Abstract
KRAS is one of the most frequently mutated proto-oncogenes in human cancers, including pancreatic and colorectal cancers. The dominant oncogenic mutations of KRAS are single amino acid substitutions at codon 12, in particular G12D and G12V. The consistency, frequency, and tumor specificity of these “neo-antigens” make them attractive therapeutic targets. Recent data associates T cells targeting mutated antigens with clinical immunotherapy responses in patients with metastatic melanoma, lung cancer or cholangiocarcinoma. We successfully generated T cells from HLA-A11*01 transgenic mice and subsequently isolated HLA-A11*01-resticted T cell receptors (TCRs) highly reactive with the mutated KRAS variants G12V and G12D. Peripheral blood lymphocytes (PBL) transduced with these TCRs can recognize multiple HLA-A*11:01+ tumor lines bearing the appropriate KRAS mutations. In a xenograft model of large established tumor, adoptive transfer of these transduced PBL reactive with a mutated pancreatic cell line could significantly reduce its growth in NSG mice. The success of adoptive transfer of TCR-engineered T cells against melanoma and other cancers support clinical trials with these T-cells recognizing mutated KRAS in patients with a variety of common cancer types. A phase I/II clinical trial targeting KRAS G12V and G12D mutations with TCR-engineered PBL in HLA-A1101+ patients will be starting soon in the Surgery Branch NCI.
Citation Format: Qiong J. Wang, Zhiya Yu, Kenichi Hanada, Nicholas P. Restifo, James C. Yang. Identification of T-cell receptors targeting KRAS-mutated human tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-242.
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