Vaccine against gastrin, a polyclonal antibody stimulator, decreases pancreatic cancer metastases

Abstract

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 programmed cell death receptor (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 with 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 matrix metalloproteinase-7. This study suggests that inhibition of the cancer-promoting effects of gastrin in pancreatic cancer can decrease metastases by altering the TME and decreasing pathways that activate the epithelial mesenchymal transition. The PAS vaccine appears to change the TME, 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. NEW & NOTEWORTHY Survival from advanced pancreatic cancer is poor, in part due to dense fibrosis of the tumor microenvironment, increased number of M2-polarized macrophages that promote angiogenesis and invasion, and lack of “target-specific” therapy. Herein, we report that a tumor vaccine that selectively targets gastrin decreases pancreatic cancer growth and metastases. Furthermore, the gastrin vaccine polyclonal antibody stimulator alters the tumor microenvironment rendering it more responsive to immunotherapy with a programmed cell death receptor-1 immune checkpoint antibody.

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Furthermore, gastrin and its receptor, GRPR, promote EMT by increasing Snail and reducing E-cadherin expression [9]. However, polyclonal antibody stimulator (PAS), an anti-gastrin cancer vaccine, inhibits tumor formation, metastases of pancreatic cancer, and gastrin-induced EMT [48]. CXCL12-induced CXCR7 receptor results in increased IL-8 and VEGF levels, and subsequently, EMT by induction of Snail through the activation of AKT, ERK, and STAT3 in bladder cancer and BC [49,50].…”

Gastrin Vaccine Alone and in Combination With an Immune Checkpoint Antibody Inhibits Growth and Metastases of Gastric Cancer

“…Furthermore, it consistently changed the microenvironment in several animal models (pancreatic and gastric) leading to a synergistic effect with checkpoint inhibitors ( 31 ). The prevention of metastases in mice treated with PAS ( 44 ) was due to the inhibition of epithelial mesenchymal transition, and this mechanism of action may help explain the long-term survivors previously observed in the clinical program. The decreased fibrosis observed with PAS therapy may help to explain the synergy previously found with gemcitabine.…”

Cholecystokinin Receptor Antagonist Improves Efficacy of Chemotherapy in Murine Models of Pancreatic Cancer by Altering the Tumor Microenvironment

“…The mT3-2D murine tumor recapitulates human PDAC in that it grows rapidly, has mutant KRAS G12D , and develops the typical dense fibrotic stroma in the TME [ 27 , 31 ]. Using this immunocompetent model, we found that therapy with the CCK receptor antagonist, proglumide, slowed the growth of pancreatic tumors by the same magnitude as gemcitabine treatment compared to PBS-treated controls ( Figure 1 A).…”