Abstract LB346: Mapping of shared tumor antigen reactivity with nanoparticle encapsulated mRNA in prostate cancer patients

Abstract

Abstract Background: Prostate cancer (PC) remains refractory immune checkpoint therapies (CPT) despite having an FDA-approved cancer vaccine. PC is known to have a low mutation burden resulting in low level of neoantigens, so shared tumor associated antigens (TAAs) and translocations presumably represent a dominant source of antigens in this disease. While PC is thought to be a poorly immunogenic tumor, the frequency and breadth of tumor antigen reactivity in PC patients is unclear. Methods: We utilized novel programmable immunogenic mRNA nanoparticle platform and created formulations encoding a range of full-length prostate TAAs (TAAmRNA) to systemically study T cell immune responses to across a range of TAAs in PC patients. We administered 8 PC TAAmRNAs (NY-ESO-1, HK2, STEAP1, TMPRSS2-ERG, PAP, PSA, PSCA and PSMA) to in-vitro cultured peripheral blood mononuclear cells (PBMC) from 43 treatment-naïve localized PC patients compared to 17 age-matched non-cancer control patients. We assessed upregulation of early T cell activation markers and interferon-gamma (INFg) cytokine production through flow cytometry and ELISPOT, respectively. Results: 20% of PC patients possessed TAA-specific CD8+ T cell responses to at least one antigen. NY-ESO-1, HK2 and TMPRSS2-ERG had the highest T cell recall responses at an average of 35%, with NY-ESO-1 demonstrating the strongest responses per patient. Of the patients that respond to any given TAA, 47% of patients responded to three or more antigens, with 11% of PC patients responding to all TAAs. PC patients also showed heightened production of IFNg, with 35% of patients showing pan-responsiveness to three or more antigens. Particularly, HK2 stimulated the highest levels of INFg production. These levels of responsiveness are not seen in the control cohort. Conclusions: Encapsulated mRNA nanoparticles can be used to systematically map antigen reactivity across a cohort of cancer patients and reveal frequent pan-responsiveness to multiple TAAs in what has considered to be an immunologically cold cancer These results also reveal a hierarchy in immunogenicity of candidates that can enable future vaccine development. Continual efforts to assess the immunogenicity of shared PC TAAs in more advanced disease, and how patient responses to TAAs are modulated by immunotherapies, can aid in refining combinatorial therapies for PC. Citation Format: Elena Montauti, Ole Haabeth, Chris Rae, Samuel Deutsch, Lawrence Fong, David Oh. Mapping of shared tumor antigen reactivity with nanoparticle encapsulated mRNA in prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB346.