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Review
. 2021 Feb;81(2):191-206.
doi: 10.1007/s40265-020-01456-z.

Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer

Nityam Rathi #  1 , Taylor Ryan McFarland #  1 , Roberto Nussenzveig  1 , Neeraj Agarwal  1 , Umang Swami  2
Affiliations
Review

Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer

Nityam Rathi et al. Drugs. 2021 Feb.

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.

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Conflict of interest statement

Neeraj Agarwal has received consultancy fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Janssen, Merck, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics, and institutional research funding from AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Roberto Nussenzveig has received advisory fees from Tempus. Nityam Rathi, Taylor Ryan McFarland, and Umang Swami declare that they have no conflicts of interest.

Figures

Fig. 1
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
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