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Genitourinary Cancer—Prostate, Testicular, and Penile
April 28, 2020

Immune Checkpoint Blockade for Prostate Cancer: Niche Role or Next Breakthrough?

Publication: American Society of Clinical Oncology Educational Book

Practical Applications

The tumor immune microenvironment of prostate cancer harbors a predominance of immunosuppressive cells (e.g., regulatory T cells and M2 macrophages).
Low levels of circulating testosterone resulting from androgen deprivation therapy modulate the prostate cancer immune microenvironment.
Data from clinical trials demonstrate that only a small subset of patients with prostate cancer have tumors that respond to single-agent immune checkpoint inhibitors.
Although many biomarkers associated with response in other tumor types have been explored in prostate cancer, the only actionable biomarker that predicts response to checkpoint inhibition for men with metastatic castration-resistant prostate cancer is microsatellite instability/mismatch repair deficiency.
Multiple trials evaluating different combination therapy strategies using immune checkpoint inhibitors and their use across the disease continuum of prostate cancer are ongoing.

Background

In the past 5 years, the earlier use of chemotherapy1,2 or the addition of more potent therapies targeting the androgen receptor (AR) or androgen biosynthesis inhibitors3-6 have been shown to improve the survival of patients with advanced prostate cancer. Although checkpoint inhibitors (CPIs) are standard of care in patients with melanoma, lung cancer, and other genitourinary tumors, such as urothelial and renal cell carcinoma, clinical trials assessing the efficacy of CPIs in advanced prostate cancer have been associated with low response rates, with benefits in only a minority of patients.7-9 Efforts are ongoing to understand mechanisms of resistance and strategies to overcome the primary resistance to CPIs (Fig. 1); these studies are likely to guide future clinical trials with immunotherapy. Biomarkers associated with a higher chance of response are critical to identify the small percentage of patients with prostate cancer who do experience a response to monotherapy checkpoint inhibition. This article reviews the characteristics of the immune microenvironment in prostate cancer, existing evidence on the use of immune checkpoint blockade in this disease, biomarkers of response to CPIs, and future clinical trials that incorporate CPIs as part of combination strategies.
Figure 1. Factors Affecting the Results of Immunotherapy Trials in Prostate Cancer
Abbreviations: AR, androgen receptor; IL-6, interleukin-6; PSMA, prostate-specific membrane antigen, TGF-β, tumor growth factor β; TIL, tumor-infiltrating lymphocyte; TMB, tumor mutational burden; TME, tumor microenvironment.

Immune Microenvironment of Prostate Cancer

The tumor microenvironment (TME) plays a crucial role in the antitumor immune response. T-cell composition, the spatial relationship of the stromal cellular background, diversity of cytokines, and the vascular network are relevant factors in the T-cell–mediated antitumor response. A complex interaction exists among the fibroblast-infiltrated stromal cellular background, the metabolic state promoted by the disturbed vasculature, and subsequent hypoxia that contributes to an immunosuppressive TME.10 Cytokines, such as VEGF, transforming growth factor β (TGF-β), interleukin-10 (IL-10), and prostaglandin E2, in the TME are responsible for the recruitment of regulatory T cells (Tregs) and the inhibition of proliferation, activation, and infiltration of cytotoxic lymphocytes.11 The importance of the TME in prostate cancer can be demonstrated early in the natural history, with chronic persistent inflammation being associated with prostate cancer development.12
The presence of tumor-infiltrating lymphocytes (TILs) is associated with response to CPIs in melanoma13 and with a better prognosis in colorectal carcinoma, melanoma, non–small cell lung cancer, and ovarian cancer14-16; however, the prostate cancer TIL population largely consists of CD4+FOXP3+CD25+ T cells, a subpopulation of Tregs that dampens the immune response by producing inhibitory cytokines and maintaining self-tolerance.17,18 A multi-institutional study demonstrated that higher levels of CD4+ T cells in the surgical prostate specimen were associated with significantly worse distant metastasis–free survival (HR, 1.57; 95% CI, 1.25–1.97; p < .001), suggesting that these early immune cell populations may be associated with recurrence or lack of immune surveillance to prevent recurrence.19 In addition to Tregs, the prostate TME is populated by tumor-associated macrophages (TAMs), including protumorigenic M2-subtype macrophages, which are responsible for the secretion of high levels of TGF-β. The presence of M2 macrophages also has been associated with a higher risk for metastatic disease at diagnosis (HR, 1.98; 95% CI, 1.17–3.33; p = .011).20 The cytokine milieu is equally relevant, and the presence of chemokines, such as CCL22, in the TME of prostate cancer contributes to immune suppression. Several chemokine receptors (e.g., CXCR4 and CXCR5) are expressed by Tregs and myeloid-derived suppressor cells (MDSCs), leading to the integration of innate and adoptive immune responses against prostate cancer cells.21,22

