Combined prostate cancer vaccine plus immune checkpoint inhibition synergizes to eliminate prostate cancer.

Immunotherapy has improved outcomes in many cancers, yet the clinical benefits remain limited in prostate cancer. We evaluated whether an adenovirus-based bivalent prostate cancer vaccine (Ad-PS2) targeting two tumor antigens could be strengthened by combination with immune checkpoint blockade. Using immunocompetent mouse models, we found that Ad-PS2 combined with low-dose anti-CTLA4 generated robust anti-tumor immunity capable of eliminating established tumors, exceeding the effects of either treatment alone. Tumor-free mice resisted subsequent tumor rechallenge, indicating durable immune protection. Tumor analysis revealed a significant increase in intratumor CD8 T cell infiltration with Ad-PS2 and anti-CTLA4, whereas anti-PD1 alone produced minimal infiltration and, with the vaccine, provided no therapeutic advantage. These results highlight a mechanistically synergistic interaction between dual antigen-targeted vaccination and CTLA4 blockade and illustrate how rational combination immunotherapy can overcome resistance in prostate cancer. This work defines a strategy that could inform future translational approaches for improving immunologic control of prostate cancer.