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In immunotherapy, prostate cancer has been at the vanguard. It was the first indication for which an active immunotherapy was granted approval by the FDA, in 2010. Today, there are a number of immune-based cancer treatments in development for prostate cancer. This page features information on prostate cancer and immunotherapy clinical trials for prostate cancer patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based cancer treatments to patients with prostate cancer.
Prostate cancer is the second most common cancer in men worldwide, and the eighth leading cause of cancer-related death. Globally, there are approximately 1,100,000 new cases and 300,000 mortalities every year, comprising nearly 4 percent of all cancer deaths. It is estimated that 1 in every 6 men will be diagnosed with the disease during his lifetime.
In the U.S., more than 90% of prostate cancers are found in local or regional stages. At these early stages, the 5-year survival rate nears 100%. When the cancer has spread (metastasized), however, the 5-year survival rate drops to 28%, and there remains a need for effective treatments for advanced-stage prostate cancer. Where conventional treatments fail, FDA-approved immunotherapies are saving lives, and many more immune-based treatments are in the pipeline.
Staging and Current Treatment
Several measures are used to determine the severity of a patient’s prostate cancer, and therefore the course of treatment. The Gleason score, based on the appearance under a microscope of a biopsy specimen of the tumor, is used to rate tumor aggressiveness from 2 (nonaggressive) to 10 (highly aggressive). Using Gleason score, clinical exam, and prostate-specific antigen (PSA) test, a tumor may be designated as low-, intermediate-, or high-risk of failing local therapy.
Initial treatment for prostate cancer may consist of localized treatments (surgery and/or radiation), systemic treatments (hormone therapy ± chemotherapy [docetaxel]), or any combination of each. Hormone therapy consists of lowering the levels of testosterone, the male hormone that fuels out-of-control cell growth. Chemotherapy is typically reserved for metastatic cancers.
When prostate cancers grow despite the lowering of testosterone levels by hormone therapy, treatment options are limited. Typically, the cancer vaccine sipuleucel-T (Provenge®), a radiopharmaceutical agent (such as radium-223 chloride), secondary hormone therapies (such as abiraterone or enzalutamide), and/or chemotherapies (docetaxel and cabazitaxel) are added to the hormonal therapy in sequence. While each of these treatments can delay growth of the cancer for several months and palliate symptoms produced by the disease, the disease ultimately becomes resistant to them. This underscores the need for more effective therapies for advanced prostate cancer.
Immunotherapy for Prostate Cancer
Current experimental immunotherapies for prostate cancer fall into five broad categories: therapeutic vaccines, oncolytic virus therapies, checkpoint inhibitors, adoptive cell therapies and adjuvant immunotherapies. The following trials are in phase III or phase II.
Therapeutic cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens.
One therapeutic vaccine is FDA approved: sipuleucel-T (Provenge®) for prostate cancer. Provenge was approved after a large, phase III trial showed an average survival improvement of more than 4 months. It is the first therapeutic vaccine approved for any type of cancer. Provenge is a dendritic cell-based therapeutic cancer vaccine. It is designed to induce an immune response targeted against the prostatic acid phosphatase (PAP) antigen, which is expressed in most prostate cancers. Studies have shown that Provenge has very few side effects, and ongoing research is devoted to improving its therapeutic effectiveness.
Therapeutic vaccines in phase II or phase III clinical trials include:
PROSTVAC (rilimogene galvacirepvac) is a therapeutic cancer vaccine being developed by Bavarian Nordic. PROSTVAC uses viruses (vaccinia and fowlpox) as vectors to deliver the PSA antigen along with three costimulatory molecules directly to cancer cells. The virus vectors stimulate an immune response against the PSA antigen, which directs the immune system to attack cancer in the prostate. Based on promising results from a randomized phase II trial involving 122 patients with metastatic castrate-resistant prostate cancer that showed an 8.5 month improvement in median overall survival, a large phase III trial of PROSTVAC-VF (PROSPECT trial; NCT01322490) was initiated in November 2011 and enrollment is now complete. They expect the results by late 2016 or early 2017.
A phase II study of sipuleucel-T (Provenge) with or without pTVG-HP DNA booster vaccine (NCT01706458) or pTVG-HP alone (NCT01341652) in prostate cancer. pTVG-HP is a DNA-based cancer vaccine containing DNA for prostatic acid phosphatase (PAP), the same cancer-associated antigen used in Provenge.
CRI Impact: After completing his CRI Postdoctoral Fellowship at Stanford University in 1993, Curtis L. Ruegg, Ph.D., joined Dendreon as a staff scientist. In 1995, he established the protein science group and led Dendreon’s program to produce and characterize novel protein pharmaceuticals as cancer vaccine candidates. His work resulted in several patents on which he is co-inventor, which laid the key groundwork for the development of Provenge .
A phase II study testing an autologous dendritic cell vaccine targeting TARP, which is highly expressed in prostate cancer (NCT02362451).
A phase II trial to test a dendritic cell vaccine loaded with prostate cell lines, in combination with androgen ablation, in patients with prostate cancer (NCT00970203).
