The Carbohydrate Antigen 19-9 Glycan Is a Viable Target for Chimeric Antigen Receptor T-Cell Therapy in Pancreatic and Other Solid Tumors

BACKGROUND & AIMS: Chimeric antigen receptor (CAR) T-cell therapy for pancreatic ductal adenocarcinoma (PDAC) has been challenging, due in part to the paucity of tumor-specific cell-surface targets. We explored the design feasibility and antitumor efficacy of CAR T cells recognizing the carbohydrate antigen 19-9 (CA19-9) glycan, a tumor antigen commonly associated with PDAC and other gastrointestinal tumors. METHODS: We designed and screened 14 CA19-9 CAR constructs harboring different single-chain variable fragments and intracellular signaling domains. After narrowing down to 1 optimal CAR configuration, we further evaluated its antitumor efficacy in various in vitro and in vivo models. RESULTS: Of 14 CAR constructs tested, we identified 1 design-AbLIFT15.28z-that enabled robust T-cell expansion and efficient tumor cell-killing properties. Experiments with human PDAC cell lines and patient-derived organoids revealed that AbLIFT15.28z CAR T-cell-mediated cytotoxicity was confined to cancer cells expressing CA19-9, both in vitro and in vivo. We then tested the efficacy of AbLIFT15.28z CAR T cells in immunocompetent murine models of PDAC, revealing significant effects against both primary and metastatic tumors. Efficacy was not limited to PDAC, as robust and specific antitumor effects were observed against CA19-9-expressing tumors of the colon, stomach, esophagus, and biliary tract. CONCLUSIONS: Our findings demonstrate the effectiveness of CA19-9 CAR T cells in gastrointestinal cancers using various preclinical tumor models, providing a rationale for further clinical development.