Pancreatic cancer is one of the most common gastrointestinal tumors with a high degree of malignancy, and its incidence is increasing year by year worldwide. Although a few chemotherapeutic agents can improve patient treatment, their efficacy is limited. In recent years, cellular immunotherapy has made new breakthroughs in the field of solid tumor treatment with the in-depth research on molecular mechanisms related to tumor immunity. Cellular immunotherapy, represented by tumor vaccine, has also made great progress in the treatment of pancreatic cancer, providing new methods and means for the treatment of pancreatic cancer. I. Monoclonal antibody therapy Erlotinib (Erlotinib) is a monoclonal antibody against epidermal growth factor receptor tyrosine kinase, Erlotinib combined with gemcitabine on 569 patients with advanced pancreatic cancer in a randomized double-blind phase III clinical study showed that Erlotinib combined with gemcitabine improved the survival rate of patients compared with placebo combined with gemcitabine group, and Although the improvement in overall survival was statistically significant, the prolongation of overall survival was limited, with median survival times of 6.24 months and 5.91 months for patients in the erlotinib versus placebo treatment groups, and 1-year survival rates of 23% and 17%, respectively. MORAb-009 is a chimeric monoclonal antibody targeting mesothelin, a differentiation antigen that is overexpressed in a variety of malignancies including pancreatic cancer, ovarian cancer and mesothelioma. 24 patients, including 7 with pancreatic cancer, were enrolled in a phase I clinical study of MORAb-009 in mesothelin-positive malignancies. Phase II clinical studies of MORAb-009 in mesothelin-positive tumors are ongoing. Mapatumumab, a human monoclonal antibody targeting the TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 protein, induces apoptosis in human tumor cells expressing the TRAIL-receptor 1 protein and has broad antitumor activity. linkedinhibitor of apoptosis (XIAP) inhibitors induced apoptosis in most pancreatic tumor cell lines. Kondo et al. used mural and suspension cells isolated from patients’ peripheral blood to induce MUC1-modified DCs vaccine and MUC1-sensitive CTLs, respectively, and transfused them back to patients. Kawaoka et al. treated 28 pancreatic cancer patients (8 inoperable pancreatic cancer patients and 20 postoperative pancreatic surgery patients) with MUC1-sensitive CTLs, and showed that The median survival time was 5.0 months for patients with inoperable pancreatic cancer and 17.8 months for patients who underwent curative surgery. It is suggested that CTLs-based primary immunotherapy can be used as an adjuvant treatment for pancreatic cancer patients after surgery. Tumor vaccine therapy Tumor vaccine therapy is to stimulate specific anti-tumor immune response by introducing tumor antigens into the patient’s body, and the key component of its function is tumor antigen. Tumor vaccines include peptide vaccine, nucleic acid vaccine, recombinant virus vaccine, bacterial vaccine, genetically modified tumor cell vaccine, dendritic cell (DC) vaccine and so on. In a phase I/II clinical study, synthetic KRAS peptide was given to pancreatic cancer patients who could not be surgically resected, and two out of five patients showed immune response. In another phase I/II clinical study, Gjertsen et al. applied mutated Ras peptide vaccine and granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjuvant to patients with advanced pancreatic cancer by subcutaneous injection, and induced ras peptide-specific CD8+T immune responses in 25 of 43 patients. +T immune response was successfully induced in 25 of 43 patients and showed long-term memory, with a significant difference in median survival between those who developed an immune response and those who did not (148 days vs. 61 days, P=0.0002), and no serious adverse events occurred. Patients with pancreatic cancer with KRAS mutations at codon 12 who received postoperative vaccine therapy targeting patient-specific KRAS mutations once a month for 3 months had a median recurrence-free survival time of 8.6 months and a median overall survival time of 20.3 months. (2) Targeted telomerase vaccine Telomerase is activated in more than 85% of pancreatic ductal adenocarcinoma (PDA) and therefore peptide vaccines targeting telomerase have been developed for the treatment of pancreatic cancer. The targeted telomerase vaccine (GV1001) is a 16-amino acid peptide derived from human telomerase and capable of binding to multiple MHC molecules. In a phase I/II clinical study, GV1001 was well tolerated and improved survival in patients with PDA. 48 inoperable PDA patients received GV1001 in combination with GM-CSF for a total of 10 weeks, and an immune response was observed in 24 of 38 evaluable patients, with the highest proportion of immune responses occurring in the intermediate dose group. The median survival time was 8.6 months, which was significantly longer compared with the low-dose and high-dose groups. Phase III clinical studies looking at the efficacy of GV1001 in patients with unresectable PDA included the PrimoVax and Telo Vax studies, the former comparing GV1001 monotherapy with gemcitabine, which was terminated due to lack of survival benefit. The latter study compared the efficacy of sequential GV1001 therapy after gemcitabine with single-agent gemcitabine for locally advanced or metastatic pancreatic cancer and showed no significant survival benefit with sequential GV1001 combination therapy compared with single-agent gemcitabine. (3) Targeted gastrin vaccine Upregulation and co-expression of gastrin and cholecystokinin B receptor (CCKBR,CCK-2) are seen in