Cancer Immunotherapy

Prostate Cancer

In immunotherapy, prostate cancer has been at the vanguard. It was the first indication for which an active systemic 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 prostate cancer patients.

Prostate cancer is the second most common cancer in men worldwide, and the sixth leading cause of cancer-related death. Globally, there are approximately 1,100,000 new cases and 300,000 mortalities every year, comprising 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 Treatment Options

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 surgery, radiation, or hormone therapy, 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 advanced-stage cancers.

When prostate cancers grow despite the lowering of testosterone levels by hormone therapy, treatment options are limited. Typically, the cancer vaccine sipuleucel-T, 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. 

 

Immunotherapies in development

Current experimental immunotherapies for prostate cancer fall into three broad categories: therapeutic cancer vaccines, checkpoint inhibitors/immune modulators, and adoptive T cell therapies. 

Therapeutic Vaccines

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.

Most notable of the therapeutic cancer vaccines is sipuleucel-T (Provenge®), which was approved by the FDA in April 2010 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. Developed by the biotech company Dendreon, 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. Active clinical trials involving Provenge include:

  • A phase II study of sipuleucel-T (Provenge) with or without radiation therapy for patients with hormone-resistant metastatic prostate cancer (NCT01807065). This study is being conducted at the City of Hope Medical Center in Duarte, California; South Pasadena Cancer Center in Pasadena, California; and the Huntsman Cancer Institute, at the University of Utah (not yet open at this site).
  • A phase II study of sipuleucel-T (Provenge) with enzalutamide (an androgen receptor inhibitor) in men with metastatic castration-resistant prostate cancer (NCT01981122).   
  • 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. This trial is open at the University of Illinois Medical Center, Chicago, IL; the Masonic Cancer Center at the University of Minnesota, Minneapolis, MN; and the VA Medical Center at the University of Nebraska, Omaha, NE (not yet recruiting at this site).
  • A phase II study of sipuleucel-T (Provenge) with or without pTVG-HP DNA booster vaccine in prostate cancer (NCT01706458). pTVG-HP is a DNA-based cancer vaccine containing DNA for prostatic acid phosphatase (PAP), the same cancer-associated antigen used in Provenge. This trial is being conducted at the University of Wisconsin Carbone Cancer Center, Madison, WI.

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 [1].


Other therapeutic cancer vaccines for prostate cancer include:

  • PROSTVAC-VF, a therapeutic cancer vaccine being developed by Bavarian Nordic. PROSTVAC-VF 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 is currently enrolling patients. This study is being conducted at many centers in the U.S. and around the world.
  • GVAX, which was first created in 1993 by Glenn Dranoff, M.D., an associate director of CRI’s Scientific Advisory Council (SAC), Drew M. Pardoll, M.D., Ph.D., a CRI Investigator from 1988-1992 and a current SAC member, and others [2]. GVAX, manufactured by Aduro Biotech, is composed of prostate cancer cell lines that are irradiated and then engineered to express the immune molecule GM-CSF. A phase III trial of GVAX was halted in 2008, but based on new evidence suggesting that GVAX may work best when administered along with androgen-suppressive therapy, trials with this vaccine have begun again. A phase I/II trial testing GVAX in combination with hormone therapy (NCT01696877) in men with localized prostate cancer prior to surgery is currently enrolling at The Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center.
  • ProstAtak (AdV-tk + valacyclovir), a virus-based therapeutic cancer vaccine given along with an anti-virus drug. ProstAtak uses a disabled virus (adenovirus) as a vector to deliver a gene, the Herpes virus thymidine kinase gene, directly to tumor cells. The viral vector is injected into the site of tumor and is followed by the oral anti-herpes drug valacyclovir (Valtrex), which kills the cancer cells containing the Herpes virus gene. ProsAtak is currently being tested along with radiation in a phase III trial for patients with localized prostate cancer (NCT01436968). This trial is being conducted at multiple centers across the U.S.

Checkpoint Inhibitors/Immune Modulators

Another promising avenue of clinical research in prostate cancer is the use of checkpoint inhibitors/immune modulators. 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.

