Mapping of shared tumor antigen reactivity with programable mRNA nanoparticles in prostate cancer patients

Prostate cancer (PC) remains refractory to immunotherapy despite having an FDA-approved cancer vaccine. As PC is thought to be poorly immunogenic with a low mutational burden, tumor associated antigens (TAAs), not neoantigens, presumably represent the targetable antigens in this disease. However, PC TAA immunogenicity remains unclear. To systematically study PC patient responses to TAAs, we utilized a novel programmable-mRNA nanoparticle platform to formulate 8 full-length PC TAA mRNAs and administered them in-vitro to peripheral blood mononuclear cells from control patients, localized (L)PC patients, and metastatic (m)PC patients. By assessing TAA recall responses through T cell activation and IFN production, we discovered a significantly higher degree and frequency of CD8⁺ T cell response in PC patients compared to controls, with the highest recall seen in mPC patients. Specifically, individual LPC and mPC patients have a significantly greater propensity to recall multiple TAAs (pan-responses). Interestingly, mPC TAA CD8⁺ T cell pan-responses are dynamic throughout pembrolizumab therapy, with treatment refractory patients significantly losing the ability to respond to key TAAs (NY-ESO-1, PSCA and PAP). Importantly, treatment responding patients tended to increase their recall responses to these TAAs. These results reveal a potential screening tool for therapeutic outcome, and hierarchy in immunogenicity of TAA that can aid in developing novel combinatorial therapies.