A phase II study of a PSA vaccine in men with recurrent prostate cancer after local therapy (NCT00583752).
Oncolytic Virus Therapy
Oncolytic virus therapy uses a modified virus that can cause tumor cells to self-destruct, in the process generating a greater immune response against the cancer.
ProstAtak uses a disabled virus as a vector to deliver a gene directly to tumor cells, and is followed by the oral anti-herpes drug valacyclovir (Valtrex), which kills the cancer cells containing the gene. ProsAtak is currently being tested along with radiation in a phase III trial for patients with localized prostate cancer (NCT01436968).
Another promising avenue of clinical research in prostate cancer is the use of checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash and/or enhance pre-existing anti-cancer immune responses.
A phase II trial testing ipilimumab (Yervoy®), an anti-CTLA-4 antibody made by Bristol-Myers Squibb, following sipuleucel-T (Provenge) for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) (NCT01804465).
A phase II trial testing ipilimumab in patients currently receiving hormone therapy in metastatic CRPC (NCT02113657).
A phase II study of ipilimumab plus androgen suppression therapy in patients with an incomplete response to androgen suppression therapy alone for metastatic prostate cancer (NCT01498978).
A phase II study combining ipilimumab, the hormone therapy degarelix, and radical prostatectomy in men with newly diagnosed metastatic castration sensitive prostate cancer or ipilimumab and degarelix in men with biochemically recurrent castration sensitive prostate cancer after radical prostatectomy (NCT02020070).
A phase II study of pembrolizumab (Keytruda®), an anti-PD-1 antibody made by Merck, in patients with metastatic CRPC previously treated with enzalutamide (NCT02312557).
A phase II trial testing atezolizumab (MPDL3280A), an anti-PD-L1 antibody made by Genentech/Roche, in patients with solid tumors, including prostate cancer (NCT02458638).
A phase II study of sipuleucel-T, CT-011 (anti-PD-1 antibody; CureTech), and cyclophosphamide for advanced prostate cancer (NCT01420965).
Adoptive Cell Therapy
Another major avenue of immunotherapy for prostate cancer is adoptive T cell therapy. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response.
A phase II trial of T cells genetically engineered to target the cancer-specific antigen NY-ESO-1 given after a preparative chemotherapy regimen (NCT01967823).
A phase II trial of T cells genetically engineered to target the cancer-specific antigen NY-ESO-1, given in combination with a dendritic cell-based vaccine also using the NY-ESO-1 cancer antigen (NCT01697527).
Adjuvants are substances that boost the immune response. They can be used alone or combined with other immunotherapies.
A phase II study of sipuleucel-T (Provenge) and indoximod, an IDO pathway inhibitor, for patients with refractory metastatic prostate cancer (NCT01560923). The IDO pathway is a biochemical pathway that is often more active in tumors; indoximod counteracts this effect.
Go to our Clinical Trial Finder to find clinical trials of immunotherapies for prostate cancer that are currently enrolling patients.
CRI contributions and impact
Since 1996, CRI has made 95 grants in support of projects and initiatives with relevance for prostate cancer, totaling nearly $26.5 million. This includes nearly $9 million for preclinical and clinical studies undertaken as part of CRI’s Prostate Cancer Initiative, established in 1996 to identify and support clinical research projects promising the most immediate benefit to patients, as well as to support prostate cancer patient outreach and to increase awareness about this disease among the public.
Some work and recent findings by CRI investigators that are advancing the understanding and treatment of prostate cancer include:
In 2011, CRI researchers Alex Knuth, M.D., and Maries van den Broek, Ph.D., reported that the CT10/MAGE-C2 cancer-testis antigen is frequently expressed in advanced prostate cancer. Moreover, its expression in early tumor stages indicates a higher risk for biochemical recurrence (i.e., increase in PSA values) after radical surgery. MAGE-C2/CT-10, therefore, could potentially serve as a marker of tumor progression that can help predict a patient’s clinical course and assist doctors in making treatment decisions. In addition, their findings suggest that patients with advanced prostate cancer, who have few treatment options, may benefit from antigen-specific immunotherapy .
Two CRI postdoctoral fellows at the University of California, San Diego, Xiaoyuan Song, Ph.D., and Chunyu Jin, Ph.D., both in the laboratory of Michael G. Rosenfeld, M.D., are trying to understand how resistance to anti-hormone therapy develops in prostate cancer, a major obstacle to effective long-term treatment. They have found a protein that is involved both in inhibiting androgen receptor target genes, such as prostate-specific antigen (PSA), as well as in regulating the inflammatory properties of innate immune cells called macrophages. Their studies will provide fundamental insights into acquired hormone resistance in prostate cancers, as well as into the relationship between androgen-insensitive prostate cancer cells and immune cells and how they contribute to prostate cancer progression.