TME Repertoire Is Modified by Androgens

Because androgen deprivation therapy (ADT) is the predominant therapy for many patients with prostate cancer, the effects of low androgen levels on the immune milieu are highly relevant. Increased levels of peripheral naive T cells have been observed in patients initially undergoing ADT, demonstrating a reactivation of thymic function following androgen suppression.23 Neoadjuvant ADT prior to radical prostatectomy is associated with tumoral infiltration with Tregs and CD4+ and CD8+ lymphocytes.24-26 The total macrophage population (CD68+) also increases after ADT.24,25 Analysis of tumor samples collected after ADT demonstrated that the T-cell repertoire is modified within the first week after treatment administration.24 Of interest, ADT leads to increased migration of cells to the tumor site as well as increased proliferation of the cells within the organ, with the exception of Tregs.24,26 Androgen suppression also has been associated with increased secretion of the myeloid chemoattractant chemokine IL-8 by releasing AR-mediated transcriptional repression, resulting in the infiltration of MDSCs into the prostate tumor.27 Enhancing our understanding of the immunomodulatory effects of more potent AR inhibitors (e.g., apalutamide) and androgen biosynthesis inhibitors (e.g., abiraterone acetate with prednisone) in the hormone-sensitive and castration-resistant settings will be important for rational trial designs.

Completed Clinical Trials Evaluating Checkpoint Blockade in Prostate Cancer

Nearly 2 decades ago, studies of transgenic prostate cancer mouse models treated with anti–CTLA-4 therapy resulted in eradication of residual disease after surgery,28 suggesting the potential of checkpoint inhibition as a therapeutic strategy in prostate cancer. A decade later, the results of the first phase I/II trial of patients with metastatic castration-resistant prostate cancer (mCRPC) to receive ipilimumab, an antibody directed against CTLA-4, as monotherapy or in combination with radiation therapy to bone metastases were published. Treatment efficacy was assessed in 50 patients treated with ipilimumab (10 mg/kg); eight patients (16%) had a prostate-specific antigen (PSA) decline of at least 50%, and there was one complete radiographic response among the 28 evaluable patients.7 Given these promising results and the enthusiasm regarding CPIs in melanoma, ipilimumab was evaluated in two phase III clinical trials enrolling men with mCRPC, with or without prior exposure to docetaxel chemotherapy.8,9 Neither trial was able to demonstrate an overall survival (OS) advantage over placebo.
The first study enrolled patients with mCRPC and at least one patient with bone metastasis who experienced progression after treatment with docetaxel. On the basis of data suggesting a synergistic effect of radiotherapy in combination with CPIs to activate an immune response,29,30 the treatment schema consisted of a single dose of radiation for at least one, and up to five, bone fields followed by ipilimumab or placebo. The median OS was 11.2 months for ipilimumab and was 10.0 months for placebo (HR, 0.85; 95% CI, 0.72–1.00; p = .053). Results of a post hoc analysis suggested a potential treatment benefit in patients with favorable prognostic features: an alkaline phosphatase concentration of less than 1.5 times the upper limit of normal, a hemoglobin concentration of 11.0 g/dL or higher, and no visceral metastases (HR for OS, 0.62; 95% CI, 0.45–0.86; p = .0038).8 Those results led to speculation as to how these prognostic features, particularly visceral metastases, may be associated with the underlying TME. Patients with visceral metastasis were excluded from the subsequent trial carried out in the mCRPC chemotherapy-naive setting, in which more patients had the previously defined favorable prognostic factors. However, there was no significant improvement in OS in this patient population, with a median OS of 28.7 months in the ipilimumab arm and 29.7 months in the placebo arm (HR, 1.1; 95% CI, 0.88–1.39; p = .3667).9
As new CPIs were developed, such as antibodies targeting anti–PD-1 and its ligand (PD-L1), they were tested in patients with metastatic prostate cancer. Seventeen patients with heavily pretreated mCRPC were included in a phase I trial assessing the safety and efficacy of the anti–PD-1 antibody nivolumab; all 17 patients had RECIST measurable disease, and none had a radiographic response.31 In vitro data revealed the presence of a high number of circulating PD-L1/L2+ dendritic cells in men who were experiencing progression while taking enzalutamide, suggesting a potential role for anti–PD-L1 antibodies in this setting.32 A clinical trial of the anti–PD-1 antibody pembrolizumab in patients experiencing progression while taking enzalutamide reported that three (30%) of the first 10 patients had a 50% or greater reduction in serum PSA—two of whom had a radiographic response.33 Later, it was confirmed that one of the patients experiencing a response had microsatellite instability (MSI), which may explain why these positive results were not substantiated in larger trials. Updated data with a larger sample of patients from this trial demonstrated PSA reductions of 50% or greater in four patients (13%), and six (25%) of 24 patients with measurable disease had radiographic responses.34 This scientific rationale also was explored in the design of the phase III trial IMbassador250, in which patients with mCRPC were randomly assigned to receive treatment with enzalutamide alone or enzalutamide and atezolizumab; however, the trial was stopped because of futility in a preliminary analysis.35
The antitumor activity of pembrolizumab also was evaluated in a phase Ib trial (KEYNOTE-028) that enrolled patients with advanced solid tumors, who had RECIST 1.1 measurable disease, and who were PD-L1+ (at least 1% expression in the tumor or stromal cells). Among the 245 patients with mCRPC who were screened, 35 met criteria for PD-L1+ expression (14.3%) using a prototype assay (QualTek, Goleta, CA), and 23 were enrolled and received treatment. Seven patients had a confirmed radiographic response, resulting in an objective response rate (ORR) of 17.4% (95% CI, 5.0%–38.8%).36 These results were not replicated in a larger cohort studied in the phase II trial (KEYNOTE-199) evaluating pembrolizumab in patients with mCRPC and prior exposure to docetaxel (258 patients); this trial stratified patients according to the level of PD-L1 expression and the presence of measurable disease. The ORRs were 5% (95% CI, 2%–11%) and 3% (95% CI, < 1%–11%) in those presenting with measurable disease in the PD-L1+ and PD-L1 cohorts, respectively.37
Given the limited activity with single-agent checkpoint inhibition, the promising preclinical data using combination therapy,38 and the clinical data of improved efficacy with combination therapy in melanoma, lung cancer, and renal cell carcinoma,39-42 the combination of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was evaluated in two cohorts of patients with mCRPC with or without prior treatment with chemotherapy (CheckMate 650). Baseline measurable disease was present in 30 patients with prior chemotherapy treatment and in 23 patients without prior chemotherapy treatment. Of patients with measurable disease, the ORRs were 25% (95% CI, 10%–48%) and 10% (95% CI, 2%–27%) in those without and with prior exposure to docetaxel, respectively. When analyzing only the patients with PD-L1 positivity (defined as ≥ 1% expression), the ORRs increased to 33.3% and 40%, respectively. An exploratory analysis of all patients demonstrated that the ORR of those with tumors with alterations in DNA damage repair (DDR) genes was 40%; of those with tumors with a tumor mutational burden (TMB) above the median, the ORR was 56.3%.43 The prevalence of patients with tumors with mismatch repair deficiency (dMMR) has not been reported for this trial.

