Abstract C016: Pre-existing T cell inflammation is a determinant of response to mesothelin chimeric antigen receptor T cell therapy in pancreatic ductal adenocarcinoma

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has a 12.5% 5-year survival rate and is predicted to become the 2nd leading cause of cancer-related death by 2030. PDAC is known to be resistant to immunotherapy. Thus, while chimeric antigen receptor (CAR) T cell therapy shows the potential to mediate durable responses against some hematologic and solid tumors, in PDAC, the efficacy of CAR T therapy has remained limited. PDAC tumors show heterogenous T cell infiltration with some tumors containing a high number of T cells. As T cell infiltration associates with prolonged survival, we hypothesized that the density of pre-existing T cell infiltration would predict response to CAR T therapy. Methods: Previously established clonal mouse PDAC cell lines, which show a T cell inflamed or non-inflamed tumor microenvironment upon in vivo implantation, were used. Mouse CAR T cells specific to mesothelin, a tumor antigen expressed by PDAC, were generated using retroviral transduction. Mice were implanted subcutaneously with T cell inflamed or non-inflamed tumor cell lines. Ten days later mesothelin CAR T cells were administered intravenously. Flow cytometry and multiplex immunohistochemistry was used to define the density and spatial location of CAR T cell infiltration. The impact of CAR T cells on tumor growth and survival was also measured. Results: CAR T cells were found to traffic to T cell inflamed tumors, which led to delayed tumor outgrowth. However, such results were not seen in T cell non-inflamed tumors. Rather in mice with T cell non-inflamed tumors, CAR T cells accumulated in the liver. Further, CAR T cells effectively eliminated T cell inflamed and non-inflamed tumor cells in vitro, demonstrating that tumor intrinsic mechanisms of resistance to T cell killing were not a major determinant of treatment efficacy. Conclusions: Our findings suggest the therapeutic potential of CAR T cells in PDAC but highlight mechanisms of T cell exclusion as a therapeutic barrier wherein CAR T cells accumulate in host organs. Citation Format: Jacqueline B. Plesset, Heather Coho, Kelly Markowitz, Dhruv Patel, Max M. Wattenberg, Meredith L. Stone, Devora Delman, Gregory L. Beatty. Pre-existing T cell inflammation is a determinant of response to mesothelin chimeric antigen receptor T cell therapy in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C016.