advances in immunotherapy for pancreatic cancer: a narrative review

Introduction

Despite improvements in survival of most solid malignancies, pancreatic cancer continues to have poor outcomes. While the greatest chance for cure is with surgical resection, fewer than 20% of patients have resectable disease at the time of diagnosis, thus there is an urgent need for new and effective therapies.

The low survival rate is multifactorial and related to the characteristics of the tumor and its microenvironment which maintain a highly immunosuppressive state. Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, has a microenvironment characterized by high expression of matrix metalloproteinases and tissue serine proteases, features that contribute to tumor invasion and metastatic spread (1). Further, stellate cells, stimulated by inflammatory cytokines and abnormal hedgehog signaling, produce collagen, fibronectin, laminin and hyaluronan deposits, causing stromal desmoplasia; this results in a physical barrier that impedes local blood supply, limiting drug delivery and the accessibility of cytotoxic immune cells (2,3). PDAC typically has a low tumor mutational burden, resulting in a depletion of tumor-specific antigens, hindering immune-surveillance and rendering it an “immunologically cold tumor”, with low response rates to immunotherapy (4,5). Additionally, in PDAC, NRB1-mediated ubiquitination of lysosomes and autophagosomes storing major histocompatibility complex (MHC)-1 leads to reduced MHC-1 expression thereby hindering neo-antigen presentation (6). Lastly, tumor cells produce tumor-promoting cytokines, which modulate the immune response to favor production of immunosuppressor cells including myeloid derived suppressor cells (MDSCs), regulatory T-cells (Tregs), cancer associated fibroblasts (CAFs), and immunosuppressive tumor associated macrophages, as opposed to tumor-inhibiting dendritic cells or cytotoxic T-cells (7,8).

This work provides an update of various immunotherapy approaches to treat pancreatic cancer, specifically using immune checkpoint inhibitors (CIs), CD40 agonists, vaccines, bi-specific antibodies, and chimeric antigen receptor (CAR) T-cell therapy. Figure 1 illustrates these treatment modalities. We present this article in accordance with the Narrative Review reporting checklist (available at https://dmr.amegroups.com/article/view/10.21037/dmr-24-2/rc).

Figure 1 Current methods in immunotherapy for pancreatic cancer. (A) Checkpoint inhibitors such as PD-1/PD-L1 blockade to reprogram CD8 T cells, TGFBR1/2 inhibition and CTLA-4 blockade to impair regulatory T cells, and CD40 agonist to activate dendritic cells. (B) CAR T cells targeting tumor-specific antigens using a chimeric antigen receptor. (C) Vaccines against tumor antigens, including mRNA and peptide vaccines, dendritic cell vaccines that are generated through pulsing of autologous dendritic cells with tumor lysate or specific antigens, and GVAX, where irradiated autologous or allogenic tumor cells are engineered to express GM-CSF to promote dendritic cell maturation. (D) Bispecific antibodies targeting two different cell surface receptors on cancer cells, such as HER2 and HER3, PD-L1 and CTLA-4, as well as bispecific antibody armed activated T cells where the antibody targets a tumor cell surface receptor such as HER2, as well as CD3 on the surface of T cells to induce their activation. CAR, chimeric antigen receptor; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; CTLA-4, cytotoxic T-lymphocyte associated protein 4; GM-CSF, granulocyte-macrophage colony-stimulating factor; DC, dendritic cell.

Methods

As noted in Table 1, a PubMed database search, Clinicaltrials.gov search and Google Scholar search were performed for articles with search terms “immunotherapy” and “pancreatic cancer” published between January 1, 2000 and December 20, 2023. Results in the English language were reviewed and included based on the authors’ discretion.

CIs

Immune checkpoints are inherent regulators of the immune system and crucial for self-tolerance but are exploited by cancer cells as a defense mechanism. Checkpoint proteins currently under investigation include cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). T-cell activation requires binding of T-cell receptor to MHC-bound antigen and co-stimulatory binding of CD28 on T-cells to B7 ligands (CD80 or 86) on antigen presenting cells (APCs), resulting in T-cell growth and differentiation (9). CTLA-4, which is expressed primarily on naïve Tregs, binds B7 ligand to regulate and limit T-cell activity. Anti-CTLA-4 antibodies block CTLA-4, thereby removing its inhibitory effect. Activated T-cells, B-cells and natural killer (NK) cells express PD-1 (10). Upon recognizing MHC-bound antigen on tumor cells, T-cells release cytokines that stimulate target cells to express PD-L1. Binding of PD-L1 to PD-1 suppresses cytotoxic T-cell activity. Blockade of either PD-1 or PD-L1 thus removes this inhibition on T-cell activity. CIs have been tested as monotherapy, in dual-therapy, and in combination with chemotherapy, as well as in a variety of other approaches, as outlined below.

Single or dual CI

Single and dual CIs, when used in isolation, have limited effectiveness for PDAC. Both phase I and phase II trials evaluating single agent CI for locally advanced or metastatic PDAC (mPDAC) found no objective response to therapy (11,12). Similarly, a randomized, phase 2 trial of 65 patients with metastatic or recurrent PDAC investigating dual vs. single agent immunotherapy failed to achieve an overall response rate (ORR) of 10% in either arm, thus was terminated (13).

The effectiveness of immunotherapy is more promising, however, for microsatellite instability-high (MSI-H) PDAC, which is hypothesized to arise from its higher mutational load and thereby higher tumor neoantigen burden (5). In a study of 32 patients with PDAC with MSI-H, patients treated with CIs achieved a 75% ORR and 20% complete remission (CR) rate, compared to cytotoxic chemotherapy, which yielded a 30% ORR (14). Single-agent CIs can thus be effective therapy for the 1–2% of mPDAC patients who have MSI-H disease (15,16). The effectiveness of CIs in this population has sparked interest in the development of combination therapies that would improve antigen presentation and T-cell activity and infiltration while reducing immunosuppressive cells (4,17).

CI with chemotherapy

Chemotherapy has cytotoxic and immunomodulatory tumor effects. Gemcitabine, an apoptotic pyrimidine antimetabolite, reduces MDSCs and Tregs, and increases antigen presentation by dendritic cells to promote cell-mediated immunity (18-20). Nab-paclitaxel, a colloidal suspension of paclitaxel and albumin nanoparticles, increases inflammatory polarization of macrophages, promotes antigen presentation and maturation of dendritic cells, and reduces immunosuppressive MDSC, Tregs and CAF activity while increasing anti-tumor NK cell and CD8⁺ activity (21).

Combination therapy of CI with chemotherapy has thus far been unsuccessful at improving outcomes. In CCTG PA.7, a randomized, multi-center phase II study, 180 patients with mPDAC were randomized to receive either chemotherapy (gemcitabine with nab-paclitaxel) alone or in combination with CIs (durvalumab and tremelimumab), and failed to yield a significant difference in median overall survival (OS) (8.8 vs. 9.8 months, respectively, P=0.72) or progression-free survival (PFS) (5.4 vs. 5.5 months, P=0.91) (22).

There are ongoing investigations to optimize the combination of chemotherapy with CIs, such as camrelizumab, botensilimab and spartalizumab (23,24). These studies aim to broaden the applicability and durability of CI response.