Biomarkers of Response to Immune Checkpoint Blockade in Prostate Cancer

CPIs are systemic treatment options for multiple types of advanced and metastatic tumors either in the first-line setting or after progression on a prior standard treatment; however, even in this setting, responses are generally only of durable benefit in a small percentage of patients. As such, multiple efforts to identify predictive biomarkers are underway in malignancies in which there is a U.S. Food and Drug Administration (FDA)–approved CPI. Many of these potential biomarkers of response have been evaluated in patients with prostate cancer.

PD-L1 Expression

PD-L1 expression in advanced melanoma, non–small cell lung cancer, and cervical cancer is associated with a higher likelihood of response to CPIs. However, there is no association between PD-L1 expression and response in renal cell carcinoma.44 Whether PD-L1 expression is associated with better response to CPIs in patients with mCRPC has been assessed by several studies. The KEYNOTE-028 trial included 23 patients with mCRPC and initially suggested that PD-L1 expression (≥ 1% modified proportion score or interface pattern)45 could predict response to CPIs (ORR, 17.4%; 95% CI, 5%–38.8%).36 However, the larger KEYNOTE-199 trial demonstrated similar response rates between the PD-L1 and PD-L1+ cohorts (ORRs, 3% and 5%, respectively), which defined PD-L1 positivity as a combined positive score of 1 or greater (22C3 pharmaDx assay, Agilent Technologies, Carpiteria, CA).37 Such results illustrate the low accuracy of PD-L1 as a biomarker of response to CPIs in patients with mCRPC. Even in malignancies for which PD-L1 expression has been associated with clinical outcomes, it remains an imperfect predictive biomarker, and there is debate as to what constitutes positivity, with different criteria and assays utilized across trials.46-49

Microsatellite Instability–High Status or Mismatch Repair Deficiency

In 2017, the FDA approved pembrolizumab for the treatment of unresectable and metastatic tumors with MSI-high (MSI-H) status or dMMR after progression on standard lines of treatment.50 This approval was a hallmark in the field, because it was tumor agnostic; interestingly, the registry that led to this approval included only two patients with mCRPC. Using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (i.e., MSK-IMPACT) next-generation sequencing, the prevalence of MSI-H/dMMR tumors was 3.1% in a large series of patients with prostate cancer,51 which is consistent with other reports.52-54 However, the frequency at which MSI-H status can be detected is assay dependent, with a prevalence as high as 12% having been reported.55 In a retrospective series of 11 patients with mCRPC characterized by MSI-H/dMMR and treated with anti–PD-1/PD-L1 inhibitors alone or in combination with another CPI, the ORR was 50%; 54.5% of the patients had a reduction in PSA greater than 50%, including four with a decline greater than 99%.51

