Current Status and Future Perspectives of Checkpoint Inhibitor Immunotherapy for Prostate Cancer: A Comprehensive Review

Abstract

The clinical spectrum of prostate cancer (PCa) varies from castration-naive to metastatic castration-resistant disease. Despite the administration of androgen synthesis inhibitors and chemotherapy regimens for castration-resistant prostate cancer, the treatment options for this entity are limited. The utilization of the immune system against cancer cells shows potential as a therapeutic modality for various solid tumors and hematologic malignancies. With technological advances over the last decade, immunotherapy has become an integral treatment modality for advanced solid tumors. The feasibility of immunotherapy has shown promise for patients with PCa, and with advances in molecular diagnostic platforms and our understanding of immune mechanisms, immunotherapy is reemerging as a potential treatment modality for PCa. Various combinations of individualized immunotherapy and immune checkpoint blockers with androgen receptor-targeted therapies and conventional cytotoxic agents show promise. This article will review the current status of immunotherapy, including new discoveries and precision approaches to PCa, and discuss future directions in the continuously evolving landscape of immunotherapy.

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

“…Notably, cytokines can be used as adjuvants in combination with other immunotherapeutic agents, as, for example, in tumor cell-based cancer vaccines [ 36 ]. Immunotherapeutic strategies employing monoclonal antibodies can be further divided into antibody-drug conjugates [ 48 , 49 , 50 , 51 , 52 ], artificial bi-specific T cell-engaging antibodies, or BiTEs [ 53 , 54 , 55 , 56 , 57 , 58 ], and immune checkpoint inhibitors [ 59 ]. Cell-based immunotherapy, on the other hand, is the adoptive cell transfer (ACT) into patients of T cells that have been genetically modified to contain a chimeric antigen receptor (hence the term CAR T cells) that targets a prostate-specific antigen [ 59 , 60 , 61 ]; nonetheless, some of these immunotherapeutic interventions are still in the pre-clinical or early clinical (phase I) stage and, as such, they do not yet provide enough evidence to support therapeutic efficacy ( Figure 1 ).…”

“…Immune checkpoint inhibitors (ICIs) represent a class of mAbs that have the ability to inhibit immune checkpoint receptors and, therefore, to prevent the inactivation of T-cell function. Immune checkpoint receptors include cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1), and antibodies (ICIs) against them have been shown to induce potent anti-tumor immune responses in a variety of cancers [ 59 ].…”

“…Following encouraging results from phase I studies in patients with mCRPC, where it was shown that ipilimumab in combination with granulocyte macrophage-colony-stimulating factor (GM-CSF) in PCa vaccines induces significant PSA declines, an open-label phase I/II multicenter study (NCT00323882) investigating ipilimumab in patients with mCRPC, suggested clinical anti-tumor activity, as supported by manageable adverse events and substantial disease control [ 65 , 66 , 67 ]. A subsequent phase III clinical trial (NCT00861614) found a significantly higher OS in mCRPC patients with favorable prognostic characteristics that received ipilimumab as compared to a placebo drug [ 59 , 68 ], with OS rates following a two to three times higher trend at three years onwards in cases where ipilimumab was administered along with radiotherapy [ 69 ]. On the contrary, patients with asymptomatic or minimally symptomatic chemotherapy-naïve PCa have not been shown to gain any clinical benefit from ipilimumab monotherapy in terms of OS [ 70 ].…”

“…ICIs that act as inhibitors of PD-1 include nivolumab and pembrolizumab, whereas ICIs of PD-L1 include atezolizumab, avelumab, and durvalumab [ 62 ]. Even though primary prostate cancers are characterized by an infiltration of PD-1 expressing CD8+ T cells, mCRPC shows minimal expression of the PD-L1 ligand, which represents a significant obstacle when applying anti-PD-1/PD-L1 monotherapy [ 59 , 72 , 73 ]; only mCRPC patients who have developed resistance to the anti-androgen enzalutamide have been associated with an upregulation of PD-L1 [ 74 ]. Clinical trials testing nivolumab or pembrolizumab as monotherapy in unselected mCRPC patients have produced unsatisfactory results in terms of demonstrating a significant survival benefit, with the only exceptions being partial responses in enzalutamide-resistant patients and in patients with microsatellite instability (MSI) [ 72 , 75 , 76 ].…”

Gonadotropin-Releasing Hormone Receptors in Prostate Cancer: Molecular Aspects and Biological Functions

“…These include anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) (ipilimumab, tremelimumab) and anti-PD-1 (programmed death protein-1) (nivolumab, pembrolizumab, lambrolizumab, avelumab, durvalumab) mAbs. Clinical trials have been already performed in PCa patients treated with checkpoint inhibitors, either alone or in combination with antiandrogens [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Unfortunately, despite the initial success in clinical use of these compounds, the efficacy of treatments was reported to be low and the majority of PCa patients showed resistance to these therapies [ 87 , 89 , 90 , 91 ].…”