Is There a Role for Immunotherapy in Prostate Cancer?

Abstract

In the last decade, immunotherapy has revolutionized the treatment landscape of several hematological and solid malignancies, reporting unprecedented response rates. Unfortunately, this is not the case for metastatic castration-resistant prostate cancer (mCRPC), as several phase I and II trials assessing programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors have shown limited benefits. Moreover, despite sipuleucel-T representing the only cancer vaccine approved by the Food and Drug Administration (FDA) for mCRPC following the results of the IMPACT trial, the use of this agent is relatively limited in everyday clinical practice. The identification of specific histological and molecular biomarkers that could predict response to immunotherapy represents one of the current challenges, with an aim to detect subgroups of mCRPC patients who may benefit from immune checkpoint monoclonal antibodies as monotherapy or in combination with other anticancer agents. Several unanswered questions remain, including the following: is there—or will there ever be—a role for immunotherapy in prostate cancer? In this review, we aim at underlining the failures and promises of immunotherapy in prostate cancer, summarizing the current state of art regarding cancer vaccines and immune checkpoint monoclonal antibodies, and discussing future research directions in this immunologically “cold” malignancy.

PD-L1, TMB, MSI, and Other Predictors of Response to Immune Checkpoint Inhibitors in Biliary Tract Cancer

“…Among the most promising predictive biomarkers of the response to immunotherapy, recent years have witnessed growing attention toward DDR gene alterations, based on preclinical and early phase clinical trials supporting this biological rationale [ 58 , 59 ]. Of note, DDR gene aberrations impair DNA damage repair processes, with subsequent accumulation of DNA damage [ 60 ]; in physiological conditions, genes such as poly (ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) play a key role in maintaining genomic stability and in avoiding the accumulation of these mutations, with the inhibition of these genes representing a timely topic in medical oncology [ 61 ].…”

Update on Prostate Cancer Diagnosis, Prognosis, and Prediction to Response to Therapy

“…The pathologist has to integrate information from the pathological evaluation with the data from different sources to achieve a final diagnosis, prognosis and prediction to the response to therapy [ 4 ]. The ultimate issue is to improve our understanding of genomics in order to identify actionable targets as well as to develop novel treatments for patients with advanced PCa to extend survival and possibly provide cure [ 5 ].…”

“…The wide range of novelties reported in this Special Issue of the journal Cells on prostate cancer (PCa) diagnosis, prognosis, and prediction to response to therapy, has led us to a series of considerations related to a better understanding of the current and future role of effective molecular biomarkers in individual patients with PCa [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]: (1) Digital pathology, including multiplexing; (2) Clinical translation of genetic information; (3) Clinical significance of liquid biopsies; and (4) Multi-criteria decision making and information fusion.…”

Immunotherapy as a Precision Medicine Tool for the Treatment of Prostate Cancer

“…Phase II clinical trials testing the efficacy of the vaccine have produced conflicting results. For example, one study evaluating DCVAC/PCa in combination with prednisone and docetaxel chemotherapy in men with mCRPC has demonstrated a manageable safety profile, a 6–7 month OS advantage and the induction and maintenance of PSA-specific T cells [ 88 , 117 ]; another study did not find this combination regimen to be beneficial in the long term, despite the induction of an immune response [ 105 , 109 , 118 ]. As a result, a randomized, double-blind, placebo-controlled, phase III clinical trial (VIABLE, NCT02111577) is currently ongoing with the aim to determine the safety and efficacy of DCVAC/PCa in combination with docetaxel and prednisone (versus docetaxel and prednisone alone) in patients with mCRPC [ 119 ].…”

“…GVAX is a tumor cell-based vaccine which, as the name implies, consists of irradiated whole tumor cells that have been genetically modified to constitutively express GM-CSF; the prostate tumor cells are extracted from the hormone-sensitive cell line LNCaP and the hormone-refractory cell line PC-3, which derive from nodal and bone sites of metastasis, respectively [ 88 , 120 ]. This strategy has the advantage of inducing immune responses to multiple TAAs without the need for HLA matching [ 121 ].…”