Ultramutated Genomic Status

There are emerging data regarding the relationship between ultramutant status and alterations in the genes that encode DNA polymerase epsilon and delta1 (POLE and POLD1, respectively), which are responsible for proofreading and DNA replication, irrespective of the microsatellite status.56 In a pooled analysis of 47,721 patients with different primary tumors registered in a genomic database, the prevalence of POLE and/or POLD1 alterations in patients with prostate cancer was 1.8%.56 The POLE/POLD1-mutated tumors carry very high rates of single nucleotide substitutions, often exceeding 100 mutations/megabyte.57 These ultramutated tumors may have a greater number of tumor-associated antigens, which has been described in at least one case report of a man with prostate cancer and a POLE-mutated microsatellite-stable tumor that responded to CPI therapy.58 If confirmed in additional analyses, these genomic alterations could be further analyzed as potential biomarkers of response to CPIs.

CDK12 Loss of Function

The possibility of biallelic somatic loss-of-function mutations in CDK12 as a biomarker of response to CPIs was proposed by Wu et al,59 because CDK12 alterations are associated with focal tandem duplications that lead to gene fusions that can generate neoantigens. Corroborating their hypothesis, the investigators reported clinical activity, with PSA decreases in two of four patients with CDK12 mutations treated with CPIs.59 Because alterations in CDK12 can be found in approximately 6.9% of patients with mCRPC,59 this result could have important implications, although the clinical data are still largely anecdotal. A multi-institutional retrospective series of cases presented at the 2019 Congress of the European Society of Medical Oncology included eight patients with monoallelic or biallelic CDK12 alterations who were treated with an anti–PD-1/PD-L1 inhibitor; a 50% reduction in PSA levels was observed in three (37.5%) patients. The median progression-free survival among the eight patients was 6.6 months (95% CI, 2.3–10.8 months).60 Clinical trials to prospectively assess the efficacy of CPIs in patients with CDK12 alterations are underway (NCT03570619 and NCT03810105).

Tumor Mutational Burden

TMB is associated with response to CPIs in some cancers (e.g., non–small cell lung cancer) but not in others (e.g., renal cell carcinoma).61 However, the mutational burden in metastatic prostate cancer is generally low (median, 2.9 mutations/megabyte),62 and only 3.0% to 8.3% of advanced prostate cancer tumors have high TMB.51,62 In a small retrospective series of 12 patients with high TMB (defined as more than 10 mutations/megabyte), four (57%) of seven patients treated with an anti–PD-1 antibody had a PSA decline greater than 50%.62 Treatment with ipilimumab and nivolumab resulted in an ORR of 56.3% in patients with a TMB above the median (74.5 mutations/patient) in the CheckMate 650 trial as well as longer radiographic progression-free survival when compared with those who had a TMB below the median (7.4 months [95% CI, 6.5 months to not estimated] vs. 2.4 months [95% CI, 1.8–3.9 months], p < .0001).43 It is plausible that high TMB may be a genomic manifestation of dMMR.63 However, given the limited data demonstrating the association between TMB and response to CPIs in randomized clinical trials, TMB is not considered a biomarker of response validated for clinical use.64-66

DNA Damage Repair

Alterations in DDR genes can lead to genomic instability, which may yield increased neoantigen formation and greater immunogenicity. DDR alterations can be found in 22.7% of patients with prostate cancer, with BRCA2 and ATM being the most frequently affected genes.52 The different DNA sequencing methods and definitions used to define an alteration (e.g., monoallelic versus biallelic) pose challenges in our understanding of DDR alterations as biomarkers of sensitivity to CPIs.67 With this in mind, an exploratory analysis of the phase II clinical trial KEYNOTE-199 suggested a potential association between alterations in DDR genes captured by whole-exome DNA sequencing (Genome Analysis Toolkit [GATK] and MuTec; Broad Institute, Cambridge, MA) and response to an anti–PD-1 antibody, but the ORR was still low (11%).37 Results of a phase II trial exploring combined treatment using the anti–PD-L1 antibody durvalumab and the PARP inhibitor olaparib included 17 patients with mCRPC, with or without a DDR gene alteration; nine patients (53%) had reductions in PSA of at least 50%, and four (33%) of 12 patients with measurable disease had a radiographic response per RECIST. Genomic analysis detected a DDR gene alteration in six (66%) of the nine patients with a PSA response (three with germline BRCA2, one with germline NBN, and two with homologous somatic BRCA2).68 Further studies are exploring the combination of CPIs and PARP inhibitors. In the phase II clinical trial CheckMate 650, treatment with ipilimumab plus nivolumab was associated with an ORR of 40% among the 10 patients with DDR gene alterations presenting with measurable disease.43

