T cell receptor gene therapy targeting KRAS G12V for advanced pancreatic cancer in a single-arm phase 1/2 clinical trial.
Publication Title
Molecular therapy : the journal of the American Society of Gene Therapy
Document Type
Article
Publication Date
3-11-2026
Keywords
oregon; portland; chiles
Abstract
Adoptive T cell transfer targeting KRAS G12D can induce tumor regression in advanced epithelial cancers. The safety, efficacy of T cell receptor (TCR)-T cells targeting KRAS G12V, and potential benefit of repeat infusions remain unknown. In a single-arm phase 1/2 clinical trial (NCT04146298), we treated five patients with recurrent pancreatic cancer using adoptive transfer of autologous T cells engineered to express an HLA-A∗11:01-restricted KRAS G12V8-16-specific TCR. Three patients received multiple infusions. Primary endpoints were safety and objective response rate. The most frequent adverse event of grade 3 or higher was hematologic toxicities due to lymphodepletion. One patient with liver metastases experienced a complete response lasting 5.5 months, and two patients experienced short-term stable disease. TCR-T cells were detected in peripheral blood of four patients at 1 month after their first infusion. No clinical responses were observed with TCR-T retreatments. In two patients, there was evidence of hyper-acute rejection of TCR-T cells after retreatment, which was likely mediated by persistent antibodies targeting the engineered KRAS G12V-reactive TCR induced from the prior TCR-T cell infusion. This study provides early results demonstrating safety, therapeutic potential, and considerations for repeat infusion of HLA-A∗11:01-restricted TCR-T cells targeting KRAS G12V in patients with recurrent pancreatic cancer.
Area of Special Interest
Cancer
Specialty/Research Institute
Earle A. Chiles Research Institute
Specialty/Research Institute
Oncology
DOI
10.1016/j.ymthe.2026.03.012