Dual CI with radiation therapy

Pre-clinical evidence demonstrates that CIs used with radiation therapy affect expression of cell surface targets of immunotherapy. An in vitro study found that murine PDAC cell lines treated with chemotherapy and radiation therapy had increased percentage and intensity of PD-L1⁺ cells (24). In vivo murine models similarly found that the combination of radiation therapy with anti-PD-L1 caused greater tumor infiltration of CD8⁺ and CD4⁺ T cells, increased CD8⁺ T cell activity [as noted by interferon-gamma (IFN-γ) expression], and reduced infiltration of MDSCs and Tregs compared to controls.

These favorable results led to the development of a phase I, open-label study which enrolled 59 patients with previously treated mPDAC (25). While combination therapy of radiation with dual CIs (durvalumab and tremelimumab) was associated with a higher PFS of 2–3 months compared to radiation alone (PFS of 1–2 months), it was associated with an increased incidence of adverse events, including grade 3–4 lymphopenia and autoimmune colitis, suggesting the combination elicited greater, albeit undesirable, pro-inflammatory response.

Alternative combinations of immunotherapy and radiation have been explored. In CheckPAC, a randomized, phase II, open-label study, 84 patients with mPDAC received stereotactic body radiation therapy (SBRT) with either dual CIs (nivolumab and ipilimumab) or nivolumab alone (26). The clinical benefit rate (complete response, partial response, or stable disease) of patients who received SBRT with nivolumab alone was 17.1% vs. 37.2% in the dual CI arm. Clinical outcomes were not correlated to PD-L1 expression or biomarkers of cytotoxic or Treg infiltration. Nevertheless, five of six patients who received SBRT with dual CIs had an abscopal effect, with reduction in tumor mass at non-radiated sites, suggesting that there are yet unmeasured immunomodulatory effects which warrant further investigation.

Building on the results of CheckPAC, the ongoing LAPTOP trial is investigating dual CI (nivolumab and ipilimumab) with chemotherapy (gemcitabine and nab-paclitaxel) and SBRT in patients with borderline resectable, locally advanced or mPDAC (27). This combination aims to increase antigen exposure and lymphocyte antitumor activity.

CI with CXCR4 inhibitor and chemotherapy

CXCR4, a G-protein coupled transmembrane chemokine receptor expressed on B-cells, naïve T-cells, monocytes, and bone marrow progenitor cells, interacts with ligand CXCL12 chemokine to modulate the tumor immune microenvironment and appears associated, if not directly implicated, in tumorigenesis (28). In pancreatic cancer, CXCR4 promotes progression of precursor pancreatic intraepithelial neoplasia to PDAC and metastatic growth (29). CXCR4-CXCL12 interaction has activating downstream effects on the MAPK, PI3K, Sonic Hedgehog, Wnt, paracrine and autocrine signaling cascades. A meta-analysis identified that CXCR4 overexpression was more common in PDAC than in normal pancreatic tissue [odds ratio (OR) =132.07, P=0.03]. CXCR4 is thus an attractive therapeutic target.

AMD3100 (plerixafor) is a small molecule CXCR4 inhibitor. In murine models, AMD3100 infusion resulted in reduction of CAFs expressing fibroblast activation protein (FAP), increased T-cell infiltration of the tumor, and improved anti-PD-L1 therapy responsiveness with an associated 15% decline in PDAC volume (30). In a study of 26 patients at two centers with colorectal cancer and PDAC, seven-day continuous infusion of AMD3100 resulted in significantly increased intratumoral CD8+ T cell density (P<0.05) (31). Patients also saw a significant decrease in circulating tumor DNA level (n=15, P=0.03), and a significant rise in FAP⁺ cells expressing CCL19 (from 5.8% to 25.7%), which indicates an immune responsive rather than immune suppressive fibroblast cell development. While CR or PR were not achieved, 13 patients (57%) had stable disease by day 24, indicating clinical potential for CXCR4 inhibitors.

Motixafortide (BL-8040) is a high-affinity small peptide inhibitor of CXCR4. In a phase II, open-label, two-cohort study, patients with mPDAC after progression on at least one line of chemotherapy were treated with motixafortide, pembrolizumab and chemotherapy had a disease control rate (DCR) of 34.5% and median OS of 3.3 months (32). Paired screening and on-treatment biopsies found that the combination of motixafortide and pembrolizumab resulted in increased tumor infiltration of T-cells (CD3⁺, CD4⁺ and CD8⁺) and activated CD8⁺ granzyme B⁺ cytotoxic T-cells, and decreased granulocyte-like MDSCs and decreased tumor cell density. These results raise optimism that the combination of CXCL4 inhibitor and chemotherapy can expand the applicability of CIs for treatment of PDAC after failure of first line therapy.

CI with poly ADP-ribose polymerases (PARP) inhibitors

PARP are a family of proteins that participate in DNA break repair and apoptosis (33). PARP inhibitors compete with NAD⁺ at the active site on PARP thus trapping inactivated PARP1 on the stalled replication fork at the site of DNA damage preventing repair, and resulting in the death of vulnerable tumor cells with homologous recombination repair deficiency, such as BRCA-deficient cancer cells (33,34). In murine models of BRCA-deficient ovarian cancer, combination therapy of PARP inhibitors with CI induced a synergistic T-cell mediated anti-tumor effect (34). The effectiveness of combination CI and PARP inhibitor has thus also been explored in platinum-sensitive advanced PDAC. In an open label, phase 1b/2 study, 91 patients with locally advanced or mPDAC with known platinum sensitivity were randomized to receive maintenance therapy with niraparib (PARP inhibitor) and either nivolumab or ipilimumab (35). The niraparib and ipilimumab combination had superior 6-month PFS of 59.6% (95% CI: 44.3–74.9%, P=0.045) compared to that of niraparib with nivolumab (PFS of 20.6%, 95% CI: 8.3–32.9%, P=0.0002). Combination of CI and PARP inhibitor is a promising tolerable and effective maintenance therapy for individuals with platinum-sensitive advanced PDAC.

Because radiation can introduce DNA breaks, investigators assessed if radiation therapy could make tumors more vulnerable to the combination of PARP inhibitor and CI. In a single-arm, open-label, phase II trial, fifteen patients with microsatellite stable (MSS) PDAC were treated with a combination of niraparib, dostarlimab (anti-PD-1 antibody), and radiation therapy, yielding a disappointing 0% DCR (36).

Ongoing investigations are exploring other CI and PARP inhibitor combinations. An open-label, single-arm phase II trial is currently recruiting patients with mPDAC with mutations in DNA damage repair genes who benefited from first line platinum-based therapy to determine if they may have improved outcomes with olaparib and durvalumab combination therapy (37).

CI with TKI

Transforming growth factor beta (TGFβ) is a cytokine which participates in cell cycle regulation by crosslinking TGFβ receptor to phosphorylated SMAD proteins, causing downstream transcription of cyclin-dependent kinase inhibitors, thereby halting cell-cycle progression from G1 to S phase (38). TGFβ can inhibit activity of cytotoxic T-cells, leading to decreased production of cytokines including IFN-γ and cytolytic molecules such as perforin1 and granzyme B.

