Abstract 2942: Efficacy of a claudin 18.2/TGFβ bi-specific CAR-T in preclinical mouse models of gastric cancer

Abstract Gastric cancer (GC) is one of the 4th leading causes of cancer-related deaths worldwide. For decades, chemotherapy and surgery has been the primary treatment modality, however, the overall five-year survival rate for GC remains at 36% and new therapies are needed. Claudin 18.2, a tight junction protein that is expressed on the GC cell surface, has been validated as a bona fide target in GC with recent FDA approval of zolbetuximab, a Claudin 18.2 directed antibody. Chimeric antigen receptor (CAR)-T cell therapies are human T cells modified to express synthetic engineered receptors designed to target and eliminate cells expressing specific antigens. However, many barriers limit the therapeutic potential of CAR T cells in solid tumors. Our study examined the anti-tumor function of a bispecific Claudin18.2/TGFβ-targeting CAR T-cell candidate in preclinical orthotopic mouse models of GC in an immune competent background, as well as in GC patient-derived organoids (PDO) in an immunodeficient orthotopic mouse model. Our data indicate prolonged tumor suppression in our PDO GC model as well as in our murine gastric tumor-bearing mice treated with Claudin 18.2/TGFβ CAR T cells relative to mice treated with untransduced control T cells. We also demonstrate remodeling of the tumor immune microenvironment in our GC model in an immune competent background with an increase in CD19+ B cells in mice treated with our bispecific Claudin18.2/TGFβ CAR-T versus mice treated with untransduced T cells. Our data suggest that a bi-specific claudin18.2/TGFβ CAR T cell candidate may be an effective therapeutic approach for the treatment of gastric tumors that express Claudin 18.2. Citation Format: Ralph F. Fleuranvil, Naryan Rustgi, Michael James, Zachary Hammer, Thomas J. Ryan, Jessica Reyes, Melanie L. Munguiam, Orit Foord, Jiajia Cui, Sandra Ryeom. Efficacy of a claudin 18.2/TGFβ bi-specific CAR-T in preclinical mouse models of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2942.