Recurrent neoantigens in treatment-resistant tumors. Systematic identification of recurrent immunogenic neoantigens in treatment-resistant tumors

New approaches that generate long-lasting therapeutic responses in cancer patients with tumors that have evolved resistance to therapies are critically needed. To handle this challenge, we have developed SpotNeoMet, a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven resistance mutations predicted to produce neo-peptides presented by common HLAs. Using HLA-immunopeptidomics, we discovered three novel neo-peptides derived from Androgen Receptor (AR) H875Y, the most common castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic, then isolated and characterized their cognate T-cell receptors (TCRs) from healthy donor PBMCs. We demonstrate that the three TCRs are highly specific and kill cancer cells presenting the AR neo-peptides. Our novel pipeline, identifies novel immunotherapy targets and potential treatment options for mCRPC patients. In addition, SpotNeoMet promises a systematic route to identifying 'HLA-peptide' pairs and their cognate TCRs across treatment-resistant cancers.