Galunisertib, an oral small molecule inhibitor of TGFβ receptor 1 (TGFβR1), was found in in vitro models to rescue TGFβ1-exposed CD8⁺ T cells (39). In murine models of triple negative breast cancer, galunisertib resulted in dose-dependent tumor volume regression. Furthermore, combination therapy of galunisertib and anti-PD-L1 checkpoint blockade lowered NIH3T3 fibroblast activity and reversed the suppression of IFN-γ and granzyme B secretion in murine and human NK and CD8⁺ T-cells (40). In light of these promising pre-clinical studies, an international, multicenter study assessed the combination of durvalumab and galunisertib for 79 patients with recurrent or refractory mPDAC (41). This combination achieved a DCR of 25% and median OS of 5.72 months (95% CI: 4.01 to 8.83). Tumor PD-L1 immunohistochemistry scores did not correlate with clinical outcome. This study was limited by lack of a comparison arm and small sample size.

CI with electroporation

Mechanical disruption of tumor cells through electroporation is also under investigation as a method to improve response to CIs. Irreversible electroporation induces tumor cell apoptosis and release of tumor antigens, eliciting heightened cytotoxic CD8⁺ T-cell response. A pilot, single-arm phase II trial is recruiting patients with mPDAC to undergo irreversible electroporation of a liver metastasis followed by nivolumab administration (42). PANFIRE-3, a randomized phase I trial, is similarly evaluating the combination of irreversible electroporation with nivolumab for mPDAC, with the addition of a toll-like receptor 9 (CpG) ligand (43). An overview of clinical trials evaluating immune CI treatments for PDAC can be found in Table 2.

CD40 agonist monoclonal antibodies

CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily expressed on APCs and nonhematopoietic tissue. CD40 ligation on naïve B-cells activates B-cells and induces immunoglobulin isotype switching (44). CD40 ligand binding to dendritic cells induces maturation and upregulates signaling cascades leading to antigen presentation and release of cytokines interleukin-12 (IL-12) and p70, resulting in an increased CD8⁺ T-cell immune response (45). CD40 activated monocytes and macrophages switch to M1 phenotype with resulting cytotoxic effects on tumor cells and degradation of extracellular stroma. Due to its potential anti-tumor activity, efforts are underway to enhance CD40 activity in patients with PDAC.

An open-label, multicenter phase I trial evaluated the benefit of neoadjuvant and adjuvant selicrelumab, a CD40 agonist monoclonal antibody, with or without chemotherapy in patients with resectable PDAC (46). Sixteen patients were randomized to receive selicrelumab single agent or in combination with gemcitabine and nab-paclitaxel preoperatively. The 1-year disease-free survival rate was 49.9% for patients treated with selicrelumab monotherapy compared to 75.0% for patients treated with selicrelumab with chemotherapy. Histologic examination suggested that selicrelumab induced changes in the tumor microenvironment. Resected tumor specimens from patients treated with selicrelumab had half the extent of fibrosis compared to control patients who did not receive selicrelumab. Patients treated with selicrelumab also had statistically higher densities of mature dendritic cells, CD8⁺ T-cells and CD4⁺ T-cells compared to controls not treated with selicrelumab. Based on CD163 expression on macrophages and monocytes, there was less M2 macrophage activation state noted in those treated with selicrelumab. Higher levels of inflammatory cytokines CXCL10 and CCL22 were also identified in patients treated with selicrelumab. Expanded T-cell clones were seen in the tumor specimens from selicrelumab treated patients. Higher expression of PD-1 on CD4⁺ and CD8⁺ T-cells was noted in selicrelumab-treated tumors, suggesting that selicrelumab may increase potency of PD-1 blocking agents. Selicrelumab, by increasing T-cell-enrichment and infiltration, may be able to convert a “cold” to “hot” tumor, thus increasing its vulnerability to cytotoxic T-cell therapies.

Similarly, the PRINCE trial compared outcomes of multimodal therapy. The PRINCE trial was a randomized, open-label phase II study of 99 mPDAC patients treated with chemotherapy combined with either nivolumab, sotigalimab (CD40 agonist antibody) or both as first line therapy (47). The primary endpoint of one year OS rate was highest for patients treated with nivolumab with chemotherapy (75.7%, P=0.006), compared to sotigalimab with chemotherapy (48.1%, P=0.062), or both with chemotherapy (41.4%, one sided P=0.23). These results were compared to historical control of 35%. CD4⁺ T-cell, B-cell and dendritic cell subsets in circulation and tumor were predictive of longer OS in patients who were treated with both sotigalimab and chemotherapy while antigen-experienced type-1 CD4 T-cells and T follicular helper cells (CD4⁺PD-1⁺CXCR5⁺) were predictive of longer survival than those treated with nivolumab and chemotherapy, illustrating that surrogate biomarkers correlating to treatment response may vary with the therapeutic agent.

The REVOLUTION trial, an open-label, non-randomized 2-stage study, is the successor of the PRINCE trial, and is recruiting treatment-naive patients with mPDAC to evaluate chemotherapy (gemcitabine and nab-paclitaxel) with combinations of nivolumab, ipilimumab, hydroxychloroquine or NG350A (an oncolytic adenoviral vector-expressing anti-CD40 antibody) (48).

Mitazalimab, a human immunoglobulin G (IgG) monoclonal anti-CD40 antibody is currently under investigation in different trials, with chemotherapy in OPTIMIZE-1, and in combination with MesoPher, a dendritic cell vaccine in REACtiVe-2 (49,50). An overview of clinical trials evaluating CD40 agonist monoclonal antibody treatments for PDAC can be found in Table 3.

Vaccines

Dendritic cell vaccines

Dendritic cells are antigen-presenting cells that help direct innate and adaptive immune response by promoting T-cell, NK cell and memory B-cell activity. The PDAC tumor microenvironment is deficient in dendritic cells, due in part to tumor-derived cytokines and exosomes which attenuate dendritic cell activity and increase levels of MDSCs, creating a tumor-tolerant environment (51). Certain CD11b⁺ dendritic cells promote Tregs and suppress CD8⁺ T-cells. Dendritic cells seize, process, and present antigens on MHC class I and II molecules, which are then recognized by CD8⁺ and CD4⁺ T-cells, promoting their activity and proliferation (52).

Wilms tumor gene 1 (WT1) antigen is an attractive antigenic candidate because it is highly expressed in PDAC, but not observed in normal pancreatic ductal cells (53). In vitro exposure of five human pancreatic cancer cell lines to WT1 antisense oligomers resulted in growth inhibition, suggesting that WT1 antigen is a tumorigenic target for inhibition. A randomized phase II study in Japan evaluated the combination of intradermal WT1 vaccine with gemcitabine compared to gemcitabine alone in 85 patients with advanced PDAC and found that combination therapy resulted in longer PFS [5.2 vs. 3.3 months, hazard ratio (HR) =0.66, P=0.08], although there was no significant difference in median OS (54). Delayed type hypersensitivity (DTH) to WT1 was associated with longer PFS and increased WT1-cytotoxic T-cells, and longer PFS (P<0.0001), suggesting that WT1 specific immune responses were required for prolonging PFS.

