Abstract A104: The CA19-9 glycan is a viable target for CAR T cell therapy in PDAC

Abstract Chimeric antigen receptor (CAR) T cell therapy for pancreatic ductal adenocarcinoma (PDAC) has been challenging, in part due to the paucity of tumor-specific cell-surface targets. Here, we explored the feasibility and efficacy of CAR T cells directed against carbohydrate antigen 19-9 (CA19-9), a clinically useful tumor marker that is significantly elevated in most PDAC cases with limited expression in normal tissues. We designed and screened 14 CA19-9 CAR constructs harboring different single-chain variable fragments (scFvs) and intracellular signaling domains. Using both in vitro tumor coculture assays and in vivo cell- and organoid-derived xenograft models of human PDAC, we identified one design – AbLIFT15.28z – that enabled efficient and specific anti-tumor activity, including a high frequency of durable complete responses. Next, we engineered a murine version of AbLIFT15.28z and tested its efficacy in a syngeneic model that reflects the immunosuppressive milieu typical of most PDAC tumors. As mouse cells do not produce the CA19-9 antigen, we generated a CA19-9-expressing PDAC cell line by overexpressing enzymes essential for CA19-9 production. Subsequent in vivo testing confirmed the anti-tumor activity of murine AbLIFT15.28z CAR T cells in both primary and metastatic tumor settings, significantly reducing tumor burden and prolonging animal survival in an immunocompetent setting (median survival, unmodified T cell vs CAR T cell: orthotopic tumor model – 24 vs 47 days, n=8-12; lung metastatic tumor model – 44 days vs undefined (75% of mice survived for over 250 days), n=8 per group). These findings demonstrate the feasibility and potency of CAR T cells targeting CA19-9, providing a rationale for further clinical development. Citation Format: Feiyan Mo, Austin L. Good, Dannielle D. Engle, Avery D. Posey, Ben Z. Stanger. The CA19-9 glycan is a viable target for CAR T cell therapy in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A104.