Biological and Therapeutic Advances in the Pursuit of Effective Immunotherapy for Prostate Cancer

Anis A. Hamid; Atish D. Choudhury

Disclosures

Curr Opin Urol. 2020;30(1):30-35. 

In This Article

Multimodal Immunotherapy Strategies

Prostate cancer is marked by a suppressive 'cold' tumor immune microenvironment and poor immunogenicity compared with other tumors, resulting in attenuated immune recognition and T-cell-mediated cytotoxicity.[1] However, prostate cancer overexpresses antigens specific to prostate tissues, such as prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA), which could potentially serve as targets for vaccine-based immunotherapeutics (Figure 1). Indeed, the IMPACT trial of sipuleucel-T (Provenge), an autologous dendritic cell-based vaccine against PAP, demonstrated an overall survival benefit in men with metastatic castration-resistant prostate cancer (CRPC) and resulted in the first Food and Drug Administration (FDA) approval of a therapeutic cancer vaccine.[2] Despite prolongation of survival, objective tumor responses and PSA declines are infrequent with sipuleucel-T. More recently, other antigen-presenting cell (APC) vaccines have been developed (GVAX, DCVAC/Pa, BPX-101) with the goal of inducing more potent and sustained APC activation. A trial of GVAX in combination with docetaxel chemotherapy (NCT00133224) was terminated early because of lack of efficacy. Results of a phase III study of DCVAC/PCa in the same setting (NCT02111577) are not yet reported, and there are no ongoing studies of BPX101.[3] Nonautologous therapeutic vaccines are appealing given that the process for ex-vivo manipulation of APCs can be cumbersome. Unfortunately, the Poxviral-based vaccine ProstVac-V/F (targeting PSA) did not demonstrate an overall survival benefit in a phase III study,[4] and an mRNA-based vaccine CV9104 (targeting PSA, PSCA, PSMA, STEAP1, PAP, MUC1) did not show a survival benefit over placebo in a phase I/IIB study.[5] Other nonautologous vaccine-based approaches being tested as monotherapy or in combination with other immunostimulatory approaches include strategies to target PSA (Proscavax, NCT03579654; ADXS31-142, NCT02325557; Adenovirus/PSA, NCT00583024), PAP (pTVG-HP, NCT02499835), telomerase (UV1/hTERT2012P, NCT01784913; GX301, NCT02293707), 5T4 (ChAdOx1.5T4, NCT03815942), brachyury (MVA-BN-Brachyury, NCT03493945), Bcl-xl (Bcl-xl_42-CAF09b, NCT03412786); or combinations of PSA, PSMA, PSCA (PF-06753512, NCT02616185) or PSA, MUC1 and brachyury (ETBX-071, ETBX-061, and ETBX-051, NCT03481816). Another strategy to promote an immune response is intratumoral injection of immunostimulants, such as poly-ICLC (NCT03262103), the TLR9 agonist SD-101 (NCT03007732), or the oncolytic virus ProstAtak(AdV-tk) (NCT01436968). However, a more personalized approach to vaccine therapy may show more promise in larger trials. For example, a neoantigen DNA vaccine based on DNA sequencing from a patient's tumor is being tested in combination with checkpoint immunotherapeutics in metastatic hormone sensitive prostate cancer (NCT03532217). A strategy taking into account preexisting host-specific immune features has been tested in a randomized controlled phase II trial, where a custom vaccine based on host immunoreactivity to a panel of HLA-type specific tumor peptides (such as PSA) in patients with chemotherapy-naïve CRPC resulted in significant improvements in PSA progression-free survival and overall survival.[6]

Figure 1.

Prostate cancer immunotherapeutics. (a) Checkpoint blockade with PD-1, PD-L1 and CTLA-4 inhibitors. (b) Bispecific T-cell engager (BiTE) antibodies. (c) Antigen-presenting cell (APC)-based therapeutic vaccines. (d) Chimeric antigen receptor (CAR) T-cell therapy.

Tasquinimod is a first-in-class oral immunomodulatory agent inhibiting S100A9, a calcium-binding protein that promotes myeloid-derived suppressor cell (MDSC) activity. In addition, tasquinimod has antiangiogenic, antiproliferative and antimetastatic properties. Having demonstrated efficacy as monotherapy in CRPC,[7] recent studies have explored combination therapy with cabazitaxel[8] and a maintenance strategy after response or stability after first-line docetaxel chemotherapy for CRPC.[9] In the latter trial, tasquinimod led to a significant improvement in radiographic progression-free survival (hazard ratio = 0.6); however, maintenance therapy was associated with excessive severe treatment-related adverse events (50 versus 27%) and deterioration in quality-of-life scores. Further development of tasquinimod in prostate cancer has since ceased.

