Identification and use of T-cell receptors recognizing common tumor mutations

Division Of Basic Sciences - Nci

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Abstract

This project expands on earlier accomplishments targeting common RAS mutations with off-the-shelf T-cell receptors (TCR) and taking such reagents into clinical trials. It will now try to expand not only the anti-RAS repertoire of TCRs, but also develop similar reagents against other commonly and consistently mutated oncogenes. In collaboration with Dr. Guha's laboratory and Dr. Andressen, a major effort will be to determine which mutations are correctly processed and presented on MHC molecules, and which MHC molecules are doing the presentation. Then T-cells from patients with those MHC alleles and appropriately mutated cancers will be screened for T-cell responses, and vigorous efforts to immunize HLA-transgenic mice will be pursued. One new TCR has been cloned that recognizes the AA746-750 Exon 19 deletion in EGFR (nearly half of EGFR-mutated NSCLCs). A new component in this effort has been to look for mutated neoepitopes from these common shared mutations by eluting peptides off of the most common HLA Class I alleles and subjecting them to mass spectroscopy. We have nearly completed a survey of a dozen of the most common tumor associated mutations and their presentation by the 15 most common Class I alleles. This led us to focus on multiple mutated epitopes from common oncogenes presented by the HLA-A3/HLA-A11 superfamily of alleles. Using HLA transgenic mice (some generated at NCI), we have found new TCRs that recognize common mutations in EGFR and PIK3CA.