Rational Combinations with Checkpoint Inhibitors

Combination With Existing Standard Therapies That Induce Cell Death

Radiation therapy

Treatment with radiation therapy is associated with changes in the tumor immune microenvironment and can cause immunogenic cell death. In addition to cell death from direct DNA damage, radiation therapy induces inflammatory cytokines and the recruitment of dendritic cells that can convert the tumor into an in situ vaccine, thus activating the tumor-specific T cells.69 Dose, fractionation, and, possibly, metastatic site are components that can contribute to the immune impact of radiation.70-73 The rationale for combining treatment with CPIs and radiation therapy is to induce a more potent immune response at the sites of irradiated disease, as well as at distant locations—a phenomenon referred to as the “abscopal effect.”29,30 Compiled data from 35 studies in a meta-analysis demonstrated that radiotherapy and CPI appeared to be safe, but the combination was not associated with an OS benefit for the majority of patients.73 Given the rationale and safety profile, the combination of other immune checkpoint agents and radiation therapy is under investigation in high-risk localized prostate cancer (NCT03543189), oligometastatic prostate cancer (NCT03795207), and mCRPC (NCT03217747 and NCT01303705).

Chemotherapy

Often misconceived as an immunosuppressive treatment, chemotherapy can have immunomodulatory effects. Chemotherapy in combination with CPIs is now standard of care in small cell lung cancer, non–small cell lung cancer, and triple-negative breast cancer.74-77 Cytotoxic chemotherapy has been used in combination with immunotherapy for several purposes, including reduction of tumor burden, activation of an antigen cascade, and reduction of MDSCs.78,79 The type, dose (low, standard, or submyeloablative), and mechanism of action of the chemotherapy can produce different effects.80 Taxanes are of particular interest, because prostate cancer is taxane sensitive. In mice, treatment with docetaxel was shown to increase cytotoxic T-lymphocyte response and decrease MDSCs.81 Studies in which tumor-bearing mice were administered docetaxel after a booster vaccination demonstrated that antigen-specific T-cell responses to tumor-derived antigens distinct from the antigen used in the vaccine were induced, suggestive of antigen cascade.82 These effects were not demonstrated when docetaxel was given prior to or during vaccination, highlighting the importance of sequencing with combination treatment. Preclinical data demonstrate that paclitaxel decreases Tregs and skews macrophages to an M1 proinflammatory phenotype.83 Of course, murine models may not faithfully recapitulate human disease, and whether these results hold true in humans needs to be determined. However, multiple trials combining chemotherapy and CPIs are underway in patients with metastatic castration-sensitive prostate cancer (NCT03951831 and NCT03879122) and in patients with mCRPC (NCT03248570 and NCT03834506).

PARP inhibitors

The combination of PARP inhibitors with CPIs has been explored preclinically, and there are several proposed mechanisms for the efficacy of the combination; in a breast cancer model, PARP inhibition leads to upregulation of PD-L1 and superior efficacy of the combined treatment over each agent alone.84 It has also been proposed that PARP inhibition causes DNA fragments to be released into the cytosol, leading to activation of the cyclic GMP-AMP synthase-stimulator of the interferon genes pathway.85,86 Clinically, the combination of olaparib and durvalumab has been evaluated in 17 patients with mCRPC in a phase II trial. Nine patients (53%) experienced a radiographic and/or PSA response, resulting in a 12-month progression-free survival of 51.5% (95% CI, 25.7%–72.3%). Genomic analysis identified alterations in DDR genes in nearly two-thirds of the patients with responses. The 12-month progression-free survival was higher in the DDR-mutated group than in the group without DDR mutations (83.3% [95% CI, 27.3%–94.5%] vs. 36.4% [95% CI, 11.2%–62.7%]; p = .031).68 How this compares to PARP inhibition alone has not been studied in a randomized fashion in prostate cancer. Additional trials evaluating CPIs and PARP inhibitors in patients with mCRPC (NCT03572478, NCT03330405, and NCT02484404) are underway. A trial assessing treatment of molecularly selected patients with biochemically recurrent prostate cancer initially without ADT is also in progress (NCT03810105).

Antiangiogenics

Regulation of the tumor vasculature has been shown to promote a proinflammatory state in the TME.11 The improved vascular network induces the polarization of TAMs toward the M1-like phenotype and facilitates tumor infiltration with CD4+ and CD8+ T cells in addition to decreasing the MDSC population in preclinical models.87 The combination of CPIs with antiangiogenic drugs has been shown to be effective in the treatment of some solid tumors, such as renal and endometrial cancers.88-90 The combination of the multiple-receptor tyrosine kinase inhibitor cabozantinib with atezolizumab is being studied in patients with mCRPC who have been previously treated with abiraterone acetate with prednisone and/or enzalutamide. Initial results of the first patients treated demonstrated an ORR of 32% (80% CI, 23%–42%) among 44 patients with measurable disease and a disease control rate of 80%. Ten (29%) of 34 patients had a reduction in serum PSA level of at least 50%.91