CPI, the model of immunotherapy that changed the therapeutic landscape of many cancer types, has been met with more modest enthusiasm in prostate cancer owing to underwhelming efficacy. Ipilimumab, an inhibitor of cytotoxic T-lymphocyte antigen 4 (CTLA-4), failed to demonstrate a survival benefit compared with placebo in both chemotherapy-resistant and minimally symptomatic, chemotherapy-naïve CRPC cohorts.[10,11] Blockade of programmed death 1 (PD-1) receptor with pembrolizumab in the refractory prostate cancer cohort of the nonrandomized KEYNOTE-028 trial (selected for patients with PD-L1 expression in ≥1% of tumor or stromal cells) demonstrated an overall response rate of 17.4%; whereas the response rate in this biomarker-selected population was modest, most of these responses were over 1 year in duration.[12] A more modest response rate (<10%) was recently reported in the KEYNOTE-199 study of docetaxel-refractory CRPC;[13] however, the response rate was reported to be higher in combination with enzalutamide in chemotherapy-naïve patients progressing on enzalutamide.[14] What remains clear is that CPI monotherapy for unselected patients is a suboptimal strategy in advanced prostate cancer. In turn, approaches combining complementary or synergistic immune mechanisms (CPI with therapeutic vaccine; CPI with MDSC-targeted therapy[15]) or combining classes of checkpoint inhibitors (CTLA-4 inhibitor with PD-1 inhibitor) are rational strategies to improve the efficacy and are currently in clinical testing. Indeed, a recent phase II study of the combination of ipilimumab with the anti-PD1 agent nivolumab in mCRPC demonstrated promising overall response rates of 26% in cohort 1 (chemotherapy-naïve patients) and 10% in cohort 2 (patients who progressed after taxane-based chemotherapy); however, significant toxicity was seen leading to only 33% of patients in cohort 1 and 24% of patients in cohort 2 completing the planned four cycles of combination therapy.[16] Furthermore, the biological underpinnings of resistance to immunotherapy in prostate cancer continues to be elucidated and will serve as a rationale for therapeutic targeting. For example, the inhibitory immune checkpoint VISTA appears to serve as a mechanism of dynamic, compensatory immunosuppression after exposure to ipilimumab in prostate cancer,[17] and thus represents a potential second therapeutic target for combination therapy in future clinical trials.

The presence of prostate lineage-specific antigens has been exploited in the study of novel targeted therapies such Lutetium-177 PSMA for metastatic CRPC.[18] In the immunotherapy space, the rationale for greater tumor specificity has led to the development of bispecific T-cell engager (BiTE) antibodies, which constitute an efficient system synapsing T cells and cancer cells to promote T-cell-mediated tumor cytotoxicity. MOR209/ES414, a BiTE targeting CD3ε and PSMA, induced robust T-cell activation and tumor kill in vitro and in vivo; however, clinical translation is limited by a short serum elimination half-life.[19] To abrogate this limitation, depot-injectable controlled delivery of a BiTE with the same antigenic targets demonstrated feasibility in preclinical prostate cancer models.[20] BiTEs have rapidly moved to early phase clinical studies of refractory prostate cancer and are distinguished by different targets including PSMA (BAY2010112, NCT01723475; AMG160, NCT03792841; ES414, NCT02262910), Her2 (NCT03406858) and EpCAM (MT110-101, NCT00635596).

Improving the efficacy of chimeric antigen receptor (CAR) T-cell therapy by overcoming a suppressive tumor-immune microenvironment remains a challenge in refractory solid tumors including prostate cancer. The global experience of CAR T-cell therapy for prostate cancer remains limited to early reports from PSMA CAR T-cell trials demonstrating some PSA declines and stable disease as best response in a small number of treated patients.[21,22] Recently, PSMA-directed CAR T cells with co-expression of a dominant-negative TGF-bRII (thereby inhibiting immunosuppressive TGF-b signaling) showed enhanced lymphocyte proliferation and tumor eradication in prostate cancer mouse models compared with wild-type PSMA CAR T cells.[23] These promising findings have led to a phase I trial in CRPC (NCT03089203). Additionally, trials employing PSMA, PSCA and EpCAM-targeted CAR cellular therapy are ongoing, including a planned trial in China of anti-PSMA CAR Natural Killer (NK) cells for CRPC, in line with increased efforts to develop non-T CAR cellular therapies in hematological and solid cancers.

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