Nanoplasmid PSMA DNA vaccine primes antitumor immunity and enhances response to PD-1 blockade against prostate cancer.

Prostate cancer (PCa) remains a leading cause of cancer-related mortality among men particularly in metastatic castration-resistant disease, which is refractory to immune checkpoint blockade. Prostate-specific membrane antigen (PSMA) is highly overexpressed and correlated with PCa aggressiveness and invasiveness. In this study, we evaluated the prophylactic and therapeutic potential of a next generation Nanoplasmid-based DNA vaccine encoding human PSMA (N-hPSMA). We demonstrated that Nanoplasmid resulted in faster, higher, and more sustained transgene expression compared with a conventional plasmid vector, which led to a significant increase in hPSMA-specific cellular and humoral immune response. Prophylactic vaccination conferred tumor eradication and prevented lung metastasis. N-hPSMA vaccination increased systemic immune activation with abated regulatory T cell population and augmentation of effector-memory CD8+ T cells. In the therapeutic setting, N-hPSMA slowed tumor growth and potentiated PD-1 blockade, resulting in enhanced tumor regression and survival, while increasing activation of myeloid antigen presenting cells. In a humanized orthotopic PCa model, N-hPSMA vaccination plus PD-1 blockade significantly increased functional human CD8+ T cells and suppressed the growth of human PCa LNCaP tumors. These findings established N-hPSMA as a preclinical proof-of-concept DNA vaccine that enhances antitumor immunity and sensitizes PCa to immune checkpoint blockade.