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, 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. This will allow us to focus on candidate tumor-specific neoepitopes of greatest abundance and proven to be processed and presented on MHC.