Abstract 2309: Chimeric antigen receptor T-cell therapy targeting glypican-1 in pancreatic cancer

Abstract

Abstract Pancreatic cancer is the fourth most common cause of death from cancer in the US, with a 5-year overall survival of 8.5%. While immunotherapy with chimeric antigen receptor (CAR) T cells has shown promise in certain hematological malignancies, their efficacy for solid tumors including pancreatic cancer remains elusive. Thus, laboratory research is urgently needed to identify and validate a new target of CAR T-cell therapy for patients with pancreatic cancer. In this study, we made CAR T cells that recognize glypican-1 (GPC1), a cell surface heparan sulfate proteoglycan protein that is overexpressed in pancreatic cancer. We isolated two GPC1-specific antibodies; the mouse monoclonal antibody HM2 that binds the C-lobe of GPC1 close to the cell surface, and the camel single domain antibody D4 that recognizes a conformational epitope in the protein core of GPC1. The transduction efficiencies of CAR (HM2) and CAR (D4) in primary T cells were 86% and 58%, respectively. GPC1-overexpressing KLM1 cells (2B9) and GPC1-overexpressing A431 cells (H8) were efficiently lysed by both CAR T cells in dose-dependent manners. By contrast, minimal cell lysis was observed in GPC1-negative cell line A431. In the presence of GPC1-positive tumor cells, greater amount of TNF-α, IFN-γ and IL-2 were produced by GPC1-specific CAR T cells than mock-transduced T cells. Although both CAR T cells showed similar cytolytic activity in vitro, CAR (D4) T cells induced 2-4 times more cytokines than CAR (HM2) T cells when co-cultured with GPC1-postive tumor cells. Notably, both GPC1-targeted CAR T cells demonstrated potent antitumor efficacy in a peritoneal dissemination xenograft mouse model. Our findings indicate that GPC1-targeted CAR T cell therapy could be a new approach for treating pancreatic cancer. Citation Format: Nan Li, Dan Li, Hua Ren, Madeline Torres, Mitchell Ho. Chimeric antigen receptor T-cell therapy targeting glypican-1 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2309.