Histologic evaluations have found that dendritic cell vaccines can alter the tumor microenvironment. In an unblinded phase I trial, a WT1 pulsed dendritic cell vaccine was studied in combination with adjuvant chemotherapy in eight human leukocyte antigen (HLA)-class II -compatible patients with WT1 expressing resectable PDAC (55). OK-432, picibanil, a streptococcal preparation known to induce cytokines which promote dendritic cell, macrophage, NK cell and type 1 helper T-cells and cytotoxic T-cell activity, was also administered (56). The OS rate at 2 years post-surgery with dendritic cell (DC) vaccination was 62.5%. ELISpot assay found a statistically significant rise in WT1-specific cytotoxic T-cell population from pre- to post-vaccination (P=0.02), however by tetramer assay of five patients, no significant difference was found. The 2-year post-surgical OS was significantly better for patients who had WT1-specific cytotoxic T-cell response compared to those who did not (71.4% vs. 0.0%, P=0.008). This study suggests that with careful selection of a tumor-associated antigen, dendritic cell vaccines can orchestrate an immunomodulatory response directed at PDAC that is safe and tolerable.

MUC1 (CD227) is also a target for vaccine therapy. Over-expressed in 90% of PDAC, this glycosylated type I transmembrane protein increases tumor invasion and angiogenesis (57,58). An open label phase I/IIa study assessed the safety and efficacy of WT1 peptide and MUC1-pulsed dendritic cell vaccine with chemotherapy as adjuvant treatment for patients with resectable PDAC expressing both WT1 and HLA-ABC (58). Although 90% of patients experienced an adverse event, none exceeded grade 1, and this combination was well tolerated overall. Median OS was 46.4 months and median relapse-free survival (RFS) was 17.7 months from time of surgical resection. Neither the quantity of cytotoxic T-cells as detected by tetramer assay, cytoplasmic WT1 staining intensity, nor tumor-infiltrating mononuclear cell immunophenotype correlated to OS or RFS; however results were limited by low sample size. Increased infiltration of CD3⁺, CD4⁺, CD8⁺ mononuclear cells was associated with induction of WT1 specific cytotoxic T-cells, but did not meet statistical significance, emphasizing the need for larger clinical trials to determine the immunomodulatory effect on the tumor microenvironment.

Autologous dendritic vaccines produced from mutant KRAS peptide antigens and vaccines produced from tumor lysate are under investigation with ongoing clinical trials (59,60).

Peptide vaccines

Peptide vaccines aim to introduce HLA restricted tumor-specific antigens to antigen-presenting cells, which in turn induce cytotoxic T-cell activity to eliminate cancer cells that express those antigens. A multicenter, non-randomized, single-arm phase II trial evaluated the combination of two HLA-A*2402 restricted peptide vaccines against VEGFR1, VEGFR2 and KIF20A peptide with gemcitabine in 68 chemotherapy-naïve patients with unresectable PDAC (61). VEGF1 and VEGF2 promote tumor vascularization, while KIL20A is involved in intracellular trafficking of molecules and organelles. The 1-year OS rates for HLA-matched and HLA-unmatched groups were similar, 27.0% and 34.5% respectively (P=0.66), and median PFS was 4.7 months and 5.2 months respectively (P=0.275). Patients who developed a peptide specific cytotoxic T-lymphocyte response had better outcomes compared to those who did not (P=0.02, P=0.009 respectively), however this did not hold true for VEGFR2 (P=0.31).

Another randomized, placebo-controlled phase I dose escalation study evaluated VXM01, an antigen vaccine developed using live attenuated Salmonella typhi harboring a VEGFR2-encoding plasmid in the treatment of 26 patients with locally advanced, inoperable or stage IV pancreatic cancer (62). Patients were concurrently treated with gemcitabine. The VEGFR2 cytotoxic T-cell response, as measured by IFN-γ ELISpot analysis was significantly higher in the higher dose VXM01 group compared to the placebo and lower dose VXM01 group, however there was no statistically significant difference in outcomes between the placebo and VXM01 patients.

To eliminate the concern of a target antigen not being present on the tumor, efforts are underway to develop personalized vaccines. A phase II retrospective study evaluated neoantigen-based peptide vaccine, iNeo-Vac-P01 in 7 patients with advanced PDAC who had progression or intolerance after initial therapy (63). Patient tissue and blood samples were evaluated via whole exome sequencing and bioinformatics studies to synthesize the 15–35 HLA classes I and II neoantigen peptide personalized vaccines. Patients were also provided with granulocyte-macrophage colony-stimulating factor (GM-CSF), concurrently with chemotherapy or CI therapy. Mean OS was 24.1 months (11 to 31.4 months). Patients with longer OS were found to have a higher IFN-γ titer after vaccination, compared to those who had shorter OS, suggesting that IFN-γ titer may be a surrogate marker for treatment efficacy. All patients had higher proportions of CD4⁺ CTLA-4⁺ and CD8⁺ CTLA-4⁺ T-cells in peripheral blood during vaccination and patients with longer OS had more effector memory T-cells compared to central memory T-cells. None of the patients developed a serious adverse event, suggesting that personalized vaccines may have safety benefits in addition to their anti-tumor effect.

GVAX

GVAX is a vaccine technology using either allogeneic pancreatic cancer cells or autologous pancreatic cancer cells transgenically modified to express GM-CSF, which promotes DC maturation. Combination therapies with GVAX aim to reduce Treg activity while promoting antigen presentation, cytotoxic T-cell activity and innate immunity. In one multicenter, open-label trial, 93 patients with mPDAC who had received one previous line of therapy were randomized to receive cyclophosphamide and GVAX vaccine, followed by either CRS-207 (Listeria monocytogenes-expressing mesothelin) and nivolumab (arm A) or CRS-207 alone (arm B) (64). Listeria monocytogenes, when phagocytosed, introduces mesothelin to APCs which then process and present the peptides on the cell surface bound to MHC. Median OS was not statistically different at 5.9 months for arm A vs. 6.1 months for arm B, with HR 0.86. Arm A patients with longer OS had notably greater densities of lymphoid cells, NK cells and CD8⁺ T-cells and increased myeloid PD-L1 expression compared to those with short OS. The combination therapy was able to induce modifications in the tumor microenvironment, and further exploration is necessary to improve clinical outcomes.

Other studies have evaluated GVAX in combination with different CIs. A phase Ib open-label study randomized 30 patients with previously treated locally advanced or mPDAC to receive either ipilimumab alone or in combination with GVAX (65). Median OS between the treatment arms were not statistically significant (5.7 months for combination therapy vs. 3.6 months for ipilimumab alone, HR =0.51, P=0.07), however combination therapy had a higher 1-year OS rate (27% vs. 7%). An OS exceeding 4.3 months was associated with greater mesothelin-specific T-cell responses (P=0.01) and larger mesothelin-specific T-cell repertoire size (P=0.009). These outcomes are again suggestive that multimodal induction of greater T-cell activity may lead to better clinical outcomes.

