An open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-112 in human leukocyte antigen-C*08:02–positive adult patients with unresectable, advanced, and/or metastatic solid tumors that are positive for the KRAS G12D mutation.

TPS2677 Background: The landscape of cancer treatment is evolving with the emergence of innovative immunotherapies. Among these, T cell receptor-engineered T cell (TCR-T) therapy has shown promise for patients with solid tumor malignancies. Targeting driver mutations, such as KRAS, may offer novel therapeutic options for patients with limited treatment options. Oncogenic driver mutations in KRAS typically involve single-base mutations at genomic hotspot locations. The KRAS isoform is mutated in 84% of RAS-driven cancers and in nearly 100% of pancreatic ductal adenocarcinoma (PDAC). The KRAS G12D mutation is the most frequent mutation in PDAC (28%), followed by colorectal cancers (12%). Despite its well-established target role in tumorigenesis, there is no FDA-approved therapy targeting the G12D variant. NT-112 is an autologous TCR-T cell therapy targeting the KRAS G12D mutation presented by HLA-C*08:02, armored by disruption of the gene encoding the transforming growth factor beta receptor type 2 (TGFBR2) in order to reduce the immunosuppressive effect of TGF-β in the tumor microenvironment. Methods: This first-in-human, open label, multicenter, Phase 1, dose escalation study aims to assess the safety, identify the MTD and evaluate potential anti-tumor activities of NT-112 in subjects with solid tumors. The study will enroll up to 24 adult subjects harboring the KRAS G12D mutation that are HLA-C*08:02 positive, who exhibit progressive or recurrent disease after at least one line of standard of care treatment. Enrolled patients will undergo leukapheresis, from which, CD4 and CD8 T cells will be enriched and activated ex vivo. The genes encoding the TGFBR2 and the endogenous TCR α and β chains are knocked out from the activated T cells utilizing clustered regularly interspaced short palindromic repeats (CRISPR-Cas9). The HLA-C*08:02-restricted TCR specific to the KRAS G12D mutation is knocked-in in the TCR α locus. Subjects will undergo standard lymphodepletion followed by a single infusion of NT-112 and concurrent, daily, subcutaneous, recombinant IL-2 for up to 8 days. Dose escalation will occur across 3 ascending dose levels following the BOIN design. Subjects will be monitored for dose-limiting toxicities for 28 days following NT-112 infusion. Disease response will be assessed according to the RECIST v1.1 criteria. Comprehensive translational analysis will be conducted to gain insights into the mechanism of action, biomarkers associated with treatment response, and potential mechanisms of resistance. All subjects will be followed for up to 15 years. Clinical trial information: NCT06218914 .