Immunotherapy of pancreatic cancer

Pancreatic cancer is one of the most common malignant tumors of digestive system, and its incidence is increasing year by year. Due to the l


Pancreatic cancer is one of the most common malignant tumors of digestive system, and its incidence is increasing year by year. Due to the lack of effective early diagnosis and treatment, the prognosis is very poor. Although a small number of chemotherapy drugs can improve the treatment of patients, but the effect is limited. In recent years, with the further research on the molecular mechanism of tumor immunity, cellular immunotherapy has made a new breakthrough in the field of solid tumor therapy. As a representative of tumor vaccine, immunotherapy has made great progress in the treatment of pancreatic cancer, which provides a new method for the treatment of pancreatic cancer.

Monoclonal antibody therapy

Erlotinib (Erlotinib) monoclonal antibody against epidermal growth factor receptor tyrosine kinase, phase III clinical study of Erlotinib combined with gemcitabine on 569 cases of advanced pancreatic cancer patients randomized double-blind, placebo plus Erlotinib plus gemcitabine gemcitabine group could improve the survival rate of patients with adverse reactions, and has low. The recommended dose is 100 mg/d. Although statistically significant improvement in overall survival for patients, but prolonged overall survival is still relatively limited, the median survival time of erlotinib and placebo treated patients were 6.24 months and 5.91 months, 1 year survival rates were 23% and 17%.

MORAb-009 is a chimeric monoclonal antibody targeting mesothlin, which is overexpressed in a variety of malignancies, including pancreatic cancer, ovarian cancer and mesothelioma. Phase I clinical study of MORAb-009 in 7 patients with pancreatic cancer, including a total of 24 patients with malignant mesothelioma, was included in the study. The results showed that the safety of MORAb-009 was good. All the patients in the study were treated with multiple therapy, 11 of them were stable. Phase II clinical studies of MORAb-009 in tumors with positive expression of mesothelioma are in progress.

Mapatumumab is targeting tumor necrosis factor related apoptosis inducing ligand (TNF-related, apoptosis-inducingligand, TRAIL) human monoclonal antibody receptor 1 protein, human tumor cell apoptosis induced by TRAIL- receptor 1 protein expression, with broad antitumor activity. Stadel et al. Study showed that Mapatumumab combined with inhibitor of apoptosis protein (X-linkedinhibitor of apoptosis, XIAP) could induce apoptosis of pancreatic cancer cell lines.

Two, adoptive immunotherapy

The use of Kondo in peripheral blood of patients with isolated adherent and suspended cells were induced by MUC1 modified DCs vaccine and sensitive to MUC1 CTLs back into the patient, the results confirmed that the treatment is effective for pancreatic cancer, the adverse reactions could be tolerated.

Kawaoka was isolated from the peripheral blood of the patients and was co cultured with the inactivated pancreatic cancer cell line YPK-1, and then cultured for 7 days after IL-2. The MUC1 specific CTLs was induced. Use of MUC1 sensitive CTLs in 28 cases of pancreatic cancer patients (8 cases of pancreatic cancer patients, for 20 patients received inoperable pancreatic surgery patients after surgery) treatment, the results showed that CTLs adoptive immunotherapy can effectively reduce the recurrence and metastasis, prolong the survival, the median survival time of patients with pancreatic cancer is inoperable 5 months, median survival time was 17.8 months for surgery in patients with pancreatic cancer. Prompt adoptive immunotherapy based on CTLs can be used for the adjuvant treatment of postoperative pancreatic cancer patients.

Three, tumor vaccine treatment

The treatment of tumor vaccine is the specific anti-tumor immune response by introducing the tumor into the patient. According to the different tumor vaccine loaded with tumor antigens and methods including polypeptide vaccine, DNA vaccine, recombinant virus vaccine, bacterial vaccine, gene modified tumor cell vaccine, dendritic cells (Dendriticcells, DC) vaccine.