pancreatic cell lines and human PDA tissue. A multicenter, randomized, controlled, double-blind clinical study showed that treatment of 154 patients with progressive pancreatic cancer who were unwilling or unsuitable for chemotherapy with an immune cross-linked peptide vaccine, G17 diphtheria toxoid, constructed from the amino-terminal sequence of gastrin G17 and diphtheria toxoid, resulted in a nearly 1-fold increase in median survival time, with median survival in the treatment and control groups of 151 and 82 days, respectively (P 151 days and 82 days in the treatment and control groups, respectively (P < 0.05), which were well tolerated. Therefore, peptide vaccines targeting gastrin are expected to be a new option for pancreatic cancer treatment. (4) Survivin-targeted vaccine Survivin is a member of the apoptosis-inhibiting family with significant anti-apoptotic activity, and its high expression is seen in most adenocarcinoma tissues, including pancreatic adenocarcinoma. Immune index monitoring showed that the vaccine triggered a strong specific immune response against survivin and that the patient's disease progressed after discontinuation of immunotherapy. In another study, survivin peptide was combined with IFN-α to immunize six patients with progressive pancreatic cancer, and tetrameric and ELISPOT assays showed specific immune responses in more than half of the patients, often accompanied by clinical benefit. However, the efficacy of this vaccine has only been demonstrated in a small number of patients and is limited to HLA-A2+ patients who may benefit. (5) HSP-peptide vaccines Heat shock proteins (HSP) are widely present in all species as molecular chaperones and are involved in maintaining peptide stability during peptide transport. In preclinical studies, tumor-derived HSP-peptide complexes were able to induce potent anti-tumor immune activity. HSP96-peptide complexes from resected tumor tissue were the first antitumor vaccine used. 10 patients with surgically resected PDA who did not receive adjuvant radiotherapy were enrolled in a phase I clinical study and received autologous HSP96-peptide complex immunotherapy four times a week. The median survival time was 2.2 years. TRICOM is a poxvirus vaccine carrying co-stimulatory molecules (B7-1, ICAM-1 and CD58). The median survival time for patients receiving immunotherapy was 6.3 months and was significantly longer in patients who developed antigen-specific immune responses compared with those who did not (15.1 vs. 3.9 months, P=0.002). In a phase III randomized clinical study enrolling 255 patients with metastatic pancreatic cancer, PANVAC-V, a cowpox virus vaccine carrying co-stimulatory molecules and expressing CEA and MUC1 antigens, was unfortunately compared with standard gemcitabine-based chemotherapy, and the results showed that vaccine treatment did not improve overall patient survival. 3. Listeria monocytogenes vaccine The ability of L. monocytogenes to elicit a strong, multiple, cell-mediated acquired immune response is due to its intracellular life cycle and in vivo targeting of DCs. Wild-type L. monocytogenes is not suitable for tumor vaccines, and L. monocytogenes strains that can be used in vaccines (actA/ΔinlB) have been developed and entered clinical studies. It requires not only a better safety profile, but also retains the properties of the wild-type strain. Results of clinical studies have shown that in patients with mesothelioma, ovarian cancer, non-small cell lung cancer, and pancreatic cancer with liver metastases, the administration of the L. monocytogenes strain (actA/ΔinlB) vaccine carrying mesothelin resulted in survival times of 15 months or longer in 37% of patients, half of whom had metastatic pancreatic cancer, and immunological analysis showed that this group of patients could observe Antigen-specific T-cell responses were observed in this group of patients. Based on the above results, a phase II clinical study of Listeria monocytogenes vaccine expressing mesothelin for metastatic pancreatic cancer has been designed. 4. Dendritic cell vaccine Dendritic cells, as specialized antigen-presenting cells, can effectively activate T cells to produce memory T cells and trigger antigen-specific immune responses. Some research groups have tried to isolate patient dendritic cells and make them loaded with tumor-associated antigens, mRNA encoding tumor-associated antigens or tumor-derived mRNA in vitro and then would be infused into patients. The safety and efficacy of dendritic cell vaccine treatment in pancreatic cancer patients was validated in 2 clinical studies. In the first, a phase I/II clinical study, 12 patients with pancreatic or bile duct cancer were treated with an in vitro MUC-1-loaded dendritic cell vaccine after surgery, and patients were followed for more than 4 years after immunotherapy, with 4 patients surviving without disease progression. In another clinical study, dendritic cell vaccine alone or in combination with LAK cells, along with gemcitabine and or S1 was used in 49 patients with inoperable pancreatic cancer. Of these, 2 patients had complete remission, 5 had partial remission, and 10 had stable disease with a median survival time of 360 days. Therefore, dendritic cell-based immunotherapy combined with chemotherapy is well tolerated in the treatment of patients with progressive pancreatic cancer, and the efficacy needs to be confirmed by further studies. 