Peter Savage, Ph.D., a CRI investigator at the University of Chicago, Chicago, IL, obtained the first direct insight into the basic biology of tumor-infiltrating regulatory T cells in a model of prostate cancer. Regulatory T cells (Tregs) are thought to pose a challenge to cancer immunotherapy because of their role in suppressing anti-cancer immune responses. However, the basic biology of tumor-associated Tregs—where they originate, which antigens they recognize, and their function within the tumor—has not been elucidated. To address these questions, Dr. Savage established a new model system, allowing him to track the life cycle of a tumor-associated Treg—from its origin, to its circulation throughout the body, to its recruitment into a developing tumor. Unexpectedly, he found that the antigen recognized by the population of Tregs he followed was not a cancer-specific antigen, but rather was a normal, prostate-associated antigen. Moreover, he found that even though prostate tissue is specific to males, Tregs specific to this antigen develop in both male and female mice. Savage has shown that Tregs develop in the thymus, and that this development is dependent on the transcription factor Aire. These fundamental discoveries were recently reported in the prestigious journal Science in 2013.
Padmanee Sharma, M.D., Ph.D., a member of the CRI/Ludwig Cancer Vaccine Collaborative (CVC) at The University of Texas MD Anderson Cancer Center, has conducted innovative studies testing the effects of anti-CTLA-4 checkpoint blockade in the pre-surgical setting. In a study involving 12 patients with bladder cancer, who also underwent prostate surgery as part of their treatment, she identified the ICOS molecule as the first immunologic marker identified in both tumor tissues and the systemic circulation that can be used as a biomarker for monitoring of anti-CTLA-4 treated patients as a possible marker of therapeutic activity. Based on these studies, as well as others showing a potential synergistic effect of CTLA-4 blockade with anti-androgen therapy, Dr. Sharma initiated a pre-surgical clinical trial of anti-CTLA-4 in patients with localized prostate cancer.
Based on data from anti-CTLA-4 monotherapy in both bladder and prostate tumors, and information from mouse models indicating that combining anti-CTLA-4 with agents that lead to tumor cell death can prime T cell responses and enhance anti-tumor immunity, Dr. Sharma and her colleague, Ana Aparicio, M.D., have completed a combination therapy clinical trial of leuprolide acetate (Lupron®), a standard hormonal therapy that leads to tumor cell death due to decrease in androgens, and anti-CTLA-4 in men with newly diagnosed metastatic prostate cancer. Correlative studies of the tumor microenvironment will help to identify mechanisms and pathways that are altered in the setting of combination therapy, as well as provide a rationale for designing combination trials with antigen-specific vaccines.
CRI predoctoral scholar Moses Donkor, at Memorial Sloan Kettering Cancer Center, has made several key discoveries about the role of the immune molecule TGFβ (transforming growth factor beta) in prostate cancers. Most recently, he showed that TGFβ1 plays a critical role in enabling cancer cells to escape immune recognition when it is produced by T cells—but not when it is produced by the cancer cells themselves. He showed that limiting TGFβ1 produced by T cells inhibited tumor growth in models of prostate and breast cancer. These studies indicate that TGFβ1 could be a target for treatments that aim to sustain or restore immune surveillance against prostate and other cancers.
CRI postdoctoral fellow Katharina Kreymborg, Ph.D., at Memorial Sloan Kettering Cancer Center, is working to determine the impact of two newly discovered costimulatory molecules, B7x and B7-H3, on anti-tumor immune responses. Expression of these molecules has been identified as predictive of poor outcome in patients with prostate cancer. Further understanding of these molecules could offer new openings for direct modulation of the anti-tumor immune response to improve outcomes for prostate cancer patients.
In 1997, CRI scientists Yongwon Choi, Ph.D., Ralph Steinman, M.D., and others discovered the TRANCE protein (now known as RANKL). This protein is the key target of the monoclonal antibody denusomab (Xgeva), which was approved by the FDA in November 2010 for the prevention of fractures and other skeletal-related injuries in patients with cancers that have spread to the bone. Because bone metastases occur in more than 80 percent of patients with advanced prostate cancer, this new treatment may help significantly improve quality of life for men with the disease. This treatment may also benefit patients with advanced breast and lung cancers, in which bone metastases are also common.
Cancer Research Institute has also developed materials for prostate cancer patients, and funds ZERO, a national nonprofit organization with the mission to end prostate cancer, through its patient support program.
Sources: National Cancer Institute; National Cancer Institute Physician Data Query (PDQ); American Cancer Society Facts & Figures 2015; Jemal A et al. (2011) Global cancer statistics. CA: A Cancer Journal for Clinicians. 61 (2): 69-90. (PMID 21296855); GLOBOCAN 2012; NCI Surveillance Epidemiology and End Results (SEER); National Comprehensive Cancer Network (NCCN) Guidelines for Patients; ClinicalTrials.gov; CRI grantee progress reports and other CRI grantee documents; Prostate cancer vaccines: Update on clinical development. Oncoimmunology. May 1, 2013; 2(5): e24523. PMCID: PMC3667918
Updated August 2015
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 von Boehmer et al. MAGE-C2/CT10 protein expression is an independent predictor of recurrence in prostate cancer. PLoS One 2011 (PMID: 21754986)
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