Vaccination with Polyclonal Antibody Stimulator (PAS) Prevents Pancreatic Carcinogenesis in the KRAS Mouse Model

Abstract

The incidence of pancreatic cancer is increasing significantly and will soon become the second leading cause of cancer-related deaths in the United States. We have previously shown that the gastrointestinal peptide gastrin, which is only expressed in the fetal pancreas and not in the adult pancreas, is activated during pancreatic carcinogenesis where it stimulates growth in an autocrine fashion. In this investigation, we used transgenic LSL-KrasG12D/+; P48-Cre mice that develop precancerous pancreatic intraepithelial neoplasia (PanIN) lesions and pancreatic cancer over time. Starting at 3 months of age, mice were either left untreated (control) or were treated with a gastrin-targeted vaccine, polyclonal antibody stimulator (PAS 250 μg) followed by a monthly booster until the mice reached 8 months of age when pancreata were excised, and analyzed by histology for PanIN grade in a blinded fashion. High-grade PanIN-3 lesions were significantly less in PAS-treated mice (P = 0.0077), and cancers developed in 33% of the control mice but only in 10% of the PAS-treated mice. Compared with the control mice, fibrosis was reduced by >50%, arginase positive M2 macrophages were reduced by 74%, and CD8+ T cells were increased by 73% in the pancreas extracellular matrix in PAS-treated mice. Prevention Relevance: PAS vaccination significantly decreased high-grade PanIN lesions and altered the pancreas microenvironment, rendering it less carcinogenic.

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

“…The decreased fibrosis observed with PAS therapy may help to explain the synergy previously found with gemcitabine. PAS vaccination in a precancerous KRAS murine model demonstrated that PAS not only decreases pancreatic fibrosis and alters the immune cell signature of the tumor microenvironment but that it also decreases proliferation and progression on precancerous PanIN lesions preventing pancreatic cancer ( 45 ). The data are compelling for PAS to return to the clinic with a much better understanding of how to use the product.…”