5.Whole cell vaccine Whole cell vaccine refers to tumor cells that have been treated with radiation or other treatments and have lost their proliferation ability but their immunogenicity still exists, and can be taken up by antigen-presenting cells in vivo to trigger anti-tumor immune response, also called tumor vaccine cells. Whole cell vaccines are capable of expressing multiple tumor antigens unambiguously, thus avoiding the limitation of finding specific tumor antigens for vaccine application. Since for a tumor cell line, they share the vast majority of the same tumor antigens, specialized antigen presenting cells (APCs) are host-driven to deliver immune antigens to specific T lymphocytes under the restriction of MHC, and thus vaccine cells can be either autologous tumor cells or homologous allogeneic tumor cells. Autologous tumor vaccines require isolation of sufficient amounts of tumor tissue from the patient, limiting their use to some extent. The use of allogeneic tumor vaccines avoids the need to isolate tumor tissue from patients, allowing not only patients without access to autologous tumor tissue to receive tumor vaccines, but also allows for mass production and better quality control, enabling more patients to enter large clinical studies. Two allogeneic whole-cell vaccines are under clinical investigation in patients with PDA. (1) GM-CSF-secreting allogeneic whole-cell vaccines The current allogeneic whole-cell vaccines are mostly GM-CSF gene modified tumor vaccine (GVAX), and the first used whole-cell antitumor vaccine for pancreatic cancer (pancreatic GVAX) contains two allogeneic human pancreatic cancer cell lines genetically engineered to express GM-CSF. Phase I studies showed that 14 patients with patients with stage 1, 2 or 3 pancreatic cancer received different doses of allogeneic GM-CSF tumor vaccine after pancreaticoduodenectomy, and 12 patients continued to receive adjuvant radiotherapy for 6 months. Six patients who did not show disease progression at 1 month after the end of adjuvant therapy received up to three additional immunotherapy treatments. The allogeneic GM-CSF whole-cell vaccine used in this study had a good safety profile, with no dose-limiting toxicity observed; a delayed hypersensitivity response against autologous tumor cells was observed in three patients who received the intermediate dose group, and disease-free survival appeared to be prolonged in these three patients, with a disease-free survival time of at least 25 months after diagnosis. In another phase II clinical study, 60 patients who underwent surgery for pancreatic cancer received the first immunotherapy with GM-CSF-secreting tumor vaccine 8-10 weeks postoperatively, followed by adjuvant 5-FU-based radiotherapy, and patients without disease progression after radiotherapy received immunotherapy again. Median disease-free survival was 17.3 months (95% CI, 14.6-22.8 months) and median overall survival was 24.8 months (95% CI, 21.2-31.6 months), and mesothelin-specific T-cell responses elicited after immunotherapy were associated with disease-free survival of patients. A phase II clinical study comparing allogeneic GM-CSF tumor vaccine alone or sequentially after cyclophosphamide for the treatment of metastatic pancreatic cancer showed that of the 50 patients enrolled, 30 patients received CG8020/CG2505 tumor vaccine and 20 patients received 250 mg/m2 cyclophosphamide intravenous chemotherapy 1 day prior to tumor vaccine treatment. Treatment-related adverse effects were mild, enhanced responses against mesothelin-specific T cells were detectable in some patients receiving CG8020/CG2505 immunotherapy, and cyclophosphamide-modulated immunotherapy for patients with gemcitabine-resistant pancreatic cancer resulted in a median survival time similar to that of chemotherapy. A recent randomized phase II clinical study of the GVAX vaccine in combination with another vaccine, CRS-207, an attenuated Listeria monocytogenes vaccine genetically engineered to express mesothelin, showed positive results. 90 patients with metastatic pancreatic cancer were randomized to 2 groups receiving 2 doses of CY/GVAX (cyclophosphamide given 1 day before GVAX) treatment followed by sequential 4 doses of CRS-207 vaccine treatment or 6 doses of CY/GVAX treatment. The results of the interim analysis showed that the combination of the two vaccines prolonged the median survival of patients (6.1 vs 3.9 months, P=0.011), especially for patients with metastatic pancreatic cancer who had received 2 or more prior lines of therapy (5.1 vs 3.7 months, P=0.011). (2) algenpantucel-L vaccine Another phase II clinical study of the allogeneic tumor vaccine algenpantucel-L (NewLink Genetics Corporation, Ames, IA) for the adjuvant treatment of pancreatic cancer showed that 70 patients with pancreatic cancer received postoperative adjuvant radiotherapy with gemcitabine and 5-FU as well as algenpantucel-L immunotherapy. The median follow-up was 21 months, with a 1-year disease-free survival rate of 62% and a 1-year survival rate of 86%. It is suggested that the addition of algenpantucel-L immunotherapy to standard adjuvant radiotherapy may improve patient survival. Multiple multicenter, phase III clinical studies are underway to further investigate whether the combination of algenpantucel-L with chemotherapy can improve survival in patients with pancreatic cancer. Although the results of clinical studies have shown exciting results for immunotherapy in the treatment of pancreatic cancer, most of the clinical studies have failed to show significant efficacy and significant improvement in patient survival. The poor efficacy of immunotherapy is related to the multiple immunosuppressive mechanisms in the patient's body, so the combination of multiple vaccines to break the immunosuppression in the tumor microenvironment is expected to improve the immunotherapy for pancreatic cancer. Also, how to optimize the combination of radiotherapy and immunotherapy is an important direction of immunotherapy for pancreatic cancer.