Combination Strategies With Other Immune Therapies

Targeting cytokines: IL-8 and TGF-β

IL-8 is a proinflammatory chemokine that is associated with cell survival and proliferation. Elevated serum levels have been associated with poor prognosis in metastatic castration-sensitive disease.92,93 IL-8 is also modulated by androgens, making this a relevant target in prostate cancer. Castration in murine models leads to secretion of IL-8 and infiltration of MDSCs, although the effects could be blocked using an antibody against CXCR2, the receptor for IL-8.27 A clinical trial using an IL-8 antibody in combination with nivolumab and ADT is underway in recurrent hormone-sensitive prostate cancer (NCT03689699).
TGF-β is present in the TME and appears to be an important mediator of immune resistance in prostate cancer, potentially as it relates to bone metastases.94 Results from a preclinical study using castration-resistant animal models suggest that bone metastases induce osteoclast-mediated bone resorption, releasing TGF-β in the bone microenvironment; in combination with IL-6, TGF-β contributes to the polarization of CD4+ T cells toward the immunosuppressive Treg and T helper 17 lineages and away from the effector T helper 1 lineage.95 In that study, combined treatment with a CPI and an anti–TGF-β antibody induced CD4+ lymphocyte polarization to the T helper 1 cell subset, promoting the expansion of CD8+ effector memory cells and control of tumor growth.95 Inhibition of TGF-β is under evaluation in combination with hormonal therapy in the treatment of patients with mCRPC (NCT03685591 and NCT02452008).

Targeting TAMs via colony-stimulating factor 1 receptor

Other mechanisms to target the immune microenvironment have focused on the elimination of TAMs. In a phase I trial of patients with breast cancer and advanced mCRPC, inhibition of colony-stimulating factor 1 (CSF1) receptor to reduce M2 macrophages and TAMs has been evaluated. Although target engagement was demonstrated through elevated levels in the CSF1 receptor ligands CSF1 and IL-34, there was no efficacy signal in this small cohort of patients with prostate cancer to support further monotherapy.96 In an all–solid tumor trial, little clinical activity was reported (ORR, 0.7%) when the anti–CSF1 receptor monoclonal antibody emactuzumab was used in combination with paclitaxel. Although analysis of pre- and post-treatment metastatic biopsies suggested a decrease in M2 macrophages, the treatments could not reprogram the remaining macrophages into proinflammatory TAMs.97 Future combination therapies may build upon these findings to decrease TAMs, but it is important to emphasize the necessity for combination therapies to modulate other aspects of the immune system to drive T effector cells and generate an antitumor response.

Adenosine pathway

Another area of great interest in prostate cancer is targeting the adenosine signaling pathway.98 Elevated levels of adenosine in the TME can impair T-cell function, and adenosine appears to enhance Tregs and MDSCs, limit the functionality of dendritic cells and T cells, and support protumorigenic and angiogenic fibroblasts.99-102 The pathway can be targeted by blocking adenosine from its receptors, such as the adenosine A2A receptor and adenosine A2B receptor, or by inhibiting key enzymatic pathways involved in the catabolism of adenosine diphosphate and nicotinamide adenine dinucleotide, such as monoclonal antibodies against the nucleotidases CD73 or CD39.101 Initial results of a phase I trial evaluating the A2A receptor inhibitor AZD4653, alone or in combination with the anti–PD-L1 antibody durvalumab, demonstrated a confirmed response rate of 37.5% in patients with mCRPC and RECIST-evaluable disease. Additionally, a durable PSA decline greater than 99% was found in one (25%) of the four patients evaluated.103 The A2A receptor antagonist ciforadenant is being evaluated when used alone or combined with the anti–PD-L1 antibody atezolizumab in an ongoing phase I trial in patients with mCRPC and measurable disease. Initial results of the first 35 patients demonstrate a disease control rate of 20%, including one patient treated with the combination who had an objective response. A PSA reduction of at least 50% occurred in three patients.104 Further studies are being conducted to explore this pathway in patients with mCRPC, including in combination with CPIs and chemotherapy (NCT03454451, NCT03629756, and NCT04089553).

Other immune checkpoints: agonists and inhibitors

Targeting immune agonists, such as glucocorticoid-induced tumor necrosis factor receptor, CD134 (OX-40), and inducible costimulator, has resulted in few objective responses in phase I trials of patients with solid tumors,105-107 although several have reported evidence of immune activation. One notable exception was with a CD40 agonist: when patients with metastatic pancreatic cancer were treated with a CD40 agonist, gemcitabine, and nab-paclitaxel chemotherapy, with or without nivolumab, 14 patients (64%) who were evaluable for dose-limiting toxicity had a partial response.108 Because pancreatic cancer shares some immunologic similarities with prostate cancer, such as the role of fibroblasts and an immunosuppressive TME, treatment using a CD40 agonist in combination with chemotherapy may be a strategy to consider for patients with prostate cancer as well.109-112
CPIs other than anti–CTLA-4 and anti–PD-1/PD-L1 also may have a role in prostate cancer; there was a notable increase in the immune infiltrate in the tumor tissue of patients with localized prostate cancer treated with a neoadjuvant course of ipilimumab and ADT. Interestingly, the majority of the T-cell population had upregulation of PD-L1 and V-domain immunoglobulin suppressor of T-cell activation.113 Coexpression with other inhibitory receptors, such as lymphocyte-activating gene 3 and T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibition motif domains, also may play a role in the lack of immune response to PD-1/PD-L1 and CTLA-4 inhibitors. Each of these checkpoints has at least one known investigational therapy targeting this pathway. Although dual-checkpoint inhibition may offer advantages, it is unlikely that this will be the optimal immunologic approach for most patients with prostate cancer, whose tumors harbor a more inert microenvironment lacking T-cell infiltration.

