Immunotherapy for Prostate Cancer
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How is Immunotherapy Changing the Outlook for Patients with Prostate Cancer?

Reviewed By: Sumit K. Subudhi, M.D., Ph.D.
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The University of Texas MD Anderson Cancer Center, Houston, TX
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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, Sipuleucel-T (Provenge®) 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 7 men will be diagnosed with the disease during his lifetime.

In the U.S., more than 99% of prostate cancers are found in the 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.

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Michael A. Curran, Ph.D.
The University of Texas MD Anderson Cancer Center
CLIP Investigator  |  2016
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Prostate Cancer Statistics
1st
Cancer type for which an immunotherapy was FDA-approved
2nd
Most common cancer in men worldwide
4%
Of all cancer-related deaths caused by prostate cancer
99%
Of prostate cancers found in local or regional stages
Staging and 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 dendritic cell-based 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.

Clinical Trials for Prostate Cancer

Current experimental immunotherapies for prostate cancer fall into seven broad categories: therapeutic vaccines, oncolytic virus therapies, checkpoint inhibitors, adoptive cell therapies, adjuvant immunotherapies, cytokines, and monoclonal antibodies.

Therapies
  • Therapeutic Vaccines
  • Oncolytic Virus Therapies
  • Checkpoint Inhibitors
  • Adoptive Cell Therapy
  • Adjuvant Immunotherapies
  • Monoclonal Antibodies
  • Cytokines

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.

Aside from Provenge, vaccines in clinical trials include:

  • PROSTVAC (rilimogene galvacirepvac) is a therapeutic cancer vaccine that uses viruses (vaccinia and fowlpox) as vectors to deliver the prostate-specific antigen (PSA) along with three costimulatory molecules—LFA-3, ICAM-1, and B7.1—directly to cancer cells. The virus vectors stimulate an immune response against PSA, 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. Other trials with PROSTVAC include:
    • A phase II trial for patients with biochemically recurrent prostate cancer (NCT02649439).
    • A phase II trial to prevent disease progression for patients with localized (stage 1 or 2) prostate cancer undergoing active surveillance (NCT02326805).
    • A phase II trial, with docetaxel, for patients with metastatic castration-sensitive prostate cancer (NCT02649855).
    • A phase II trial for patients with high-risk for relapse after radical prostatectomy (NCT02772562) (not yet enrolling).
    • A phase II trial, +/- ipilimumab (Yervoy®), for patients undergoing radical prostatectomy (NCT02772562) (not yet enrolling).
  • A phase III trial of DCVAC, combined with chemotherapy, for patients with metastatic castration-resistant prostate cancer (NCT02111577).
  • A phase II study of sipuleucel-T (Provenge) with or without the pTVG-HP DNA vaccine (NCT01706458) in prostate cancer, or a phase I/II study of pTVG-HP DNA vaccine plus pembrolizumab (see checkpoint inhibitors below) for patients with hormone-resistant metastatic prostate cancer (NCT02499835). pTVG-HP is a DNA-based cancer vaccine containing DNA for prostatic acid phosphatase (PAP), the same cancer-associated antigen used in 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, for patients with prostate cancer (NCT00970203).
  • A phase II trial of GX301, a telomerase vaccine, for patients with castration-resistant prostate cancer (NCT02293707).
  • A phase II trial of a dendritic cell vaccine pulsed with antigens NY-ESO-1 and MUC1 for patients with metastatic castration-resistant prostate cancer (NCT02692976).
  • A phase I/II trial of ADXS31-142, a PSA vaccine, +/- pembrolizumab for patients with metastatic castration-resistant prostate cancer (NCT02325557).
  • A phase I/II trial of a dendritic cell vaccine pulsed with the prostate cancer tissue and antigens hTERT and survivin for patients with metastatic castration-resistant prostate cancer (NCT01197625).
  • A phase I/II trial of Ad5-SGE-REIC/Dkk3, which uses an adenovirus to deliver a protein that causes death of target cancer cells, for patients with localized prostate cancer (NCT01931046).
  • A phase I trial of two viruses (ChAdOx1 and MVA) that produce 5T4 for patients with metastatic castration-resistant prostate cancer (NCT02390063).
  • A phase I trial of a PSA vaccine for recurrent prostate cancer in hormone-naïve and hormone-independent patients (NCT02058680).
  • A phase I trial of PF-06755992 combined with PF-06755990 for patients with prostate cancer (NCT02616185).
  • A phase I trial of pTVG-AR patients with metastatic prostate cancer (NCT02411786).

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® (aglatimagene besadenovec) 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. ProstAtak is currently being tested along with radiation in a phase III trial for patients with localized prostate cancer (NCT01436968) and a phase II/III trial for patients undergoing active surveillance for prostate cancer (NCT02768363).
  • A phase I/II trial of HSV-tk plus valacyclovir, combined with brachytherapy, which helps cancer metastasize, for patients with recurrent prostate cancer (NCT01913106).

 

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.