A phase II multicenter trial of 80 individuals with PDAC found that combination therapy of GVAX with ipilimumab was inferior to FOLFIRINOX (median OS 9.38 vs. 14.7 months, respectively, HR =1.74, P=0.02) (66).

mRNA vaccines

mRNA vaccines introduce neoantigens into a patient to stimulate both humoral and cell-mediated targeted anti-tumor responses. Because they are personalized, non-infectious, manufacturable, and do not insert into the host genome, mRNA vaccines are a popular treatment modality under investigation for cold tumors like PDAC (67).

A phase I trial evaluated the ability of autogene cevumeran, a personalized mRNA neoantigen vaccine, to promote T-cell activity in patients with surgically resected PDAC (68). The study enrolled 32 patients of whom 16 patients underwent surgery and received treatment with atezolizumab (anti PD-L1 antibody), autogene cevumeran, and the chemotherapy regimen mFOLFIRINOX (including 5-fluorouracil, folinic acid, oxaliplatin and irinotecan). Eight out of 16 (50%) patients who received autogene cevumeran had increased T-cell activity directed against at least one vaccine neoantigen. Furthermore, patients with measurable T-cell response, responders, had substantially expanded de novo polyclonal neoantigen-specific CD8 cells in the tumors that remained functional and durable for up to 2 years post-surgery. Responders had a longer median RFS compared to nonresponders, with a median RFS that was not reached compared to median RFS of 13.4 months (HR =0.08, P=0.003). Further studies are needed to optimize the process of neoantigen screening and improvise mRNA vaccine potency.

There is continued interest in the applicability of mRNA vaccines in PDAC and other KRAS mutated solid tumors, and results of a phase I trial evaluating the safety and tolerability of the combination of mRNA-5671/V941 monotherapy compared to combination therapy with pembrolizumab are pending (69). An overview of clinical trials evaluating vaccine treatments for PDAC can be found in Table 4.

CAR T-cell therapy

CAR T-cells are generated by procuring patient’s T-cells via leukapheresis of peripheral blood, then genetically modifying the T-cell receptor (using viral vectors) to recognize a specific tumor antigen target, thereby directing its anti-tumor immune response. CAR T-cells can modify the immunosuppressive tumor microenvironment by producing cytokines that improve T-cell infiltration into the tumor (70). To improve CAR T-cells’ likelihood of engraftment and expansion, patients receive conditioning chemotherapy to cause lymphodepletion prior to CAR T-cell infusion. Although approved for several hematological malignancies, CAR T-cell therapy is not yet approved for treatment of solid tumors. There are ongoing efforts to identify pancreatic cancer tumor antigenic targets for CAR T-cell development.

Mesothelin is a glycoprotein that is highly expressed in PDAC, pleural mesothelioma, and ovarian adenocarcinoma, but also present in lower levels on pleural, pericardial, peritoneal, tracheal and tonsillar tissues (71). In a phase-I study, two of six patients with chemotherapy-refractory mPDAC who were treated with CAR-T-targeting mesothelin (CART-meso) cells achieved stable disease, with PFS of 3.8 to 5.4 months (72). The levels of reactive IgG doubled from baseline in five of the six patients studied. While CAR transcripts were noted in the blood after each infusion, they were not detected in the few available post-treatment biopsies, suggesting that CART-meso cell infusion caused transient changes in the tumor microenvironment or that the CART-meso durability was limited. This study was limited in that biopsies were not obtained to confirm tumor cell surface expression of mesothelin prior to initiation of therapy.

CART-meso cells feature a two-pronged approach to antitumor effect. Through binding to mesothelin, CART-meso cells induce tumor cell death and trigger the release of tumor antigens and inflammatory cytokines. CART-meso furthermore expresses CD40L which binds to CD40 on dendritic cell and macrophages, activating them to uptake tumor peptide antigens and present them via MHC to naïve T cells, promoting their maturation, thus broadening, and amplifying the immune response by a process called epitope spreading.

A phase I trial found that CART-meso cells had minimal tumor infiltration and limited durability on patients with mPDAC, thus further efforts are necessary to improve outcomes with this emerging therapy (73). An overview of clinical trials evaluating CAR T-cell treatments for PDAC can be found in Table 5.

Bispecific antibodies

Bispecific antibodies are an increasingly popular immunotherapy drug category because they can potentially achieve better tumor specificity, reduce on-target, off-tumor adverse effects and lower the risk of resistance by simultaneous alteration of two tumorigenic pathways (74). Zenocutuzumab is an antibody-dependent cellular cytotoxicity-enhanced anti-HER2xHER3 bispecific antibody designed for patients who harbor neuregulin 1 gene fusion (NRG1) rearrangements. NRG1 fusion rearrangements are driver mutations that occur in 1.5% of KRAS wild-type pancreatic cancers. NRG1 results in a mutant protein which binds members of the ERBB RTK family, triggering heterodimerization, activating the phosphoinositide-3 kinase pathway and promoting tumorigenesis (75). Zenocutuzumab functions by a “dock and block” approach; one Fab arm binds prevalent cell-surface-expressed HER2 protein (“docks”), while the other Fab arm blocks NRG1 interaction with HER3 (“blocks”), thereby inhibiting this stimulatory pathway. In vitro studies found that zenocutuzumab inhibited proliferation of lung adenocarcinoma and breast cancer cell lines expressing NRG1 fusion rearrangements.

In preclinical trials, zenocutuzumab prevented cell cycle progression and promoted apoptosis (75). Zenocutuzumab effectively shrank NRG1 fusion xenograft tumors by 63%±17% in murine models. Two mPDAC patients with NRG1 gene fusion treated with zenocutuzumab had symptomatic improvement and reduction in tumor size for 11–14 months. These early successes raised interest in increased NRG1 fusion testing for patients with mPDAC. A phase I/II open-label clinical trial assessing zenocutuzumab for patients with solid tumors and NRG1 fusion mutation found that among patients with pancreatic cancer, the investigator-assessed ORR was 39% (76).

Other bispecific antibodies are also under investigation. KN046, a recombinant humanized bispecific antibody, is composed of a PD-L1 inhibitor and a CTLA-4 inhibitor. KN046 was assessed as single agent therapy in the second line setting for 21 patients with unresectable or mPDAC in a phase II trial, achieving an ORR of 11.1%, median PFS of 2.1 months and median OS of 7.5 months (77). In China, there are ongoing clinical trials evaluating KN046 and a PD-L1/CTLA-4 bispecific antibody (78,79).

There is persistent optimism that bispecific antibodies will help overcome exhaustion of tumor infiltrating lymphocytes and spur anti-tumor activity. An overview of clinical trials evaluating bispecific antibody treatments for PDAC can be found in Table 6.

Bispecific antibody armed activated T-cells (BATs)

Efforts to increase T-cell trafficking and T-cell binding to specific tumor antigen independent of MHC binding led to the development of the BAT, an activated T-cell with one antibody arm that binds a tumor associated antigen and another that stimulates T-cell activity (80). An in vitro study found that BATs armed with anti-CD3/anti-EGFR or anti-CD3/anti-HER2 bispecific antibody had statistically greater cytotoxicity against cell lines resistant to cisplatin, gemcitabine or both compared to unarmed activated T cells (P<0.001) (81). Furthermore, sequential use of HER2-BATs followed by EGFR-BATs showed statistically higher cytotoxicity compared to BAT monotherapy (77% vs. 25%, P<0.05). Priming pancreatic tumor cells by exposing them to BATs prior to cisplatin resulted in increased cytotoxicity at lower concentrations of cisplatin compared to pancreatic tumor cells that were not primed. Priming is associated with downregulation of ABC transporters, regulators of small molecule transport across cell membranes, which may reduce the efflux of chemotherapy from pancreatic cancer cells, thereby improving cytotoxicity. As such, BATs may lower the effective dose of chemotherapy, thus reducing the risk of adverse events.

