Chimeric antigen receptor-engineered (CAR)-T cell therapy for metastatic prostate cancer

Abstract

Metastatic prostate cancer is associated with a significantly reduced survival rate, often indicating a more aggressive disease phenotype with diminished responsiveness to conventional therapies. Several FDA-approved treatments have demonstrated improved overall survival in men with metastatic disease. These include androgen receptor signaling inhibitors such as enzalutamide and abiraterone acetate, taxane-based chemotherapies including docetaxel and cabazitaxel, and bone-targeting radiopharmaceuticals like radium-223. Immunotherapeutic agents have also contributed to expanding treatment options with Sipuleucel-T, a dendritic cell-based vaccine, and pembrolizumab, a PD-1 immune checkpoint inhibitor approved for select patient populations. Furthermore, the introduction of poly (ADP-ribose) polymerase inhibitors like olaparib and rucaparib, has transformed the therapeutic landscape, particularly for patients with DNA repair deficiencies in metastatic prostate cancer. More recently, prostate-specific membrane antigen (PSMA)-targeted immunotherapies have shown promise for the treatment of advanced-stage malignancy. Ongoing developments in immunotherapy, particularly those targeting the tumor microenvironment, are expected to significantly reshape the management of metastatic prostate cancer. Among these, chimeric antigen receptor T-cells (CAR-Ts) have revolutionized the treatment of hematologic malignancies, are now being extensively evaluated in solid tumors. In this review, we highlight adoptive cellular therapies utilizing CAR-T cells engineered to recognize prostate cancer-specific antigens, aiming to overcome immune evasion mechanisms. We summarize current CAR-T modalities with their limitations and prospects being evaluated in both preclinical and clinical settings of metastatic prostate cancer.

Keywords: CAR-T cell therapy; Castration-resistant prostate cancer; Immune tolerance; Natural killer cells; Neuroendocrine prostate cancer; Prostate cancer; T-cell receptor; Targeted therapy.