Immunotherapy for castration-resistant prostate cancer: has its time arrived?

Abstract

Introduction: Within the last decade, multiple innovative immune platforms have been developed and tested in patients with metastatic castration-resistant prostate cancer (mCRPC) with only one demonstrating a survival benefit. The advent of immunogenomics along with the availability of diverse checkpoint inhibitors provides inroads in treating these patients, in many cases with significant clinical impact but unfortunately not in all patients. How to exploit these novel platforms remains an area of increased interest especially in the setting of new agents that can affect the tumor microenvironment and potentially render a 'cold' tumor to become 'hot.'Areas covered: This review highlights the current changes and challenges in this field and how to best use our current knowledge for better trial designs in patients with mCRPC.Expert opinion: Recent understanding of the inhibitory milieu within the tumor microenvironment has fostered the use of combinatorial strategies that target not only tumor cells but capitalize on controlling inhibitory cell populations and cytokines that induce a hostile setting for immune cells. Immunogenomics and genomic interrogation of prostate cancers have opened a vista as to how patients' tumors that can respond to immune agents that previously were thought have minimal antitumor activity.

Keywords: Prostate cancer; bites; car T cells; immunotherapy; tumor microenvironment.

Figures

Figure 1:

Pathways and enzymatic regulation in fatty acid synthesis and cholesterol metabolism and biosynthesis that can be used as tools that are predictive of a tumor’s behavior and may be considered as potential therapeutic targets. Reproduced from European Urology Oncology, 2, Giunchi F, Fiorentino M, Loda M, The metabolic landscape of prostate cancer, 28–36., Copyright 2019, with permission from Elsevier [6]

Figure 2:

Illustration of how adenosine is generated within the tumor environment with subsequent suppression of a diversity of immune subsets. Arrows correspond to increased activation or expression; T bars indicate inhibition or decreased activity. Reproduced with permission from [12] under the Creative Commons Attribution License.

Figure 3:

Immunohistochemistry on fixed tumor specimens using anti-T cell (CD3) antibody. Six cases discussed by Wu, et al including two CDK12 mutant tumors, one MMRD (mismatch repair deficient) tumor, and three tumors that were wildtype for CDK12, MMR (mismatch repair deficient) genes, and HR (homologous recombinant) genes. Reproduced via open access and permission of creative commons. Reproduced from Cell, 173/7, Wu Y-M, Cieslik M, Lonigro R et al, Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer, 1170–1782, Copyright 2018, with permission from Elsevier [29].