Abstract
Simple SummaryImmunotherapy has changed the treatment paradigm of numerous malignancies such as non-small cell lung cancer and melanoma. To date, there has been only modest demonstrable efficacy of immunotherapy for prostate cancer. This lack of efficacy is likely due to the immunosuppressive tumor microenvironment. When we consider the fact that metastatic castrate-resistant state is the most lethal form of prostate cancer, there is an unmet need to increase the efficacy of immune therapies for this disease. The treatment paradigm has now shifted towards combinatorial regimens to enhance the anti-tumor immune response. These combinations with immunomodulatory agents in ongoing clinical trials include conventional agents such as chemotherapy and numerous novel agents. This review summarizes the clinical trials recruiting patients with metastatic castrate-resistant prostate cancer utilizing immunotherapeutic approaches.Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically “cold” malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents’ combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC.
Highlights
There is evidence suggesting an increase in myeloid-derived cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) of prostate cancer is associated with tumor progression [106]
Chronic inflammation induced by the tumor, inflammatory cytokines such as soluble tumor necrosis factor, interleukin 1 beta (IL-1β), transforming growth factor-β (TGF-β), and interleukin 10 (IL-10) cause myeloid cells to differentiate into MDSCs, which have been implicated in worsened prognosis, and resistance to checkpoint inhibitors (CPIs) immunotherapy [108,109,110]
ADP ribose polymerase (PARP) inhibitors have already demonstrated efficacy in patients with homologous recombination deficiency (HRD), clinical trials are currently ongoing in combination with agents such as radiopharmaceuticals, CPIs, and chemotherapy evaluating whether they are effective in patients without HRD. (K) Chemotherapeutic agents have potential synergy with checkpoint inhibitors, and clinical trials to test this hypothesis in patients with metastatic castration-resistant prostate cancer (mCRPC) are currently ongoing
Summary
Sipuleucel-T was the first therapeutic vaccine to be approved by the United States. Food and Drug Administration (FDA) for patients with metastatic castration-resistant prostate cancer (mCRPC) based on the pivotal phase III IMPACT trial [19], and the first autologous cellular therapeutic vaccine for any cancer. Was strongly correlated with resistance to AR-directed therapy and worse survival [36] Increasing knowledge of such correlates of immune response could hold the. As of July 2020, there three are being evaluated in patients with mCRPC in combination with CPIs. While vaccineare thirteen vaccine clinical trials actively recruiting patients with prostate cancer. Of based therapies have several advantages, one possible drawback is that an effective imthese, three are being evaluated in patients with mCRPC in combination with CPIs. While mune response to a specific TAA might be variable, limited in part by human leukocyte vaccine-based therapies have several advantages, one possible drawback is that an effecantigen (HLA) expression haplotype, which affect presentation of by thehuman immunogenic tive immune response to and a specific.
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