Discussion

Given that current systemic therapies for advanced PDAC have poor efficacy, there is an urgent need for improved treatment options (82,83). MSI-H PDAC appears to benefit from checkpoint inhibition. In the MSS population, ongoing investigations aim to modulate the tumor microenvironment to generate an enhanced anti-tumor response. While checkpoint inhibition alone is insufficient to elicit a clinically significant disease regression, synergistic combination therapies aim to increase tumor killing by augmenting antigen exposure and cytotoxic response. Many upcoming phase I and phase II trials are assessing such new classes of immuno-therapeutic agents.

Despite expansion of candidate drug molecules in the recent years as reviewed in this article, there remain several limitations to the studies. Several of these trials have low sample size, limiting the ability of the investigator to make determinations regarding the clinical efficacy of these novel therapies. Moreover, studies reviewed here did not investigate the expression pattern of the targets of drug candidates in each patient, making it further difficult to interpret the clinical efficacy. Most of the studies with CIs failed to indicate tumor mutational burden, MSI-status or mismatch repair (MMR) deficiency status routinely. Pre-intervention, few studies ascertained PD-L1 status, adequate expression of the molecular targets such as, mesothelin or VEGR. While a heterogeneous group of patients may not have a statistically significant response to the targeted intervention, it is possible that patients with tumor expressing the investigational target demonstrate superior outcomes, and thus should be the focus of the phase I trials.

Nonetheless, these studies serve as a valuable platform and indicate the potential for immunotherapy strategies as emerging landscape in PDAC treatment in the near future. These initial studies suggest most of the candidate drugs are safe and well tolerated. While the role of immunotherapies in PDAC treatment is evolving, further studies should personalize treatments, pairing therapeutic interventions with patients based on their molecular profiles, which in turn will help predict the response rate more accurately. Furthermore, there remain challenges to identify better biomarkers that accurately reflect measurable changes over time in the local tumor microenvironment for the purpose of monitoring durability of response.

Conclusions

Although pancreatic cancer has historically yielded poor responses to chemotherapy due to its immunosuppressive microenvironment, recent innovations in immunotherapy have introduced new tools to the arsenal against this devastating illness. These multimodal therapies aim to increase tumor antigen presentation, stimulate cytotoxic activity, and disrupt tumor proliferative signaling cascades. Ongoing clinical trials investigating targets identified through careful inspection of tumors’ molecular profiles hold the potential to improve the treatment of pancreatic cancer.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Michael D. Chuong) for the series “Novel Therapies for Pancreas Cancer” published in Digestive Medicine Research. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://dmr.amegroups.com/article/view/10.21037/dmr-24-2/rc

Peer Review File: Available at https://dmr.amegroups.com/article/view/10.21037/dmr-24-2/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dmr.amegroups.com/article/view/10.21037/dmr-24-2/coif). The series “Novel Therapies for Pancreas Cancer” was commissioned by the editorial office without any funding or sponsorship. D.A.K. reports that he has received payment or honoraria for lectures or presentations from Omni Health Media, Ipsen Biopharmaceuticals, Inc., Skysis. He participates on the data safety monitoring board or advisory board for AstraZeneca. 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/.