1 peptide vaccine

(1) targeted KRAS vaccine

KRAS mutations in more than 90% of patients with pancreatic cancer, in the phase I/II clinical study in patients with unresectable pancreatic cancer patients with synthetic KRAS peptide segment, in which 5 cases of patients with immune response. Mutations in another phase I/II clinical study of Gjertsen in application of Ras peptide vaccine and granulocyte macrophage colony stimulating factor (granulocyte-macrophage colonystimulatingfactor, GM-CSF) as adjuvant on patients with advanced pancreatic cancer subcutaneous injection, 43 patients in 25 cases of successful induction of specific immune response to CD8+T Ras peptide, and shows long-term memory of the immune response in patients with non responders median survival significantly (148 days vs 61 days, P=0.0002), and no serious adverse reaction occurred. With pancreatic cancer patients with KRAS mutation in codon twelfth after receiving vaccines for treatment of patients with specific mutations in KRAS, 1 times per month for 3 months, the median disease-free survival time was 8.6 months, median overall survival time was 20.3 months.

(2) targeted telomerase vaccine

Telomerase is activated in more than 85% of pancreatic ductal carcinoma (pancreatic ductal adenocarcinoma, PDA), so the targeted peptide vaccine of telomerase has been developed for the treatment of pancreatic cancer. Targeted telomerase vaccine (GV1001) is a 16 amino acid polypeptide derived from human telomerase and capable of binding to multiple MHC molecules. In a phase I/II clinical trial, GV1001 was well tolerated in patients with PDA and improved survival. 48 cases of PDA patients received the combined treatment of GV1001 and GM-CSF for 10 weeks, among 38 evaluable patients in 24 cases of immunoreactivity could be observed in the middle dose group showed the highest proportion of the immune response, the median survival time of the middle dose group of patients was 8.6 months, compared with the low dose group and the high dose group was significantly prolonged. Phase III clinical studies of GV1001 in patients with unresectable PDA, including PrimoVax and Telo, were observed in the study. The former was treated with GV1001 monotherapy and gemcitabine, and was discontinued because of a lack of survival benefit. The efficacy of gemcitabine after GV1001 sequential therapy with gemcitabine alone in treatment of bureau of advanced or metastatic pancreatic cancer, the results show that compared with gemcitabine sequential GV1001 combined treatment had no significant survival benefit.

(3) targeted gastrin vaccine

Gastrin and cholecystokinin B receptor (CCKBR, CCK-2) expression and co expression in pancreatic cell line and human tissue PDA. A multi center clinical study, randomized, double-blind showed that patients with advanced pancreatic cancer using G17 N-terminal sequence constructed by gastrin and diphtheria toxoid immunoconjugate G17 polypeptide vaccine diphtheria toxoid to treating 154 cases of chemotherapy or not suitable for chemotherapy, results showed that the vaccine treatment. The median survival time of patients extension of nearly 1 times, the treatment group and the control group the median survival time was 151 days and 82 days (P < 0.05), well tolerated. Therefore, the polypeptide vaccine targeting gastrin is expected to be a new choice for the treatment of pancreatic cancer.

(4) targeted Survivin vaccine

Survivin is the inhibitor of apoptosis family members, has significant anti apoptotic activity, its high expression in pancreatic cancer, most adenocarcinoma, a 72 year old gemcitabine resistant pancreatic cancer patients after receiving the survivin vaccine, the complete remission of August. Surveillance of the immune parameters showed that the vaccine was able to induce a strong immune response to survivin and the progression of the disease after cessation of immunotherapy. In another study, four patients with advanced pancreatic cancer were treated with survivin peptide and IFN-, and the results showed that more than half of the patients had a specific immune response and were often associated with clinical benefit, with a combination of and ELISPOT. However, the effectiveness of this vaccine is only validated in a small number of patients, and may be limited to patients with HLA-A2+.

(5) HSP- peptide vaccine

Heat shock proteins (heat proteins, HSP), as molecular chaperones, are widely present in all species, and are involved in maintaining the stability of peptide segments during the transport of peptides (shock). HSP- peptide complexes can bind to class MHC-1 molecules to the cell surface. In the preclinical study, tumor derived HSP- peptide complex can induce effective anti-tumor immune activity. HSP96- peptide complexes from the tumor is the earliest application of anti tumor vaccine in phase I clinical studies enrolled 10 cases of patients with PDA have surgery, did not receive adjuvant chemotherapy, weekly received autologous HSP96- peptide complex immune therapy, a total of 4 times. Median survival time was 2.2 years.

