UCLA

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of cancer with no effective treatment available. One promising way to treat cancer is T cell receptor (TCR) immunotherapy. Our efforts to develop immunotherapy targeting late-stage prostate cancer include epitope identification, cognate TCR isolation, and functional verification. We aim to define the epitopes and TCRs targeting prostatic acid phosphatase (PAP). PAP, a prostate tissue antigen, was used to develop the first FDA-approved cancer vaccine, Provenge. A multi-modal immunopeptidomic analysis of PAP on HLA-A*02:01 was performed with both physical and in silico methods. Eleven PAP peptides that are presumably A*02:01-restricted were defined. Seven TCRs isolated from healthy donors’ PBMCs showed reactivity with exogenously added peptides. One candidate, PAP-TCR-156, demonstrated a weak response targeting a cell line expressing full-length PAP. Site-directed mutagenesis was also performed on PAP-TCR-156 to improve its potency. Multiple mutated candidates showed significantly stronger responses. Our results show that a combined approach of profiling the tissue antigen immunopeptidome is sufficient to generate targets for cognate TCR development. Those TCRs can be enhanced by alternative methods to generate candidates for potential therapeutic usage.