Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

Abstract

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.

Macrophages as a Therapeutic Target in Metastatic Prostate Cancer: A Way to Overcome Immunotherapy Resistance?

“…Thus, to overcome these challenges, biomarker-based precision medicine approaches guiding the sequence of systemic therapy as well as new therapeutic strategies are needed. In this setting, an increasing effort has been made in recent years to incorporate immunotherapy in the treatment of mPC, however, with no successful results [ 19 ]. In this review we will discuss the current status of immunotherapy in the mPC therapeutic scenario as well as the mechanisms involved in immunotherapy resistance, focusing on PC immunosuppressive tumor microenvironment (TME) and specifically on the role of tumor-associated macrophages (TAMs).…”

“…However, Sipuleucel-T has limited acceptance by the medical community and is not approved by the European Medicines Agency (EMA) due to the complex and costly production of this cellular immunotherapy combined with its limited benefit and the appearance of ICIs in the clinical setting. Nevertheless, as previously stated, several clinical trials have evaluated the efficacy of ICIs in mPC patients who were not selected based on predictive molecular biomarkers, either as single agents or in combination with other checkpoint inhibitors or with other therapies with limited overall activity and inconclusive results [ 19 , 31 ]. Thus, an important current challenge is to improve the efficiency of ICIs in the mPC therapeutic setting.…”

“…Thus, an important current challenge is to improve the efficiency of ICIs in the mPC therapeutic setting. In fact, at present, a large number of immunotherapy-based clinical trials are ongoing in PC, many of which are testing combination therapies or new ICIs [ 19 ].…”

Insights of RKIP-Derived Suppression of Prostate Cancer

“…Immune evasion is essential for cancer progression. PD-L1 is an immune checkpoint protein and plays a major role in PC to escape immune attack [ 164 ]. Using TISIDE (an integrated repository portal for tumor-immune system interaction) platform [ 165 ], we observed a significant reverse correlation (Spearman r = −0.503, p < 2.2 × 10 −16 ) between RKIP and CD274 (PD-L1) expression in PC ( n = 498, TCGA PC dataset) ( Figure 5 ).…”

Updates on Molecular and Biochemical Development and Progression of Prostate Cancer

“…In the new era of immune checkpoint inhibitors (ICIs), these new medications such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors have been showing promising results through the stimulation of anti-tumoral immunity. In fact, there is a growing body of evidence that shows how the use of ICIs could be more beneficial in PCa patients belonging to a specific sub-group characterised by high PD-L1 tumour expression or high tumour mutational burden [ 10 ].…”