Advancing Immunotherapy in Pancreatic Cancer: A Brief Review of Emerging Adoptive Cell Therapies

1. Introduction

Pancreatic cancer is among the most lethal malignancies, representing a significant global health challenge. In 2024, it is projected to cause approximately 51,000 deaths out of 66,000 newly diagnosed cases in the United States alone [1]. With a 5-year survival rate of just 13%, pancreatic cancer has the lowest survival rate among major cancers. Its incidence is similar among African-American and Caucasian populations. Despite accounting for only 3% of new cancer diagnoses in the United States, pancreatic cancer is currently the third leading cause of cancer-related deaths and is expected to become the second in the near future [2]. Globally, the European region exhibits the highest age-standardized incidence and mortality rates, while the Southeast Asia region reports the lowest [3]. The high lethality of pancreatic cancer is attributed to its insidious onset, late-stage diagnosis, aggressive progression, and limited treatment options. Addressing these challenges requires a deeper understanding of the tumor microenvironment (TME) to identify novel therapeutic targets and expand treatment options, ultimately improving patient outcomes in the long term.

Pancreatic cancer risk factors are broadly categorized into modifiable and non-modifiable factors [4]. Key modifiable risk factors include smoking, excessive alcohol consumption, diets high in red or processed meats, obesity, chronic pancreatitis, and infections such as Helicobacter pylori. These factors contribute to the higher incidence observed in developed countries. Non-modifiable risk factors include advanced age, male gender, ethnicity, specific blood groups, microbiota composition, genetic predisposition, and diabetes mellitus. A comprehensive understanding of these risk factors is critical for developing effective prevention and intervention strategies.

2. Current Management of Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinomas (PDAC) account for approximately 90% of primary pancreatic cancers, with the remainder comprising less common types such as squamous, acinar, signet-ring (exocrine), ampullary, neuroendocrine, and undifferentiated carcinomas [5]. PDAC is typically stratified for risk and management using the tumor-node-metastasis (TNM) system outlined in the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual [6]. While TNM staging informs treatment and prognosis, it does not include resection status, which is critical for surgical planning. Another widely used classification system focuses on tumor resectability and the presence of distant metastatic disease at diagnosis. Based on this approach, PDAC is categorized as resectable (R), borderline resectable (BR), locally advanced (LA), or metastatic [7,8,9,10]. Resectability is determined by the degree of tumor involvement with surrounding arteries and veins, typically assessed in a multidisciplinary setting. In R-PDAC, there is no tumor contact with adjacent blood vessels. BR-PDAC involves some tumor contact with blood vessels, with the expectation that systemic chemotherapy (CT) or radiation therapy (RT) can convert these cases to R-PDAC. LA-PDAC, a less clearly defined category, includes tumors with significant involvement of major arteries (e.g., celiac trunk or superior mesenteric artery interface >180°) or veins, rendering both resection and vascular reconstruction infeasible.

Following stratification, treatment plans are tailored to the disease stage. For R-PDAC and BR-PDAC, neoadjuvant chemotherapy (NAT), often combined with RT, is now preferred prior to surgical resection. In LA-PDAC, NAT helps identify patients who may benefit from subsequent surgery. For metastatic PDAC and certain LA cases, clinical trial enrollment is recommended. Systemic chemotherapy, using regimens such as FOLFIRINOX or gemcitabine/nab-paclitaxel (G/NP), remains the cornerstone of treatment for advanced PDAC. However, outcomes for metastatic PDAC remain poor, with a 5-year survival rate of only 3% [11,12].