Cancer vaccines

Cancer vaccines use a cellular antigen to induce an antigen-specific adaptive immune response. In prostate cancer, vaccines have been studied for decades because of the common tumor antigens PSA, prostate-specific membrane antigen (PSMA), prostatic stem cell antigen, and prostatic acid phosphatase (PAP), which are expressed on the surface of prostate cancer cells.114,115 Sipuleucel-T is a cellular immunotherapy product derived from a patient’s peripheral blood mononuclear cells that are exposed to a fusion protein of PAP and granulocyte-macrophage colony-stimulating factor. It is the only FDA-approved immunotherapy in prostate cancer, with a modest survival benefit in castration-resistant prostate cancer, although a biomarker to assess efficacy on an individual level is lacking. Of note, black patients with low serum PSA levels treated with sipuleucel-T had longer median OS compared with white patients.116
Several vaccine-based approaches for prostate cancer have failed in the late stages of development.117-121 Immune tolerance to self-antigen is one mechanism mediating the intrinsic resistance to vaccine therapies in prostate cancer, and successful vaccination may indeed be enhanced with combination approaches, including checkpoint inhibition. Many vaccine trials incorporate intravenous administration of CPIs. Others have used subcutaneous administration at the same site as the vaccination, with the goal of maximizing delivery to the draining lymph nodes, optimizing antigen presentation, and potentially reducing toxicity by limiting systemic exposure (NCT02616185). Initial results using the combination of pembrolizumab and the PAP-encoding DNA vaccine pTVG-HP in patients with mCRPC showed promising efficacy and safety (NCT02499835).122 In the phase I/II KEYNOTE-046 trial, the combination of pembrolizumab and ADXS31-142 (an attenuated Listeria monocytogenes–listeriolysin O immunotherapy) is being explored in the treatment of patients with mCRPC (NCT02325557).123 There are no trials of personalized cancer vaccines specifically for patients with prostate cancer, perhaps over concerns that low TMB will decrease the likelihood of finding predictive neoepitopes to generate a personalized vaccine.

Bispecific T-cell engagers

The targeting of common tumor antigens is also the foundation for other nonvaccine immune-based therapies. Designed to engage a tumor cell surface–specific antigen (e.g., PSMA) and the CD3 co-receptor on T cells, bispecific T-cell engagers (also known as "BiTEs") drive T cells toward tumor sites, and the efficacy in prostate cancer is under investigation. Preclinical data demonstrated regression of tumors and improved survival in xenograft models.124 Pasotuxizumab, a BiTE-targeting PSMA, was shown to be active in patients with mCRPC in a dose-escalation study of 15 patients reported at the American Society for Clinical Oncology Annual Meeting in 2019. Two patients had durable responses of greater than 1 year, with others experiencing decreases in PSA.125 Currently, at least three phase I clinical trials are exploring BiTEs in patients with mCRPC, some in combination with CPIs (NCT00635596, NCT01723475, and NCT03792841).

Chimeric antigen receptor T-cell therapy

Given the success of chimeric antigen receptor (CAR) T-cell therapy in the treatment of hematologic malignances,126-132 cellular therapies are also under investigation in solid tumors. Different tumor-associated antigens can potentially be targeted in the development of CAR T-cell agents for prostate cancer: PSA, PAP, T-cell receptor gamma alternate reading frame protein, transient receptor potential-p8, prostatic stem cell antigen, and PSMA, among others.133 Most studies have focused on prostatic stem cell antigen and PSMA because of their specific expression in prostate cancer and high expression in advanced disease. Two phase I trials have reported results on these agents in the treatment of mCRPC. A first-generation PSMA CAR T-cell was evaluated in combination with the continuous administration of low-dose IL-2 in five patients with mCRPC. Two patients had clinical responses, with PSA decreases of 50% and 70%.134 In another phase I study, Slovin et al135 reported on seven patients who were treated with a second-generation PSMA CAR T cell. The treatment was safe, and two patients had prolonged stable disease (more than 6 and 16 months). Multiple clinical trials evaluating this class of agents are ongoing, as are studies with CAR T cells targeting other tumor-associated antigens, such as epithelial cell adhesion molecules (NCT03873805, NCT03089203, NCT04053062, NCT03013712, and NCT02744287). Clinical trials using CAR natural killer cells are also underway (NCT04107142 and NCT03692663).

