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Vaccine Against Gastrin, Polyclonal Antibody Stimulator, Decreases Pancreatic Cancer Metastases.

Growth of pancreatic cancer is stimulated by gastrin in both a paracrine and an autocrine fashion. Traditional therapies have not significantly improved survival, and recently pancreatic cancer has been deemed a 'cold' tumor due to its poor response to immunotherapy. Strategies to improve survival of pancreatic cancer are desperately needed. In the current investigation, we studied the effects of an anti-gastrin cancer vaccine, polyclonal antibody stimulator (PAS, formerly called G17DT and Gastrimmune) used alone or in combination with a PD-1 immune checkpoint antibody on pancreatic cancer growth, metastases, and the tumor microenvironment (TME). Immune competent female C57BL/6 mice bearing syngeneic orthotopic murine pancreatic cancer treated with PAS had significantly smaller tumors and fewer metastases. Examination of the TME demonstrated decreased fibrosis with fewer M2, and more M1 tumor-associated macrophages. Expression of the E-cadherin gene was significantly increased and expression of the TGFβR2 gene was decreased compared to controls. Mice treated with PAS or the combination of PAS and PD-1 antibody exhibited significantly less tumor expression of phospho-paxillin, the focal adhesion protein, β-catenin, and of Matrix metalloproteinase-7. This study suggests that inhibition of the cancer promoting effects of gastrin in pancreatic cancer can decrease metastases by altering the tumor microenvironment (TME) and decreasing pathways that activate the epithelial mesenchymal transition (EMT). PAS vaccine appears to change the tumor microenvironment, making it more susceptible to therapy with an immune checkpoint antibody. This novel combination of two immunotherapies may improve survival of pancreatic cancer by decreasing both tumor growth and metastasis formation.