Immunotherapy in PDAC focuses on leveraging the tumor microenvironment (TME) and the host immune system [13]. Immune checkpoint inhibitors (ICIs), targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), have shown efficacy in mismatch repair-deficient (MMR-D) tumors, but this subgroup represents only 2% of PDAC patients [14,15,16]. While ICIs have revolutionized outcomes for esophageal, liver, and biliary tract cancers, their success in mismatch repair-proficient PDAC remains limited [17,18,19,20,21,22,23,24,25,26]. Emerging immunotherapy approaches, including oncolytic virus therapy (OVT), adoptive cell transfer therapy (ACT), and cancer vaccines, hold promise for all tumor types, including PDAC [20]. Among these, chimeric antigen receptor (CAR) T-cell therapy is being actively investigated as a novel therapeutic strategy in PDAC. The urgent need for new targets and treatment modalities highlights the potential of immunotherapy as a critical avenue for improving outcomes in this challenging and aggressive disease.

3. Adoptive Cell Therapy in PDAC

TME is a complex ecosystem that surrounds tumor cells, comprising various immune cell populations that play critical roles in maintaining its pro-tumorigenic nature [18]. These immune cells include lymphocytes (T and B cells), macrophages, natural killer (NK) cells, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), neutrophils, and mast cells, as illustrated in Figure 1. Each cell type contributes uniquely to the dynamic interplay within the TME, promoting tumor growth, immune evasion, and resistance to therapy. Immune-related TME is important not only for the effectiveness of ICI or other cellular therapy modalities but also for the outcomes, affecting both prognosis and treatment response. High infiltration of anti-tumor immune cells significantly improved the outcomes of PDA irrespective of the ICI use [27,28,29,30,31,32,33,34].

There is a growing interest in targeting TME to treat PDAC, and ACT is emerging as a key strategy in this effort [20,35]. While ACT has shown remarkable success in treating hematological malignancies, its application in solid tumors, including PDAC, remains in the early stages of development [36,37]. ACT broadly involves isolating immune cells—such as T lymphocytes, NK cells, and macrophages—from the patient, followed by their re-engineering and genetic modification to enhance their anti-tumor activity [38]. Various ACT modalities are under investigation for PDAC, including chimeric antigen receptor T cells (CAR-T), chimeric antigen receptor NK cells (CAR-NK), tumor-infiltrating lymphocytes (TILs), T cell receptor (TCR)-engineered T cells, and cytokine-induced killer cells (CIK-cells). These approaches are currently being evaluated in clinical trials to improve outcomes for this challenging malignancy. The following sections will delve deeper into these ACT modalities and their potential impact on PDAC treatment.

4. CAR- T in PDAC

CAR-T cell is a form of ACT that redirects a patient’s T cells to specifically target cancer cells through genetic engineering [39]. CARs are synthetic receptors designed with four main components: an extracellular antigen-binding domain, a hinge region, a transmembrane domain, and one or more intracellular signaling domains [37]. Since the development of first-generation CARs in 1989, subsequent generations have undergone significant advancements to enhance clinical efficacy [40]. To date, five generations of CAR-T cells have been developed, each featuring modifications to the domain structure and the inclusion of additional co-stimulatory molecules. Newer generations of CAR-T cells demonstrate improved T cell activation, enhanced efficacy, and greater persistence, with the ability to rapidly expand and survive long after infusion. However, CAR-T cell therapy's success heavily depends on identifying actionable tumor-specific antigens. This remains a significant challenge for PDAC despite the therapy’s transformative impact on hematological malignancies. We summarized the results of completed early-phase clinical trials (Phase I or I/II) in Table 1 and ongoing trials in Table 2.

The principal toxicities associated with CAR-T cell therapy are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) [61]. CRS presents clinically with a spectrum of symptoms, ranging from mild flu-like manifestations to severe vasodilatory shock and end-organ dysfunction, potentially leading to life-threatening complications. Management of CRS involves supportive care, including symptomatic treatment, and the use of tocilizumab, an interleukin-6 (IL-6) receptor antagonist, with or without corticosteroids, depending on the severity of the condition. ICANS typically develops after the onset of CRS and exhibits a range of neurological symptoms, from temporary cognitive deficits to fatal cerebral edema. The management of ICANS is stratified by severity: mild cases are treated with supportive measures, severe cases with corticosteroids, and anti-IL-6 therapy is employed only if ICANS occurs alongside CRS. The underlying factors contributing to these toxicities include antigen overlap between cancerous and normal tissues, leading to off-target effects and an exaggerated immune response triggered by CAR-T cell activation.

