Developing TCR-T cell therapy in renal cell carcinoma

Abstract T cells play a central role in the anti-cancer immune response. Engineering and administrating tumor-specific T cells have successfully treated some types of cancer. Compared to chimeric antigen receptor (CAR)-T cell therapies, T cell receptor (TCR)-T cells engage tumor cells through engineered TCRs that bind peptides presented by human leukocyte antigen (HLA). These peptides can be derived from tumor antigens in any cellular compartment, making TCR-T an attractive approach to developing novel engineered T cell therapies. Identifying suitable tumor-specific TCR is the most critical step for developing TCR-T therapies. However, only a small number of TCRs that recognize shared tumor antigens have been identified, which is the major bottleneck for developing novel TCR-T therapies. Here, we have identified two tumor-infiltrating lymphocytes (TILs) from the sample patient that can be dramatically activated by three independent ccRCC cell lines, indicating that these TILs contain T cells recognizing a shared tumor antigen. We further found that ccRCC- TCR1 was dominant in these TILs and was shared by all activated T cells. This ccRCC-TCR1 is HLA-B0702 restricted, which is carried by ~26% of Americans. In vitro killing assays showed that these TILs are highly cytotoxic to the ccRCC cell lines in an MHC-I-dependent manner. These data collectively suggested a high- affinity TCR that potentially recognizes a widely shared ccRCC tumor antigen. We propose two aims to develop TCR-T therapy with ccRCC-TCR1 to treat kidney cancer: 1) determine antigen specificity of ccRCC- TCR1; 2) determine in vivo antitumor activity of ccRCC-TCR1 T cells. By identifying the antigen of ccRCC- TCR1 and evaluating its antitumor activity in vivo, this translational project will pave the way for future clinical applications. At the completion of the project, the expected outcomes are to have tumor-shared antigens identified and move forward to conduct additional pre-clinical studies and prepare to initiate a clinical trial for ccRCC-TCR1 T therapy.