Adoptive T-Cell Therapy in Solid Tumor with KRASG12V/G12D Mutation

KRAS, the most commonly mutated oncogene, plays a central role in the pathogenesis of many cancers. Identifying T cell receptors (TCRs) reactive to mutant KRAS enables the exploration of TCR gene-modified T cell (TCR-T) therapy for solid tumors with KRAS mutations. An investigator-initiated trial (IIT) evaluated adoptive TCR-T therapy using autologous T cells engineered to target KRAS G12V or KRAS G12D mutations in HLA-A*11:01-positive patients. Eligible individuals had advanced pancreatic or other solid tumors with these mutations and received a single infusion of 1 × 10⁹ to 1 × 10¹⁰ TCR-T cells. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), overall survival (OS), duration of response (DOR), disease control rate (DCR), and safety. So far, we observed that ORR (100%), PFS (10, 8, and 27 months), DOR (10, 8, and 13 months), and OS (17, 10, and 30 months) in two patients with PDAC and NSCLC. No grade 3–4 toxicities occurred. All patients exhibited cytopenia, characterized by anemia, transient thrombocytopenia, and a reduction in white blood cells due to the lymphodepletion required for TCR-T therapy. These results demonstrate that TCR-T therapy targeting KRAS ^G12V/D is feasible and beneficial in patients with advanced solid tumors. The IIT trial is ongoing to recruit more patients with KRAS ^G12V/D mutations (NCT05438667).