Therapeutic interventions to harness the immune system against prostate cancer (PCa) have thus far only resulted in modest effects, but recent discoveries related to immune mechanisms coupled with advanced molecular diagnostic platforms may set the stage for immunotherapies that have a more profound beneficial effect, especially for men with castration-resistant disease, according to a recent article published by Ha-Ram Cha, PhD, PharmD, and colleagues in Cancer Research.1
“Immunotherapy is reemerging as a powerful alternate therapy for many cancers,” corresponding author Selvarangan Ponnazhagan, PhD, Professor of Pathology at the University of Alabama at Birmingham, told Renal & Urology News. “However, the potential of immunotherapy as a standalone approach may not yield long-term benefits. Hence, based on patient-specific molecular signatures, immunotherapy needs to be combined with other therapies.”
He and his coauthors hypothesize that PCa outcomes may improve by combining patient-tailored immunotherapy and immune checkpoint inhibitors with conventional cytotoxic agents and androgen receptor (AR)-targeted therapies. Immune checkpoint inhibitors, which have demonstrated benefits in many solid tumors, may be part of combination therapies for PCa.
Inflammation plays a significant role during different stages of PCa growth and metastasis, and this is characterized by molecular heterogeneity of driver mutations. PCa is a “cold tumor,” meaning that it is characterized by low infiltration of T-cells at the tumor microenvironment. “Although the reasons vary for this phenomenon, an important reason is limited neoantigens,” Dr Ponnazhagan explained. “Some solid tumors, like a subset of colorectal cancers, are characterized by high mutation rates that make them immunologically reactive tumors, characterized by high T-cell infiltration. For successfully treating cold tumors by immunotherapy, approaches should take into effect strategies to overcome this limitation.”
Immunotherapies can be divided into 2 categories: passive and active. Passive immunotherapies provide a short-term innate immune boost or adoptive immune restoration of T-helper cells. Active immunotherapies rally immune cells, natural killer cells, or antibody production targeting tumor-specific antigens. Sipuleucel-T (Provenge) is an active immunotherapy that targets prostatic acid phosphatase (PAP). The recently completed phase 3 IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial demonstrated that sipuleucel-T improved median overall survival (OS) among men with mCRPC by 4.1 months, with a 22% reduction in mortality risk.3 The study also showed men with the lowest disease burden experienced the greatest benefit. “Now that we understand more about the potential of immunotherapy in various tumor contexts, the results are encouraging to adapt them in the context of prostate cancer even though prostate cancer was thought of as not an immunogenic tumor,” Dr Ponnazhagan said.
Chimeric antigen receptor (CAR)-T cell therapy, which is a passive immunotherapy, shows considerable promise in several tumor types. One of its limitations, however, is the immunosuppressive tumor microenvironment (TME). Another concern is the emergence of resistant clones. Among the strategies for passive immunotherapy being studied is radiolabeled monoclonal antibodies targeting prostate-specific membrane antigen (PSMA). Findings from a recent study of an alternative PSMA ligand PSMA-617 radiolabeled with lutetium-177 (177 Lu-PSMA-617) suggests a 50% or greater decrease in PSA in 32 of 50 patients with metastatic castration-resistant prostate cancer (CRPC).2
Future implementation of immunotherapy by multiple platforms to activate antitumor immunity should change how PCa is treated over the next few years, Dr Ponnazhagan said. Combining immunotherapies with conventional therapies, including chemotherapy, androgen/androgen receptor targeting and radiation therapies, hold significant promise. “Early data from trials of checkpoint inhibitors suggest prostate cancer can be amenable to immunotherapeutic strategies, which will likely involve multiple immune-based platforms,” he said.
Matthew R. Zibelman, MD, Assistant Professor, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, said immunotherapy in various forms has changed the treatment landscape for several types of cancer, but unfortunately it has had little impact so far for men with PCa. “I would advocate for cautious optimism at this time,” Dr Zibelman said. “Other than sipuleucel-T, which demonstrated a very modest survival benefit in low-volume castrate-resistant metastatic prostate cancer, immunotherapeutics have failed to establish clinically relevant efficacy in the majority of patients with metastatic prostate cancer.”
It is likely that combination approaches and innovative trial designs enriching studies with biomarker-defined patient populations will be essential to identify patients most likely to benefit from individual therapeutic combinations, he added.
Emmanuel S. Antonarakis, MBBCh, Professor of Oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, agrees that a single immunotherapeutic modality will not be sufficient to induce meaningful clinical responses in the majority of men with advanced PCa. For this reason, he said, it will be necessary to develop dual-targeting approaches, such as those using active vaccination plus immune checkpoint inhibition. “Furthermore, a number of checkpoints other than PD-1 and CTLA-4 might be of increasing significance in prostate cancer, namely VISTA and B7-H3,” said Dr Antonarakis, a member of the National Comprehensive Cancer Network guidelines panel for prostate cancer. “Finally, strategies to target M2 (tumor-associated) macrophages in the tumor microenvironment will be required in order to mitigate immune suppression and enhance immunotherapeutic responses.”
Robert Dreicer, MD, Section Head of Medical Oncology and Deputy Director of the University of Virginia Cancer Center in Charlottesville, stressed that immune checkpoint inhibitors, which are approved for many cancers, unfortunately has not had the same impact in men with PCa. Still, he noted, “There is enthusiasm for a range of new agents targeting PSMA, and many studies with a variety of agents are underway. Thus, while results to date have been disappointing, there remains realistic hope for newer immune therapeutic approaches in advanced prostate cancer.”
- Cha HR, Lee JH, Ponnazhagan S. Revisiting immunotherapy: A focus on prostate cancer. Cancer Res. 2020;80(8):1615-1623. doi: 10.1158/0008-5472.CAN-19-2948
- Vapiwala N, Hofman MS, Murphy DG, et al. Strategies for evaluation of novel imaging in prostate cancer: Putting the horse back before the cart. J Clin Oncol. 2019;37(10):765-769. doi: 10.1200/JCO.18.01927
- Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422. doi: 10.1056/NEJMoa1001294