Immune checkpoint inhibitors and prostate cancer: a new frontier?

Abstract

Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC), agents that provide durable disease control and long-term survival are still needed. It is a fact that a tumor-induced immunosuppressive status (mediated by aberrant activation of inhibitory immune checkpoint pathways as a mechanism to evade host immune surveillance) plays a crucial role in the pathogenesis of cancer, including prostate cancer (PC), making CRPC patients suitable candidates for immunotherapy. Therefore, growing interest of anticancer research aims at blocking immune checkpoints (mainly targeting CTLA-4 and PD1/PD-L1 pathways) to restore and enhance cellular-mediated antitumor immunity and achieve durable tumor regression. In this review, we describe the current knowledge regarding the role of immune checkpoints in mediating PC progression, focusing on CTLA-4 and PD1 pathways. We also provide current clinical data available, an update on ongoing trials of immune checkpoint inhibitors in PC. Finally, we discuss the necessity to identify prognostic and predictive biomarkers of immune activity, and we analyze new immune checkpoints with a role as promising targets for PC therapy.

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

“…Immune checkpoint inhibitors represent a significant breakthrough in the treatment of various advanced tumor types (such as melanoma, renal cancer, lung cancer, head and neck cancer, and urinary bladder cancer) in recent years that has dramatically changed the prognosis of patients with cancer (98)(99)(100)(101)(119)(120)(121). In some cases, therapy with these drugs means long-term disease control or hopefully even cure.…”

“…There has been dramatic success in the treatment of various advanced solid tumor types such as melanoma, renal cancer, lung cancer, head and neck cancer with the novel class of immunomodulatory anticancer agents called immune checkpoint inhibitors (98)(99)(100)(101)(119)(120)(121). These therapeutics are able to block inhibitory molecules and their receptors on effector immune cells, which leads to a robust T-cell response against the tumor.…”

Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance

“…Also tremelimumab, as a wholly human IgG2-mediated specific anti-CTLA-4 mAb, has allowed to obtain, either alone or in combination with bicalutamide-mediated ADT, in patients suffering from recurrent PCa, a prolonged decrease in serum PSA levels together with a delay in metastatic PCa progression (9,14).…”

“…It results that CTLA-4 is one of the most powerful immunosuppressive molecular factor on T-cell surface. In addition, Tregs can make easier the drop of immune responses also by release of both interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) immunosuppressive agents (4)(5)(6)(7)(8)(9)(10). Since the CTLA-4 link with tumor cell B7-1/B7-2 ligands can suppress T-cell immune responsiveness, it follows that the disruption of CTLA-4 activity by anti-CTLA-4 mAbs (so-called immune T-cell check point modulators) can Active immunotherapy, triggering the host immune system to focusly target cancer cells.…”

The Changing Therapeutic Landscape in Metastatic Prostate Cancer

“…The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1 pathways that inhibit both T-cell activation and T-cell function, have been the most well-defined and therapeutically active targets for checkpoint blockade. 22 Ipilimumab is an immuno-stimulatory antibody that inhibits CTLA-4 activity thereby enhancing the immune system's T cell's response to cancer. In a phase III randomized clinical trial, patients with mCRPC who had progressed on docetaxel were treated with a single dose of bone-targeted radiotherapy, and then randomized to Ipilimumab at a dose of 10 mg/kg or placebo, every 3 weeks for up to four cycles.…”