References

1. Pandol S, Edderkaoui M, Gukovsky I, et al. Desmoplasia of pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol 2009;7:S44-7. [Crossref] [PubMed]
2. Ho WJ, Jaffee EM, Zheng L. The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nat Rev Clin Oncol 2020;17:527-40. [Crossref] [PubMed]
3. Looi CK, Chung FF, Leong CO, et al. Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment. J Exp Clin Cancer Res 2019;38:162. [Crossref] [PubMed]
4. Osipov A, Zaidi N, Laheru DA. Dual Checkpoint Inhibition in Pancreatic Cancer: Revealing the Limitations of Synergy and the Potential of Novel Combinations. JAMA Oncol 2019;5:1438-9. [Crossref] [PubMed]
5. Lawlor RT, Mattiolo P, Mafficini A, et al. Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Pancreatic Cancer: Systematic Review and Still-Open Questions. Cancers (Basel) 2021;13:3119. [Crossref] [PubMed]
6. Yamamoto K, Venida A, Yano J, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 2020;581:100-5. [Crossref] [PubMed]
7. Timmer FEF, Geboers B, Nieuwenhuizen S, et al. Pancreatic Cancer and Immunotherapy: A Clinical Overview. Cancers (Basel) 2021;13:4138. [Crossref] [PubMed]
8. Padoan A, Plebani M, Basso D. Inflammation and Pancreatic Cancer: Focus on Metabolism, Cytokines, and Immunity. Int J Mol Sci 2019;20:676. [Crossref] [PubMed]
9. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol 2016;39:98-106. [Crossref] [PubMed]
10. Simon S, Labarriere N. PD-1 expression on tumor-specific T cells: Friend or foe for immunotherapy? Oncoimmunology 2017;7:e1364828. [Crossref] [PubMed]
11. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65. [Crossref] [PubMed]
12. Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010;33:828-33. [Crossref] [PubMed]
13. O'Reilly EM, Oh DY, Dhani N, et al. Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol 2019;5:1431-8. [Crossref] [PubMed]
14. Coston T, Desai A, Babiker H, et al. Efficacy of Immune Checkpoint Inhibition and Cytotoxic Chemotherapy in Mismatch Repair-Deficient and Microsatellite Instability-High Pancreatic Cancer: Mayo Clinic Experience. JCO Precis Oncol 2023;7:e2200706. [Crossref] [PubMed]
15. Hu ZI, Shia J, Stadler ZK, et al. Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. Clin Cancer Res 2018;24:1326-36. [Crossref] [PubMed]
16. Luchini C, Brosens LAA, Wood LD, et al. Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications. Gut 2021;70:148-56. [Crossref] [PubMed]
17. Longo V, Brunetti O, Azzariti A, et al. Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, Other Than Abscopal Effect: A Systematic Review. Cancers (Basel) 2019;11:539. [Crossref] [PubMed]
18. Heinhuis KM, Ros W, Kok M, et al. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann Oncol 2019;30:219-35. [Crossref] [PubMed]
19. Mandili G, Curcio C, Bulfamante S, et al. In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination. J Immunother Cancer 2020;8:e001071. [Crossref] [PubMed]
20. Liu WM, Fowler DW, Smith P, et al. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer 2010;102:115-23. [Crossref] [PubMed]
21. Chen Y, Liu R, Li C, et al. Nab-paclitaxel promotes the cancer-immunity cycle as a potential immunomodulator. Am J Cancer Res 2021;11:3445-60. [PubMed]
22. Renouf DJ, Loree JM, Knox JJ, et al. The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma. Nat Commun 2022;13:5020. [Crossref] [PubMed]
23. Pancreatic Cancer Action Network. Precision Promise Platform Trial for Metastatic Pancreatic Cancer [Internet]. clinicaltrials.gov; 2023 Oct [cited 2022 Dec 31]. Report No.: NCT04229004. Available online: https://clinicaltrials.gov/study/NCT04229004
24. Azad A, Yin Lim S, D'Costa Z, et al. PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med 2017;9:167-80. [Crossref] [PubMed]
25. Xie C, Duffy AG, Brar G, et al. Immune Checkpoint Blockade in Combination with Stereotactic Body Radiotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2020;26:2318-26. [Crossref] [PubMed]
26. Chen IM, Johansen JS, Theile S, et al. Randomized Phase II Study of Nivolumab With or Without Ipilimumab Combined With Stereotactic Body Radiotherapy for Refractory Metastatic Pancreatic Cancer (CheckPAC). J Clin Oncol 2022;40:3180-9. [Crossref] [PubMed]
27. Chen I. LAPTOP: Phase 1/2 Study in Borderline Resectable, Locally Advanced or Metastatic Pancreatic Cancer to Assess Safety and Potential Efficacy of Dual Checkpoint Inhibition in Combination With Gemcitabine and Nab-paclitaxel Followed by Immune-chemoradiation. [Internet]. clinicaltrials.gov; 2023 Jun [cited 2022 Dec 31]. Report No.: NCT04247165. Available online: https://clinicaltrials.gov/study/NCT04247165
28. Sun X, Cheng G, Hao M, et al. CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev 2010;29:709-22. [Crossref] [PubMed]
29. Ding Y, Du Y. Clinicopathological significance and prognostic role of chemokine receptor CXCR4 expression in pancreatic ductal adenocarcinoma, a meta-analysis and literature review. Int J Surg 2019;65:32-8. [Crossref] [PubMed]
30. Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A 2013;110:20212-7. [Crossref] [PubMed]
31. Biasci D, Smoragiewicz M, Connell CM, et al. CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response. Proc Natl Acad Sci U S A 2020;117:28960-70. [Crossref] [PubMed]
32. Bockorny B, Semenisty V, Macarulla T, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med 2020;26:878-85. [Crossref] [PubMed]
33. Rose M, Burgess JT, O'Byrne K, et al. PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance. Front Cell Dev Biol 2020;8:564601. [Crossref] [PubMed]
34. Higuchi T, Flies DB, Marjon NA, et al. CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer. Cancer Immunol Res 2015;3:1257-68. [Crossref] [PubMed]
35. Reiss KA, Mick R, Teitelbaum U, et al. Niraparib plus nivolumab or niraparib plus ipilimumab in patients with platinum-sensitive advanced pancreatic cancer: a randomised, phase 1b/2 trial. Lancet Oncol 2022;23:1009-20. [Crossref] [PubMed]
36. Parikh AR, Weekes CD, Blaszkowsky LS, et al. A phase II study of niraparib and dostarlimab with radiation in patients with metastatic pancreatic cancer. J Clin Oncol 2022;40:564. [Crossref]
37. Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD). Olaparib and Durvalumab (MEDI4736) in Patients With Metastatic Pancreatic Cancer and DNA Damage Repair Genes Alterations [Internet]. clinicaltrials.gov; 2023 Dec [cited 2022 Dec 31]. Report No.: NCT05659914. Available online: https://clinicaltrials.gov/study/NCT05659914
38. Principe DR, Timbers KE, Atia LG, et al. TGFβ Signaling in the Pancreatic Tumor Microenvironment. Cancers (Basel) 2021;13:5086. [Crossref] [PubMed]
39. Holmgaard RB, Schaer DA, Li Y, et al. Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade. J Immunother Cancer 2018;6:47. [Crossref] [PubMed]
40. Yingling JM, McMillen WT, Yan L, et al. Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor. Oncotarget 2018;9:6659-77. [Crossref] [PubMed]
41. Melisi D, Oh DY, Hollebecque A, et al. Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer. J Immunother Cancer 2021;9:e002068. [Crossref] [PubMed]
42. University Hospital, Basel, Switzerland. Irreversible Electroporation (IRE) Followed by Nivolumab in Patients With Metastatic Pancreatic Cancer: a Multicenter Single-arm Phase II Trial [Internet]. clinicaltrials.gov; 2023 Jul [cited 2022 Dec 31]. Report No.: NCT04212026. Available online: https://clinicaltrials.gov/study/NCT04212026
43. Meijerink MR. Irreversible Electroporation and Nivolumab Combined With Intratumoral Administration of a Toll-like Receptor Ligand as a Means of in Vivo Vaccination for Oligometastatic Pancreatic Ductal Adenocarcinoma [Internet]. clinicaltrials.gov; 2022 Dec [cited 2022 Dec 31]. Report No.: NCT04612530. Available online: https://clinicaltrials.gov/study/NCT04612530
44. Aversa G, Punnonen J, Carballido JM, et al. CD40 ligand-CD40 interaction in Ig isotype switching in mature and immature human B cells. Semin Immunol 1994;6:295-301. [Crossref] [PubMed]