Nivolumab (Opdivo®): A PD-1 Antibody +/- Ipilimumab (Yervoy®): A CTLA-4 Antibody
  • A phase II trial of ipilimumab following sipuleucel-T (Provenge) for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (NCT01804465).
  • A phase II trial testing ipilimumab in patients currently receiving hormone therapy in metastatic castration-resistant prostate cancer (NCT02113657).
  • A phase II trial of PROSTVAC +/- ipilimumab for patients undergoing radical prostatectomy (NCT02772562) (not yet enrolling).
  • A phase I study to test ipilimumab combined with MGA217, an antibody that targets B7-H3, in patients with refractory cancer, including prostate cancer (NCT02381314).
Pembrolizumab (Keytruda®, MK-3475): A PD-1 Antibody
  • A phase II study for patients with metastatic castration-resistant prostate cancer previously treated with enzalutamide (NCT02312557).
  • A phase II study for patients with metastatic castration-resistant prostate cancer previously treated with chemotherapy (NCT02787005).
  • A phase I/II study, combined with the pTVG-HP DNA vaccine, for patients with hormone-resistant metastatic prostate cancer (NCT02499835).
  • A phase I/II trial of ADXS31-142, a PSA vaccine, +/- pembrolizumab for patients with metastatic castration-resistant prostate cancer (NCT02325557).
  • A phase I study in patients with refractory cancer, including prostate cancer, combined with MGA271 (NCT02475213).
Atezolizumab (Tecentriq™, MPDL3280A): A PD-L1 Antibody
  • A phase II trial for patients with solid tumors, including prostate cancer (NCT02458638).
  • A phase I trial for patients with metastatic castration-resistant prostate cancer who have already been treated with an androgen pathway inhibitor (NCT02814669) (not yet enrolling).
Durvalumab (MEDI4736): A PD-L1 Antibody +/- Tremelimumab: A CTLA-4 Antibody
  • A phase II trial of durvalumab +/- tremelimumab for patients with metastatic castration-resistant prostate cancer (NCT02788773) (not yet enrolling).
  • A phase I/II trial of durvalumab plus tremelimumab , combined with Poly-ICLC, a Toll-like receptor 3 agonist, for patients with advanced, biopsy-accessible cancers, including prostate cancer (NCT02643303) (not yet enrolling). This trial is sponsored by the Cancer Research Institute.
  • A phase I/II trial of durvalumab for patients with advanced or recurrent prostate cancer (NCT02484404).
MGA271: A B7-H3 Antibody
  • A phase I study in patients with refractory cancer, including prostate cancer (NCT01391143).
  • A phase I study in patients with refractory cancer, including prostate cancer, combined with pembrolizumab (NCT02475213).
  • A phase I study in patients with refractory cancer, including prostate cancer, combined with ipilimumab (NCT02381314).
MGD009: A B7-H3 x CD3 Protein
  • A phase I study to test MGD009 in patients with unresectable or metastatic B7-H3-expressing cancer, including prostate cancer (NCT02628535).

 

Another major avenue of immunotherapy for prostate cancer is adoptive cell therapy. In this approach, immune 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 in combination with a dendritic cell-based vaccine also using the NY-ESO-1 cancer antigen (NCT01697527).
  • A phase I trial of natural killer cells for patients with prostate cancer (NCT00720785).

 

Adjuvants are substances that boost the immune response. They can be used alone or combined with other immunotherapies.

  • A phase I trial of mobilan (M-VM3), a Toll-like receptor 5 agonist, for patients with prostate cancer (NCT02654938).

 

Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors. Many antibodies are currently used in cancer treatment, and some appear to generate an immune response.

  • A phase I/II trial and a phase I trial of tisotumab vedotin (HuMax-TF-ADC), an antibody-drug conjugate targeted to tissue factor, a protein involved in tumor signaling and angiogenesis, for patients with solid tumors, including castration-resistant prostate cancer (NCT02001623NCT02552121).
  • A phase I/II trial of sacituzumab govitecan (IMMU-132), an anti-TROP-2 antibody-drug conjugate, for patients with epithelial cancers, including hormone-refractory prostate cancer (NCT01631552).
  • A phase I trial of LY3022855, an antibody designed to target the CSF1R region, for patients with prostate cancer (NCT02265536).
  • A phase I trial of BI 836845, an IGF ligand-neutralizing antibody, combined with enzalutamide, for patients with castration-resistant prostate cancer (NCT02204072).
  • A phase I trial of MOR209/ES414, an anti-prostate specific membrane antigen (PSMA)/anti-CD3 bispecific antibody, for patients with metastatic castration-resistant prostate cancer (NCT02262910).

 

Cytokines are messenger molecules that help control the growth and activity of immune system cells.

  • A phase II trial of CYT107, an IL-7 cytokine, after sipuleucel-T (Provenge), for patients with metastatic castration-resistant prostate cancer (NCT01881867).
  • A phase I trial of IL-12 for patients with locally recurrent prostate cancer (NCT02555397).

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  [2].
  • 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.

National Cancer Institute; National Cancer Institute Physician Data Query (PDQ); American Cancer Society Facts & Figures 2016; 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 July 2016


[1]  Patent#: U.S. 5,976,546; Patent#: U.S. 6,080,409; Patent#: U.S. 6,210,662; Patent#: U.S. 6,812,023; Patent#: U.S. 7,414,108.

[2] von Boehmer et al. MAGE-C2/CT10 protein expression is an independent predictor of recurrence in prostate cancer. PLoS One 2011 (PMID: 21754986)

*Immunotherapy results may vary from patient to patient.

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