KRAS G12V /HLA-A*02:01–targeted chimeric antigen receptor T cells exhibit potent preclinical activity against solid tumors

Abstract

Despite advances in chimeric antigen receptor T cell (CAR T cell) therapy for leukemia and lymphoma, solid tumors remain challenging because of limited target specificity and safety concerns. Neoantigens like KRAS G12V , a highly prevalent yet undruggable mutation in solid tumors, offer tumor-exclusive specificity. This study developed CAR T cells targeting KRAS G12V /HLA-A*02:01 using phage antibody display to identify high-affinity single-chain variable fragments. Engineered B9 CAR T cells specifically lysed tumor cells and patient-derived cancer organoids expressing KRAS G12V /HLA-A*02:01, demonstrating potent antitumor activity. Animal studies showed that B9 CAR T cells effectively controlled tumor growth in subcutaneous pancreatic ductal adenocarcinoma (PDAC) xenografts, as well as in metastatic and peritoneal PDAC models. Safety assessments in NCG-HLA-A2.1 and C57BL/6 mice revealed no detectable in vivo toxicity, supporting the clinical applicability of B9 CAR T cells. Collectively, our neoantigen-targeted CAR T cell therapy against solid tumors shows great potential for future clinical trials in patients with KRAS G12V /HLA-A*02:01, paving the way for clinical translation. CAR T cells targeting KRAS G12V safely eliminate solid tumors in preclinical models, offering a promising neoantigen therapy.