First-in-human trial of a TCR-T therapy targeting KRAS G12V reports a significant response rate

Encouraging safety and efficacy data were presented at the ESMO Congress 2025 (Berlin, 17–21 October) from the first-in-human phase I study of NW-301V, an autologous T-cell receptor-engineered T-cell therapy (TCR-T) targeting mutant KRAS G12V in advanced solid tumours (Abstract 1514O).

Three dose levels of NW-301V were evaluated in 14 patients with unresectable or advanced pancreatic or colorectal cancer positive for HLA-A*11:01 and KRAS G12V, who had no alternative treatment options. The most common grade ≥3 adverse events were decreased lymphocytes (78.6%), decreased white blood cells (50.0%) and decreased neutrophils (50.0%); all related to lymphodepletion. Grade 1–2 cytokine release syndrome (CRS) was reported in 6 (42.9%) patients and there were no occurrences of immune effector cell-associated neurotoxicity syndrome (ICANS). Preliminary efficacy with NW-301V was positive, with an objective response rate of 42.9% for the overall study population. Across 10 patients who received target dose levels two and three (1.5 x 109 and 7.5 x 109 cells, respectively), 50% achieved a partial response and 50% achieved stable disease, with median progression-free survival of 5.8 months.

“The aim of a phase I study is usually to establish the toxicity profile and less about determining efficacy, but the extent of the activity seen with NW-301V is encouraging and demonstrates a potentially potent therapy,” says Dr Jonathan Lim from The University of Manchester and The Christie NHS Foundation Trust, Manchester, UK. Patients in the study had received a median of three prior lines of systemic therapy, which Lim notes make these results in a heavily pre-treated population even more remarkable. Lim adds, “I am particularly heartened by the lack of serious side-effects at the doses tested. All the CRS events reported – which we often see with T-cell-based therapies – were grade 1–2, meaning they are relatively straightforward to control medically.”

Recent advances against the KRAS G12C mutation provide hope for the development of much-needed therapies for G12V, which is a well-established driver mutation in many pancreatic and colorectal cancers (NPJ Precis Oncol. 2022;6:91). KRAS mutations can weaken tumour-infiltrating T cell function and create an immunosuppressive tumour microenvironment (Front Immunol. 2025;16:1509173), making TCR-T therapy a potentially advantageous approach. However, there are challenges to overcome: “There can be a long lead-time for the manufacture of TCR-T and the current high cost could prohibit broad use in clinical practice,” cautions Lim. Additionally, the specificity of NW-301V for the G12V mutation alone could also be restrictive. A recent study of an autologous neoantigen-specific T-cell therapy was generated to display specificity toward multiple mutants in patients with metastatic melanoma (Nat Med. 2025;31:881–893), which may be advantageous considering the intra- and inter-tumoural heterogeneity often seen in solid tumours. Nevertheless, Lim is optimistic for the future of NW-301V, concluding, “Further trials would be eagerly awaited considering the response rate seen in this small sample size, and it would be interesting to test NW-301V as an earlier line of therapy. Patient selection will be critical given the logistic and cost issues.”