Ipilimumab (Yervoy®), which targets the CTLA-4 checkpoint molecule on activated immune cells, has been at the vanguard of this new immunotherapy approach. First tested by James P. Allison, Ph.D., the director of CRI’s Scientific Advisory Council, ipilimumab was the first treatment ever proven to extend survival in patients with metastatic melanoma, the most deadly form of skin cancer, and was approved for that indication in 2011. Ipilimumab was tested in two phase III trials as a treatment for advanced, castration-resistant prostate cancer. In the patients receiving ipilimumab after docetaxel, the drug failed to improve overall survival. Results of the trial in which patients received ipilimumab prior to chemotherapy are not yet available. Ipilimumab is also now being tested in several phase II trials: 

  • A phase II trial testing ipilimumab following sipuleucel-T (Provenge) for patients with chemotherapy-naïve metastatic castration resistant prostate cancer (CRPC) (NCT01804465). This trial is being conducted at the University of California, San Francisco and The University of Texas MD Anderson (not yet open at this site).
  • 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). This trial is being conducted at the OHSU Knight Cancer Institute in Portland, Oregon.
  • 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). This study is being conducted at Memorial Sloan Kettering Cancer Center in New York.

Other checkpoint inhibitor/immune modulator trials include:

  • A phase II study of sipuleucel-T, CT-011 (anti-PD-1 antibody; CureTech), and cyclophosphamide for advanced prostate cancer (NCT01420965). This study is being conducted at Georgia Regents University in Augusta, Georgia. 
  • A phase I/II trial of an OX40 antibody (made by AgonOx) for patients with metastatic prostate cancer who have failed prior androgen suppression therapy and docetaxel (NCT01303705). OX40 is a costimulatory molecule expressed after T cell activation that enhances T cell survival and anti-cancer effector function; the OX40 antibody stimulates this pathway. This study is being conducted at Providence Portland Medical Center in Oregon.
  • A phase I study of lirilumab (anti-KIR antibody; Bristol-Myers Squibb) in combination with nivolumab (anti-PD-1 antibody; BMS) in patients with advanced solid tumors (NCT01714739). This trial is being conducted at several sites across the U.S.
  • A phase I study of MSB0010718C (anti-PD-L1 antibody; EMD Serono) in solid tumors (NCT01772004). This study is being conducted at several centers in the U.S. and around the world. 

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. Several clinical trials are currently under way:

  • 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). This trial is being conducted at the National Institutes of Health Clinical Center in Rockville, MD.
  • 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). This trial also involves a stem cell transplant. The trial is being conducted at UCLA’s Jonsson Comprehensive Cancer Center in Los Angeles, CA. 

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 91 grants in support of projects and initiatives with relevance for prostate cancer, totaling nearly $18.5 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.

Through these initiatives, CRI-funded investigators have identified and validated several antigens that could serve as targets for therapeutic cancer vaccines, including: NY-ESO-1, which is expressed in approximately 38% of prostate cancers; MUC1, which is the target of several immunotherapy approaches currently in clinical trials; and MAGE.

Some work and recent findings by CRI investigators that are advancing the understanding and treatment of prostate cancer include:

  • CRI postdoctoral fellow Chunyu Jin, Ph.D., of the Howard Hughes Medical Institute at the University of California, San Diego, is investigating a new biochemical pathway that suppresses the inflammatory response in the prostate. Chronic inflammation has been linked to many human cancers, such as esophagus, stomach, colon, liver, urinary bladder, and prostate. A study released in 2014 showed that men with chronic inflammation in non-cancerous prostate tissue have nearly twice the risk of having prostate cancer than those with no inflammation. However, the molecular mechanisms that control inflammatory responses in prostate tissue remain incomplete understood. Dr. Jin’s research focuses on a protein called GPS2. He has found that this protein is critical for preventing a hyper-inflammatory state in macrophages. This work reveals GPS2 as a potential new therapeutic target for the treatment of prostate cancer.
  • 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. (This study is ongoing, but no longer recruiting patients.)
  • 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. (This study is ongoing but no longer recruiting patients.)
  • In 2011, CVC researchers Alex Knuth, M.D., and Maries van den Broek, Ph.D., at the University of Zurich 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  [3].
  • 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.
  • 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.
  • CRI Young Philanthropists 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 2014; Jemal A et al. (2011) Global cancer statistics. CA: A Cancer Journal for Clinicians. 61 (2): 69-90. (PMID 21296855); GLOBOCAN 2008; 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 September 2014.



[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] Dranoff et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A 1993; 90: 3539-3543 (PMID: 8097319); Patent#: U.S. 5,637,483.

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

 

Prostate Cancer News & Stories

Reviewed By:

Sumit K. Subudhi, M.D., Ph.D.
Sumit K. Subudhi, M.D., Ph.D.
The University of Texas MD Anderson Cancer Center, Houston, TX

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