2 recombinant virus vaccine

Clinical studies have shown that recombinant viral vaccines targeting CEA and MUC-1 have no significant effect on patients with pancreatic cancer. TRICOM is carrying costimulatory molecules (B7-1, ICAM-1 and CD58) virus vaccine, the phase I study of targeting CEA and MUC1 virus vaccine for 10 patients with advanced pancreatic cancer patients treated with the median survival time was 6.3 months, and generate antigen-specific immune responses in patients with and without immune reaction compared with the survival time was prolonged (15.1 vs 3.9 months, P=0.002). In randomizedphase III enrolled 255 cases of metastatic pancreatic cancer patients, compared with the standard PANVAC-V vaccinia virus vaccine carrying costimulatory molecules and the expression of CEA and MUC1 antigen with gemcitabine based chemotherapy, unfortunately the result shows that the total survival of vaccine therapy can improve the clinical.

3 Lester vaccine

L. monocytogenes can induce strong, multiple, cell-mediated immune responses due to its intracellular life cycle and in vivo targeting of DC. Wild type L. monocytogenes is not suitable for tumor vaccine and monocytogenes vaccine strain can be used for L. (actA/ inlB) has been developed and entered into clinical research. It not only needs better security, but also retains the characteristics of wild type strains. The clinical results showed that patients with liver metastasis of mesothelioma, ovarian cancer, non-small cell lung cancer, pancreatic cancer, L. monocytogenes strains carrying mesothelin (actA/ inlB) vaccine, the survival time of patients 37% to 15 months or longer, half of which is the transfer of patients with pancreatic cancer, immunological analysis this part shows the patient can go to antigen-specific T cells was observed. Based on the above results, a phase II clinical study of the expression of the Lester vaccine for the treatment of metastatic pancreatic cancer has been designed.

4 dendritic cell vaccine

As a professional antigen presenting cell, dendritic cells can effectively activate T cells to produce memory T cells and induce antigen-specific immune responses. Some research groups have attempted to isolate dendritic cells from patients with mRNA, which is associated with tumor associated antigens, tumor associated antigens, or tumor derived mRNA. The safety and efficacy of dendritic cell vaccine therapy in patients with pancreatic cancer was validated in 2 clinical studies. The first is the phase I/II clinical study of 12 cases of pancreatic carcinoma or cholangiocarcinoma treated with dendritic cell vaccine on in vitro load MUC-1, patients after immunotherapy were followed up for more than 4 years, 4 patients survived without disease progression. In another clinical study, dendritic cell vaccines alone or in combination with LAK cells, combined with gemcitabine and / or S1, were used in 49 patients with inoperable pancreatic cancer. Complete remission was achieved in 2 cases, partial remission in 5 cases, stable disease in the 10 patients, median survival time was 360 days. Therefore, dendritic cell based immunotherapy combined with chemotherapy is well tolerated in the treatment of patients with advanced pancreatic cancer.

5 whole cell vaccine

Whole cell vaccine refers to tumor cells after radiation or other treatment, loss of proliferation but its immunogenicity still exists in vivo can be antigen-presenting cell uptake, anti tumor immune response induced by tumor cells, also known as. The whole cell vaccine can express a variety of tumor antigens, so as to avoid the restriction of the application of the specific tumor antigen. Due to a tumor cell line, they have the same vast majority of tumor antigen, antigen presenting cells (antigen presenting cells, APCs) presenting antigens to specific T lymphocytes is driven by the host under MHC, so the vaccine cells in autologous tumor cells, can also be the same allogeneic tumor cells. Autologous tumor vaccine needs to separate a large number of tumor tissue from patients, which limits its application to some extent. The use of allogeneic tumor vaccine can prevent tumor tissue from patients with not only the link, unable to obtain autologous tumor tissue of patients undergoing tumor vaccine therapy, but also can batch production and have better quality control, so that more patients can enter large clinical studies. Clinical study of 2 allogeneic whole cell vaccines in PDA patients.

