Abstract 109: Vaccination with Polyclonal Antibody Stimulator (PAS) prevents pancreatic carcinogenesis in the KRAS mouse model

Abstract

Abstract Background: Survival from pancreatic cancer is poor in part because it is not recognized or treated in the precancerous or early cancer stages. Gastrin is expressed in the fetal pancreas but silenced in the adult pancreas. Gastrin is re-expressed in precancerous pancreatic intraepithelial neoplasia (PanINs) where it acts to promote epithelial growth and fibrosis of the extracellular matrix. When gastrin is knocked-out in KRAS mice, PanINs fail to progress to cancer. Polyclonal Antibody Stimulator (PAS) is a target-specific vaccine to gastrin that activates B and T-cells to neutralize the actions of gastrin Hypothesis: It was hypothesized that treatment of transgenic LSL-KrasG12D/+; P48-Cre (KC) mice with PAS will slow PanIN progression and prevent pancreatic cancer. Methods: Nineteen age-matched littermates of KC mice were divided into two groups: control/untreated (N=9) and PAS-treated (N=10). Starting when the mice were 3 months of age, when PanIN lesions are developing, the PAS-mice received an initiation dose of PAS 250µg subcutaneously (sc) at baseline, week 1 and week 3. The PAS-treated mice then received a booster dose of PAS 250µg sc every 4 weeks until the mice reached 8 months of age for a total of 4 boosters. The control mice were untreated. The pancreata were dissected and paraffin embedded for analysis. H&E stained slides were evaluated for PanIN stage, extent of PanINs, inflammation, and fibrosis by a pathologist blinded to the treatment. Sections were stained with Masson's trichrome for fibrosis analysis and arginase for M2 macrophages. Results: When euthanized at 8-months of age, 67% of the control mice had high grade PanIN-3 lesions and 33.3% had invasive carcinoma. In contrast, the histologic stage in the age-matched PAS- treated mice was significantly lower, with more stage PanIN-2 lesions and only 10% with invasive carcinoma. The volume of normal pancreas present in the PAS-treated mice was 60% greater than in the control mice. Quantitation of the extracellular matrix showed 50% less fibrosis in the mice vaccinated with PAS as compared to controls (P=0.0001). Pancreata of PAS-treated mice also had fewer M2-polarized tumor-promoting macrophages than control mice (P<0.001). Conclusion: Pancreatic cancer and the progression of PanIN lesions can be prevented by a vaccine that targets gastrin. PAS treatment alters the microenvironment rendering it less carcinogenic. This vaccine has the potential to decrease pancreatic cancer in high risk populations and to prevent recurrence in surgically treated patients. Citation Format: Jill P. Smith, Hong Cao, Bhaskar Kallakury, Teresa Phillips, Lynda Sutton, Allen Cato. Vaccination with Polyclonal Antibody Stimulator (PAS) prevents pancreatic carcinogenesis in the KRAS mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 109.