5. Tumor-Infiltrating Lymphocyte Therapy (TIL) in PDAC

TIL-based ACT involves isolating TILs from tumor tissues, expanding them in vitro, and reinfusing them into patients to identify and destroy tumor cells [62]. TIL therapy, which has shown promising results in solid tumors such as melanoma, breast, and ovarian cancers, is now being investigated for PDAC [63,64,65,66,67,68,69,70,71,72,73,74,75,76]. In a meta-analysis that examined PDAC-TME, a higher CD8+ T cell subgroup was associated with significant survival benefits, highlighting the potential of TIL-therapy in PDAC [77]. TILs therapy has unique advantages, including its ability to target tumor-specific neoantigens due to the presence of multiple T-cell receptor clones, its ease of extraction from tumor tissue owing to the high number of effector memory T cells, and its low toxicity profile since it utilizes autologous cells without genetic modification [78,79]

In a study involving 17 patients, including 5 with PDAC, the best response was observed in a PDAC patient with stable disease for 17 months [79]. However, this patient, who had liver and peritoneal metastases, exhibited no response at the primary tumor site. Overall, no objective responses (OR) were recorded among the PDAC cohort, with 3 achieving stable disease (SD) and 2 progressing (PD). Progression-free survival (PFS) and overall survival (OS) for PDAC patients were 2.43 months and 14.49 months, respectively, which were worse compared to the overall study population (PFS: 2.53 months, OS: 18.86 months) [70]. Bone marrow suppression emerged as a concerning high-grade adverse event across the entire study cohort. TIL therapy for PDAC remains in its early stages, and ongoing clinical trials are summarized in Table 3. Continued research is essential to optimize this approach and improve patient outcomes with PDAC.

6. Oncolytic Virus

The development of oncolytic virus (OV) therapy began in the 1990s, but its integration into clinical practice has accelerated only within the last decade [80]. OVs are genetically engineered viruses designed to selectively infect, replicate within, and ultimately destroy cancer cells. The first OV therapy to receive regulatory approval was talimogene laherparepvec (T-VEC or OncoVEXGM-CSF), approved in 2015 for the treatment of refractory melanoma [81]. Since then, several other OVs—including H-1 parvovirus, VCN-01 adenovirus, LOAd703 adenovirus, and pelareorep reovirus—have shown promising preclinical efficacy in pancreatic cancer cell lines [82,83,84,85]. In an early clinical study reported in 2018, the HF10 virus was injected directly into the primary tumor of patients with locally advanced pancreatic ductal adenocarcinoma (PDAC), alongside systemic erlotinib and gemcitabine therapy [86]. Among the nine patients who completed the study, three achieved PR, four had SD, and two experienced disease progression (PD). Severe adverse events such as bone marrow suppression, gastrointestinal perforation, and liver dysfunction were reported but were unrelated to OV therapy.

Subsequent investigations have demonstrated the safety and potential efficacy of other OVs, such as VCN-01 and LOAd703, when combined with chemotherapy (e.g., gemcitabine/nab-paclitaxel) or immune checkpoint inhibitors (ICIs) like pembrolizumab [85,87,88,89]. These studies highlight the potential of OVs to act synergistically with existing therapies. OVs also enhance the effectiveness of CAR-T cell therapy in solid tumors by improving tumor-associated antigen presentation, increasing T cell infiltration and tumor penetration, and mitigating immune suppression within the tumor microenvironment. This combination generates a more robust and durable anti-tumor response, making OVs a promising adjunctive therapy in PDAC treatment [90]. We discussed ongoing OV therapy trials in Table 3.