(1) allogeneic whole cell vaccine secreting GM-CSF

Allogeneic whole cell vaccine is currently mostly tumor vaccine modified by GM-CSF (GM-CSF gene modified tumor vaccine, GVAX), whole cell tumor vaccine therapy for pancreatic cancer is the earliest use of (contains 2 types of pancreatic GVAX) allogeneic human pancreatic cancer cell line, the expression of GM-CSF can be modified by genetic engineering.

I study showed that 14 cases of 1, 2 or 3 patients with pancreatic cancer pancreatic duodenal resection, were treated with different doses of GM-CSF allogeneic tumor vaccine, 12 patients continued to receive adjuvant chemotherapy for 6 months. The 6 patients who did not develop the disease in January after the end of adjuvant therapy received up to a maximum of 3 immunotherapy. In this study, the use of allogeneic GM-CSF whole cell vaccine was safe and no dose limiting toxicity was observed. 3 patients in the observation group to accept the middle dose for delayed type hypersensitivity reactions, autologous tumor cells, and disease-free survival for the 3 patients seemed to be prolonged, the disease-free survival time for at least 25 months after diagnosis. Clinical study of another II show, for the first time the secretion of GM-CSF immune therapy of tumor vaccine received 8-10 weeks in 60 cases of pancreatic cancer patients after surgery, then received adjuvant 5-FU based chemotherapy, without disease progression after chemotherapy in patients receiving immunotherapy again. The median disease-free survival time was 17.3 months (95%CI 14.6-22.8 months), the median overall survival was 24.8 months (95%CI 21.2-31.6 months), and no disease survival after immunotherapy by mesothelin specific T cell responses and patients.

Comparison of allogenic GM-CSF tumor vaccine alone or in sequential cyclophosphamide use after the treatment of metastatic pancreatic cancer II clinical study showed that 50 cases were enrolled, 30 patients received treatment of CG8020/CG2505 tumor vaccine, 20 patients received tumor vaccine for 1 days before receiving 250mg /m2 intravenous cyclophosphamide chemotherapy. Treatment related adverse reactions were mild, the patients received immunotherapy of CG8020/CG2505 detected in enhanced targeting mesothelin specific T cell response, immune regulation and cyclophosphamide treatment for gemcitabine resistant pancreatic cancer patients have a median survival time and chemotherapy similar.

A recent randomized phase II study of GVAX vaccine and another vaccine, CRS-207, for metastatic pancreatic cancer has shown positive results. CRS-207 is an attenuated Lester strain vaccine that can be expressed by genetic engineering. 90 patients with metastatic pancreatic cancer were randomly divided into 2 groups, and received the treatment of CY/GVAX () for the first time before 2 days (GVAX) for the first time after the treatment of 4 times of CRS-207 vaccine or the treatment of CY/GVAX for 6 times. The interim analysis showed the median survival time of two combined vaccine can prolong patients (6.1 vs 3.9 months, P=0.011), especially to improve the overall survival of patients with metastatic pancreatic cancer 2 line and above receive treatment for the past is more obvious (5.1 vs 3.7 months, P=0.011).

(2) algenpantucel-L vaccine

Another allogeneic tumor vaccine algenpantucel-L (NewLink Genetics Corporation, Ames, IA) for phase II clinical study of the adjuvant therapy of pancreatic cancer, aided by gemcitabine and 5-FU based chemotherapy and algenpantucel-L immune therapy 70 patients received postoperative pancreatic cancer patients. The median follow-up time was 21 months, and the disease-free survival rate was 62% and the survival rate was 86% in the 1 year (1). It is suggested that the use of algenpantucel-L immunotherapy on the basis of standard chemoradiotherapy may improve the survival of patients. In order to further investigate whether algenpantucel-L combined with chemotherapy can improve survival in patients with pancreatic cancer, a multicenter, phase III clinical trial is underway.

Although the results of clinical studies have shown exciting results in immunotherapy for pancreatic cancer, the majority of clinical studies have failed to show significant efficacy and improved survival. The therapeutic effect of immunotherapy is not good enough to be related to the mechanism of multiple immunosuppression in patients. Therefore, it is possible to improve the immune therapy of pancreatic cancer by the combination of multiple vaccines and the immune suppression in tumor microenvironment. At the same time, how to optimize the combination of chemotherapy and immunotherapy is an important direction of immunotherapy for pancreatic cancer.

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