Selection of Patients in Clinical Trials

As the next wave of studies explores new immunotherapy targets and different combinations (Table 1), understanding the optimal timing of these therapies and the patient populations in which to test them is key. The majority of reported trials using CPIs have focused on mCRPC and have yielded disappointing results; however, evaluation of CPIs in earlier disease states of prostate cancer is underway (Fig. 2). It has been hypothesized that the immune system may be more susceptible to modulation earlier in the disease course, such as in the localized, biochemically recurrent or metastatic castration-sensitive setting. Tumor burden also may have a complex role; greater tumor heterogeneity in the later stages of disease may yield increased potential for the creation of neoantigens. Patients with biochemically recurrent prostate cancer may have a lower burden of disease and possibly fewer MDSCs and immune suppressive cells, as well as less tumor heterogeneity. Many trials are underway in the neoadjuvant setting as window-of-opportunity studies that will allow for interrogation of tissue samples before and after treatment. It is possible that immunotherapy combinations with different mechanisms of action may be better suited to one clinical state over another. As previously reviewed, the effects of androgen deprivation and castration resistance on the immune system are highly relevant and dynamic and require further study. In addition to having a better understanding of which clinical state may be optimal for a given therapy, there is a lack of understanding of the challenges that may be inherent to a bone-tropic disease and the bone-metastatic niche that require investigation.
Table 1. The Current Landscape: Ongoing Clinical Trials Using Checkpoint Inhibition in Prostate Cancer
Figure 2. Breakdown of Current Clinical Trials Using CPIs by Clinical State and Phase in Development
Abbreviations: BCR, biochemically recurrent prostate cancer; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer.

Conclusions

Although CPIs have transformed the therapeutic landscape for many tumors, their role in prostate cancer as a monotherapy is very limited, with FDA approval for patients with MSI-H status or dMMR tumors only. Insights from other malignancies that have a “cold” microenvironment and that are intrinsically resistant to CPIs may be applicable to prostate cancer. However, understanding what is unique about prostate cancer from an immune perspective—the bone-metastatic niche; hormone sensitivity and the use of ADT; the presence of common tumor antigens, such as PSMA; and the well-defined clinical states—will aid in the design of combination immunotherapies that just may take CPIs from niche to breakthrough.

Acknowledgment

We thank Sara DiNapoli (Memorial Sloan Kettering Cancer Center) for editorial support.
Authors’ Disclosures of Potential Conflicts of Interest and Data Availability Statement
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc.

Karen Autio

Research Funding: Amgen (Inst) ARMO BioSciences (Inst) AstraZeneca (Inst) CytomX Therapeutics (Inst) GlaxoSmithKline (Inst) Merck (Inst) Pfizer (Inst) Pfizer (Inst) Tizona Therapeutics, Inc. (Inst)

Lawrence Fong

Consulting or Advisory Role: Atreca Bioalta Bolt Biotherapeutics Nutcracker TeneoBio
Research Funding: Abbvie (Inst) Bavarian Nordic (Inst) Bristol-Myers Squibb (Inst) Dendreon (Inst) Janssen Oncology (Inst) Merck (Inst) Roche/Genentech (Inst)

Matthew Rettig

Consulting or Advisory Role: Johnson & Johnson
Speakers' Bureau: Bayer Johnson & Johnson
Research Funding: Johnson & Johnson (Inst) Medivation/Astellas (Inst) Novartis (Inst)
Patents, Royalties, Other Intellectual Property: #I am a co-inventor on a patent for novel inhibitors of the N-terminal domain of the AR. There are NO commercial partnerships as of yet.
Travel, Accommodations, Expenses: Johnson & Johnson

Daniel Vargas P. de Almeida

Travel, Accommodations, Expenses: Pfizer
No other potential conflicts of interest were reported.

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American Society of Clinical Oncology Educational Book
Pages: e89 - e106
PubMed: 32343604

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Published online: April 28, 2020

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Daniel Vargas P. de Almeida, MD
Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY
Medical Oncology Department, Beneficencia Portuguesa de Sao Paulo, Sao Paulo, SP, Brazil
Lawrence Fong, MD
Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
Matthew B. Rettig, MD
Departments of Medicine and Urology, University of California, Los Angeles, CA
VA Greater Los Angeles Healthcare System, Los Angeles, CA
Karen A. Autio, MD, MSc [email protected]
Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY

Notes

Karen A. Autio, MD, MSc, Memorial Sloan Kettering Cancer Center, 353 East 68th St., New York, NY 10065; email: [email protected].

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Daniel Vargas P. de Almeida, Lawrence Fong, Matthew B. Rettig, Karen A. Autio
American Society of Clinical Oncology Educational Book 2020 :40, e89-e106

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