Combining antigen-specific vaccination with radiopharmaceutical therapy (RPT) to enhance anti-tumor immunity and efficacy

PROJECT SUMMARY Prostate cancer is the second leading cause of cancer-related death among men in the U.S. With a median life expectancy of less than 3 years for patients with metastatic castration-resistant prostate cancer, additional life prolonging therapies are needed. Currently approved therapies for this late-stage prostate cancer include immunotherapy and radiopharmaceutical therapy (RPT). Therapeutic cancer vaccines activate tumor-specific CD8+ T cells to infiltrate and kill tumor cells. Yet, tumors have evolved resistance mechanisms against the vaccine, in particular, the recruitment of immunosuppressive CD4+ regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). A recently approved RPT targeting prostate-specific membrane antigen (PSMA) can deliver radiation specifically to prostate cancer cells (177Lu-PSMA-617, also known as Pluvicto). As the radioisotope decays, additional tumor-infiltrating cells, such as Tregs and MDSCs, are irradiated as well. The physical properties of the radioisotope can largely affect the magnitude of radiation-induced cell killing as well as type I interferon in surviving cells. Therefore, selecting radioisotopes that effectively deplete Tregs and MDSCs while enhancing CD8+ T cells recruitment, might be advantageous in combination with targeted immunotherapy. We hypothesize the initial priming of tumor-specific CD8+ T cells using an anti-tumor vaccine, followed by depletion of Tregs and MDSCs by RPT, will enhance the infiltration of tumor-specific CD8+ T cells with memory phenotypes, enhancing anti-tumor efficacy. We have recently generated a novel immunocompetent transgenic mouse strain tolerant of human PSMA (hPSMA) in which hPSMA is expressed in the native mouse prostate. These mice will be implanted with syngeneic murine prostate cancer cell lines expressing human PSMA (TRAMP-C1-hPSMA or RM-1-hPSMA). Aim 1 will evaluate the depletion and functional suppression of tumor-infiltrating Tregs and MDSCs induced by the radionuclides of varying therapeutic emissions (α-emitting Actinium-225, β/Auger electron emitting Terbium- 161, and β-emitting Lutetium-177) linked to a PSMA-targeting moiety. Aim 2 will determine the anti-tumor efficacy of combining tumor-specific vaccination with PSMA-targeting RPT and characterize tumor-infiltrating CD8+ T cells. The immunomodulatory effects of PSMA-targeting RPT have been mostly unexplored due to the lack of an appropriate preclinical model. Our novel mouse model provides the opportunity to study the timing and mechanism of combining PSMA-targeting RPT with T-cell activating therapy. The translatable findings from this proposed work have the potential to be developed as a novel therapeutic approach to prolong the lives of patients with prostate cancer.