IND-Enabling Studies for a TCR-T Targeting a Pancreatic Cancer KRASG12V Mutation

PURPOSE: To develop adoptive T-cell therapy with genetically engineered T-cell receptor (TCR; TCR-T) that recognizes the KRASG12V mutation, we performed an Investigational New Drug (IND)-enabling preclinical study of a new TCR (051). This TCR was isolated from a patient with pancreatic ductal adenocarcinoma with the KRASG12V mutation that could be presented by the HLA-A*11:01 allele, the most common allele of the Chinese population. EXPERIMENTAL DESIGN: In vitro experiments using T cells from healthy donors transduced with a retroviral vector expressing 051 TCR were performed to determine the TCR specificity and functionality. The tumor reactivity strictly depended on the expression of the G12V mutation and HLA-A*11:01 molecules. The alanine scan experiment did not detect potential "off-target" cross-reactivity against the human genome. Good Laboratory Practice studies were carried out to assess the antitumor efficacy, persistence, safety, and toxicities of adoptively transferred human 051 TCR-T cells (IX001) in immunodeficient mice bearing human pancreatic cancer xenografts. RESULTS: After T-cell infusion, a potent antitumor effect was observed with or without IL-2 administration. The analysis of TCR gene integration in host T cells by retrovirus indicated a low risk of developing secondary malignancy. There was no evidence of TCR-T-related toxicity and genotoxicity induced by the retroviral vector. CONCLUSIONS: IX001 was safe and highly efficacious in a pancreatic cancer CDX model. Our data support further clinical development of IX001 for HLA-A*11:01 patients with the KRASG12V mutation.