45. Vonderheide RH. CD40 Agonist Antibodies in Cancer Immunotherapy. Annu Rev Med 2020;71:47-58. [Crossref] [PubMed]
46. Byrne KT, Betts CB, Mick R, et al. Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer. Clin Cancer Res 2021;27:4574-86. [Crossref] [PubMed]
47. Padrón LJ, Maurer DM, O'Hara MH, et al. Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial. Nat Med 2022;28:1167-77. [Crossref] [PubMed]
48. Parker Institute for Cancer Immunotherapy. A Multicenter, Open-label, ExploRatory Platform Trial to EValuate ImmunOtherapy Combinations With Chemotherapy for the Treatment of Patients With PreviousLy UnTreated MetastatIc Pancreatic AdenOcarciNoma (REVOLUTION) [Internet]. clinicaltrials.gov; 2023 Oct [cited 2022 Dec 31]. Report No.: NCT04787991. Available online: https://clinicaltrials.gov/study/NCT04787991
49. Lau SP, van 't Land FR, van der Burg SH, et al. Safety and tumour-specific immunological responses of combined dendritic cell vaccination and anti-CD40 agonistic antibody treatment for patients with metastatic pancreatic cancer: protocol for a phase I, open-label, single-arm, dose-escalation study (REACtiVe-2 trial). BMJ Open 2022;12:e060431. [Crossref] [PubMed]
50. Van Laethem JL, Borbath I, Prenen H, et al. Mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (PDAC): Safety data from part of the OPTIMIZE-1 study. J Clin Oncol 2022;40:e16237. [Crossref]
51. Deicher A, Andersson R, Tingstedt B, et al. Targeting dendritic cells in pancreatic ductal adenocarcinoma. Cancer Cell Int 2018;18:85. [Crossref] [PubMed]
52. Santos PM, Butterfield LH. Dendritic Cell-Based Cancer Vaccines. J Immunol 2018;200:443-9. [Crossref] [PubMed]
53. Oji Y, Nakamori S, Fujikawa M, et al. Overexpression of the Wilms' tumor gene WT1 in pancreatic ductal adenocarcinoma. Cancer Sci 2004;95:583-7. [Crossref] [PubMed]
54. Nishida S, Ishikawa T, Egawa S, et al. Combination Gemcitabine and WT1 Peptide Vaccination Improves Progression-Free Survival in Advanced Pancreatic Ductal Adenocarcinoma: A Phase II Randomized Study. Cancer Immunol Res 2018;6:320-31. [Crossref] [PubMed]
55. Yanagisawa R, Koizumi T, Koya T, et al. WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study. Anticancer Res 2018;38:2217-25. [PubMed]
56. Ryoma Y, Moriya Y, Okamoto M, et al. Biological effect of OK-432 (picibanil) and possible application to dendritic cell therapy. Anticancer Res 2004;24:3295-301. [PubMed]
57. Ullman NA, Burchard PR, Dunne RF, et al. Immunologic Strategies in Pancreatic Cancer: Making Cold Tumors Hot. J Clin Oncol 2022;40:2789-805. [Crossref] [PubMed]
58. Nagai K, Adachi T, Harada H, et al. Dendritic Cell-based Immunotherapy Pulsed With Wilms Tumor 1 Peptide and Mucin 1 as an Adjuvant Therapy for Pancreatic Ductal Adenocarcinoma After Curative Resection: A Phase I/IIa Clinical Trial. Anticancer Res 2020;40:5765-76. [Crossref] [PubMed]
59. University of Pennsylvania. Pilot Study of Mature Dendritic Cell Vaccination Against Mutated KRAS in Patients With Resectable Pancreatic Cancer [Internet]. clinicaltrials.gov; 2023 Oct [cited 2022 Dec 31]. Report No.: NCT03592888. Available online: https://clinicaltrials.gov/study/NCT03592888
60. Musher BL. Phase I Study of Th-1 Dendritic Cell Immunotherapy in Combination With Standard Chemotherapy for the Adjuvant Treatment of Pancreatic Adenocarcinoma (DECIST) [Internet]. clinicaltrials.gov; 2023 Nov [cited 2022 Dec 31]. Report No.: NCT04157127. Available online: https://clinicaltrials.gov/study/NCT04157127
61. Suzuki N, Hazama S, Iguchi H, et al. Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study. Cancer Sci 2017;108:73-80. [Crossref] [PubMed]
62. Schmitz-Winnenthal FH, Hohmann N, Schmidt T, et al. A phase 1 trial extension to assess immunologic efficacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer. Oncoimmunology 2018;7:e1303584. [Crossref] [PubMed]
63. Chen Z, Zhang S, Han N, et al. A Neoantigen-Based Peptide Vaccine for Patients With Advanced Pancreatic Cancer Refractory to Standard Treatment. Front Immunol 2021;12:691605. [Crossref] [PubMed]
64. Tsujikawa T, Crocenzi T, Durham JN, et al. Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer. Clin Cancer Res 2020;26:3578-88. [Crossref] [PubMed]
65. Le DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 2013;36:382-9. [Crossref] [PubMed]
66. Wu AA, Bever KM, Ho WJ, et al. A Phase II Study of Allogeneic GM-CSF-Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer. Clin Cancer Res 2020;26:5129-39. [Crossref] [PubMed]
67. Lorentzen CL, Haanen JB, Met Ö, Svane IM. Clinical advances and ongoing trials on mRNA vaccines for cancer treatment. Lancet Oncol 2022;23:e450-e458. Erratum in: Lancet Oncol 2022;23:e492. [Crossref] [PubMed]
68. Rojas LA, Sethna Z, Soares KC, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 2023;618:144-50. [Crossref] [PubMed]
69. Merck Sharp & Dohme LLC. A Phase 1, Open-Label, Multicenter Study to Assess the Safety and Tolerability of mRNA-5671/V941 as a Monotherapy and in Combination With Pembrolizumab in Participants With KRAS Mutant Advanced or Metastatic Non-Small Cell Lung Cancer, Colorectal Cancer or Pancreatic Adenocarcinoma [Internet]. clinicaltrials.gov; 2022 Sep [cited 2022 Dec 31]. Report No.: NCT03948763. Available online: https://clinicaltrials.gov/study/NCT03948763
70. Akce M, Zaidi MY, Waller EK, et al. The Potential of CAR T Cell Therapy in Pancreatic Cancer. Front Immunol 2018;9:2166. [Crossref] [PubMed]
71. Shen J, Sun X, Zhou J. Insights Into the Role of Mesothelin as a Diagnostic and Therapeutic Target in Ovarian Carcinoma. Front Oncol 2020;10:1263. [Crossref] [PubMed]
72. Beatty GL, O'Hara MH, Lacey SF, et al. Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial. Gastroenterology 2018;155:29-32. [Crossref] [PubMed]
73. Haas AR, Tanyi JL, O'Hara MH, et al. Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers. Mol Ther 2019;27:1919-29. [Crossref] [PubMed]
74. Huang S, van Duijnhoven SMJ, Sijts AJAM, et al. Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy. J Cancer Res Clin Oncol 2020;146:3111-22. [Crossref] [PubMed]
75. Schram AM, Odintsov I, Espinosa-Cotton M, et al. Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements. Cancer Discov 2022;12:1233-47. [Crossref] [PubMed]
76. Schram AM, Goto K, Kim DW, et al. Efficacy and safety of zenocutuzumab, aHER2 x HER3 bispecific antibody, in advancedNRG1 fusion-positive (NRG1+) cancer. J Clin Oncol 2022;40:105. [Crossref]
77. Gang J, Guo S, Zhang Y, et al. A phase II study of KN046 monotherapy as 2nd line and above treatment for unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol 2020;40:e16305. [Crossref]
78. Guo S. Multicenter, Open-label Clinical Study of PD-L1/CTLA4 BsAb Combined With Chemotherapy in Locally Advanced and Metastatic Pancreatic Cancer [Internet]. clinicaltrials.gov; 2023 Aug [cited 2022 Dec 31]. Report No.: NCT04324307. Available online: https://clinicaltrials.gov/study/NCT04324307
79. Jiangsu Alphamab Biopharmaceuticals Co., Ltd. A Multicenter, Randomized, Double-Blind Phase III Study to Assess the Efficacy and Safety of KN046 Combined With Gemcitabine and Nab-Paclitaxel Versus Placebo Combined With Gemcitabine and Nab-Paclitaxel in First Line Advanced Pancreatic Ductal Adenocarcinoma Subjects (ENREACH-PDAC-01). [Internet]. clinicaltrials.gov; 2023 May [cited 2022 Dec 31]. Report No.: NCT05149326. Available online: https://clinicaltrials.gov/study/NCT05149326
80. Bhutani D, Lum LG. Activated T cells armed with bispecific antibodies kill tumor targets. Curr Opin Hematol 2015;22:476-83. [Crossref] [PubMed]
81. Thakur A, Ung J, Tomaszewski EN, et al. Priming of pancreatic cancer cells with bispecific antibody armed activated T cells sensitizes tumors for enhanced chemoresponsiveness. Oncoimmunology 2021;10:1930883. [Crossref] [PubMed]
82. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med 2018;379:2395-406. [Crossref] [PubMed]
83. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703. [Crossref] [PubMed]