Phase 1 trial of a KRAS G12V/HLA-A*11:01–restricted TCR-engineered T-cell therapy in advanced solid tumors.

Abstract

2542 Background: KRAS G12V is a prevalent oncogenic driver in solid tumors, particularly pancreatic cancer (PC), occurring in approximately 20-30% of patients (pts). Advanced solid tumors harboring this mutation carry a poor prognosis and limited treatment options following standard chemotherapy. This phase 1 study evaluates a novel TCR-engineered T cell (TCR-T) therapy derived from a naturally occurring, KRAS G12V/HLA-A*11:01–restricted T cell receptor (TCR) isolated from patient tumor-infiltrating lymphocytes. Methods: This open-label, single-arm, dose-escalation phase 1 trial assessed the safety, tolerability, and preliminary efficacy of autologous TCR-T cells in pts with advanced solid tumors. Eligible pts had confirmed KRAS G12V mutation and HLA-A*11:01 positivity. Using a standard 3+3 design, autologous T cells were transduced with a lentiviral vector encoding the TCR and a CD8 co-receptor. Pts received lymphodepletion with cyclophosphamide and fludarabine, followed by a single infusion of TCR-T cells at either 5×10⁹ (DL1) or 1×10¹⁰ (DL2) cells, with adjunctive interleukin-2. Results: As of January 2026, 8 pts were enrolled; of whom 6 (median age 69.5 years, ECOG PS 1) received the planned infusion, including pts with colorectal cancer (n = 2), pancreatic cancer (n = 3), and endometrial cancer (n = 1). All pts had liver or lung metastases and > 2 metastatic sites. No dose-limiting toxicities (DLTs) or grade ≥3 treatment-related adverse events (TRAEs) were observed. The treatment was generally well-tolerated; the most common (≥50%) treatment-emergent adverse events (TEAEs) were pyrexia, cytokine release syndrome (CRS), neutropenia, anemia, and thrombocytopenia. Grade 1-2 CRS occurred in 4/6 pts and resolved without sequelae. No immune effector cell–associated neurotoxicity syndrome (ICANS) was observed. TCR-T cells peaked in peripheral blood at a median of day 4 (range, 1–10), with a median peak expansion of 61,863 copies/µg DNA (range, 40,394–80,824). The objective response rate (ORR) was 50.0% (3/6), with a disease control rate (DCR) of 83.3% (5/6). In the pancreatic cancer subset, the ORR was 66.7% (2/3) and the DCR was 100%. Conclusions: This KRAS G12V/HLA-A*11:01–restricted TCR-T therapy demonstrated a favorable safety profile and encouraging preliminary antitumor activity in advanced solid tumors. Notably, a high response rate was observed in heavily pretreated pancreatic cancer patients, supporting further clinical development of this novel cellular therapy. Clinical trial information: NCT06767046 .