7. Genetically Modified T Cell Therapy

NK cells play a pivotal role as part of the body’s first line of defense against cancer. Genetically engineered NK cells have demonstrated the ability to mount specific and targeted anti-tumor responses, offering a promising avenue for cancer immunotherapy [91]. Preclinical studies involving chimeric antigen receptor NK (CAR-NK) cells targeting prostate stem cell antigen (PSCA) and mesothelin in pancreatic ductal adenocarcinoma (PDAC) have shown encouraging results, raising hope for their clinical application in select patient populations [92,93]. Compared to CAR-T cells, CAR-NK cells offer potential advantages, including reduced toxicity due to their shorter half-life and distinct cytokine profile, as well as a lower likelihood of inducing alloreactivity, making them suitable for "off-the-shelf" therapeutic products [20,94]. However, several limitations hinder their clinical implementation. These include technical challenges in manufacturing, poor tumor infiltration, and the short half-life of NK cells, which necessitates repeated administrations to sustain therapeutic effects. [95,96]. We discussed ongoing CAR-NK trials in Table 3.

In addition to NK cells, T cells can be genetically modified to express tumor-specific T-cell receptors (TCRs), enabling robust and precise anti-tumor responses [97]. Commonly targeted antigens in TCR therapy include mesothelin (MSLN), epidermal growth factor receptor (EGFR), claudin 18.2 (CLDN), CD133, and human epidermal growth factor receptor 2 (HER2). Notably, a study by Leidner et al. demonstrated that TCRs targeting mutant KRAS (KRAS12D) elicited responses in patients with metastatic PDAC, highlighting the potential of TCR-based therapies in this challenging cancer type [98]. We discussed ongoing TCR trials in Table 3.

8. Cytokine-Induced Killer (CIK) Cells

CIK cells are a heterogeneous group of CD8+ T cells that exhibit a hybrid phenotype, combining features of both T cells and natural killer (NK) cells. These cells are generated by incubating human-derived peripheral lymphocytes with anti-CD3 antibodies and cytokines [99,100,101]. CIK cells have shown potential to enhance the efficacy of other anti-cancer therapies, such as immune checkpoint inhibitors (ICIs) and chemotherapy, by amplifying anti-tumor responses [102].

Preclinical and clinical studies have demonstrated synergistic effects when CIK therapy is combined with chemotherapy in pancreatic cancer [100,101]. n a randomized study evaluating the addition of the chemotherapy agent S-1 to CIK therapy, a slight improvement in progression-free survival (PFS) was observed (2.5 months vs. 2.9 months, p = 0.03), although overall survival (OS) was comparable between the groups (6.1 months vs. 6.6 months, p = 0.09) [101]. Hematological toxicity was similar across both groups, but the incidence of non-infectious fever was significantly higher in the CIK group (32% vs. 3.3%, p = 0.004). In another study involving 47 patients with advanced pancreatic ductal adenocarcinoma (PDAC), median OS and PFS were notably higher in the group treated with dendritic cell-CIK (DC-CIK) therapy combined with S-1 (212 and 136 days, respectively) compared to those receiving DC-CIK therapy alone (128 and 85 days), chemotherapy alone (141 and 92 days), or supportive care only (52 and 43 days) [103]. These findings suggest that CIK-based therapies, particularly when combined with other modalities, hold promise for improving outcomes in advanced PDAC patients. We discussed ongoing CIK cells therapy in PDA in Table 3.

9. Conclusions

PDAC is a highly aggressive and challenging cancer that requires a multimodal approach to identify new therapeutic targets and develop innovative treatments. A comprehensive understanding of the TME in PDAC is critical to overcoming the limitations of current therapies and improving clinical outcomes. Cancer immunotherapy, particularly CAR-T therapy, has shown remarkable success in hematological malignancies and is now expanding its scope to solid tumors, including PDAC. However, the effectiveness of CAR-T therapy in PDAC is limited by factors such as tumor heterogeneity, T-cell exhaustion, and the suppressive influence of tumor-associated immune cells within the TME. Advances in next-generation CAR-T therapies, coupled with combination strategies integrating other treatment modalities, hold promise for addressing these challenges and unlocking the potential of CAR-T cell therapy in PDAC.