Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer

Abstract

Immunotherapies have shown remarkable success in the treatment of multiple cancer types; however, despite encouraging preclinical activity, registration trials of immunotherapy in prostate cancer have largely been unsuccessful. Sipuleucel-T remains the only approved immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer based on modest improvement in overall survival. This immune evasion in the case of prostate cancer has been attributed to tumor-intrinsic factors, an immunosuppressive tumor microenvironment, and host factors, which ultimately make it an inert 'cold' tumor. Recently, multiple approaches have been investigated to turn prostate cancer into a 'hot' tumor. Antibodies directed against programmed cell death protein 1 have a tumor agnostic approval for a small minority of patients with microsatellite instability-high or mismatch repair-deficient metastatic prostate cancer. Herein, we present an overview of the current immunotherapy landscape in metastatic castration-resistant prostate cancer with a focus on immune checkpoint inhibitors. We describe the results of clinical trials of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer; either as single agents or in combination with other checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, novel hormonal therapies, chemotherapies, and radioligands. Finally, we review upcoming immunotherapies, including novel monoclonal antibodies, chimeric-antigen receptor (CAR) T cells, Bi-Specific T cell Engagers (BiTEs), therapies targeting the adenosine pathway, and other miscellaneous agents.

Fig. 1

An overview of immune system pathways and targets in prostate cancer. Tumor specific-antigens from viral vectors (e.g. PROSTVAC) are displayed on MHCs. Prostate cancer cells often express unique markers such as PSMA that are targetable with CAR-Ts. Patient-specific neoantigens are also potential targets with custom NeoTCRs. Other cell-mediated therapies, such as Sipuleucel-T, use prostate cancer-specific antigen-presenting cells displaying PAP to stimulate the immune system. Increased levels of extracellular adenosine, myeloid-derived suppressor cells, and immune checkpoints such as PD-1/PD-L1 prevent anti-tumor immunity but are also targetable with various monoclonal antibodies. Use of PARPi can cause the cells to not only increase chemokine production but also increase PD-L1 expression. MHCs major histocompatibility complexes, PSMA prostate-specific membrane antigen, CAR-Ts chimeric antigen receptor T cells, NeoTCRs neoantigen T-cell receptors, PAP prostatic acid phosphatase, PD-1 programmed cell death protein 1, PD-L1 programmed cell death ligand 1, PARP poly(ADP ribose) polymerase, PARPi PARP inhibitor, mAb monoclonal antibody, TGF tumor growth factor, EpCAM epithelial cell adhesion molecule, MHC-I major histocompatibility complex class I, ATP adenosine triphosphate, AMP adenosine monophosphate, IFN 1 interferon 1, cGAS/STING cyclic GMP-AMP Synthase/Stimulator of Interferon Genes, TGF-β transforming growth factor beta