Project 466701

T cell receptor (TCR) gene therapy involves the adoptive transfer of T cells engineered with high-affinity TCRs to induce a clinically effective anti-tumor response. Results of recent clinical trials show that TCR gene therapy is a promising treatment for cancer. TCRs expressed on the surface of T cells consist of alpha and beta chains, which together recognizes cancer peptides or antigens presented by human leukocyte antigens (HLAs) on the surface of cancer cells. We and others previously showed that most, if not all, TCRs exhibit chain centricity, where one chain predominantly determines antigen recognition and the other contributes to modulating TCR affinity for the antigen-HLA complex. By applying the concept of chain centricity, our group previously isolated TCRs that optimally targeted cancer antigens WT1 and MART1. Another important cancer antigen often being investigated is NY-ESO-1. However, the vast majority of clinical trials use TCRs that target NY-ESO-1 peptide presented on HLA-A2 only. This greatly limits anti-NY-ESO-1 TCR gene therapy to only a very small portion of HLA-matched cancer patients.To make anti-NY-ESO-1 TCR gene therapy available to a broader population of cancer patients, we will generate a highly diverse set of TCRs recognizing NY-ESO-1 displayed on another major HLA allele, HLA-B7, by exploiting TCR chain centricity. From this repertoire, we will isolate a TCR with optimal targeting of NY-ESO-1 and minimal toxicity for pre-clinical and clinical studies.