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Cancer Therapy: 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 2nd most common cancer in men worldwide, and the 6th leading cause of cancer-related death. Globally, there are approximately 899,000 new cases and 260,000 mortalities every year, comprising 6 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

There are several components to determining prostate cancer staging, which will also determine the course of treatment. The Gleason score is used to rate tumor aggressiveness from 2 (nonaggressive) to 10 (highly aggressive).  Using information from the biopsy results (Gleason score), clinical exam, and 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 the hormone therapy, treatment options are limited: Typically sipuleucel-T, 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, their use is often associated with side effects and the disease ultimately becomes resistant to them. This underscores the need for safer and more effective therapies for advanced prostate cancer. See below for information on immunotherapies recently approved and in development for prostate cancer.

Clinical Trial Recommendations

Prostate cancer patients have the possibility of and are encouraged to enter clinical trials at all stages of the disease.

Go to our Clinical Trial Finder to find clinical trials of immunotherapies for prostate cancer that are currently enrolling patients.

The Promise of Immunotherapy

Several approaches to immunotherapy for prostate cancer have shown promise in clinical trials in recent years. Most notable has been the FDA approval in April 2010 of sipuleucel-T (Provenge®), for hormone therapy-resistant prostate cancer, the first therapeutic vaccine approved for any type of cancer. Provenge was approved after a large, phase III trial showed an average survival improvement of more than 4 months. Provenge, developed by the biotech company Dendreon, is an autologous cellular immunotherapy. While the precise mechanism of action is unknown, Provenge is designed to induce an immune response targeted against the PAP antigen, which is expressed in most prostate cancers. Study after study has shown that Provenge comes with very few side effects, exemplifying one of the major potential advantages of immune-based treatments over conventional cancer-fighting therapies.

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 immunotherapies showing promise in clinical testing include:

PROSTVAC-VF, a therapeutic vaccine being developed by BN ImmunoTherapeutics, a member of CRI’s Cancer Immunotherapy Consortium. PROSTVAC-VF is composed of a cell line engineered to contain the PSA antigen along with three costimulatory molecules. 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 was initiated in November 2011 and is currently enrolling patients.

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 is composed of prostate cancer cell lines that are irradiated and then engineered to express the immune molecule GM-CSF. The development of GVAX was temporarily halted in 2008, but based on new evidence suggesting that androgen deprivation therapy may synergize with immunotherapies such as GVAX, this program has been resumed. A phase I/II trial testing GVAX in combination with hormone therapy in men with localized prostate cancer prior to surgery is currently enrolling at The Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center.

Another promising avenue of clinical research in prostate cancer is the use of immune 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.

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. Based on promising results from a phase II trial, it is now being tested in phase III trials for hormone-resistant prostate cancer, one testing it in combination with radiotherapy in patients who have not responded to chemotherapy and one testing its efficacy prior to chemotherapy.

Both PROSTVAC and GVAX have been tested in phase I clinical trials in combination with ipilimumab, and have shown promising results.

Based on preclinical and an early-phase study in multiple cancer types, an activating anti-OX40 antibody is being tested in a phase Ib trial for patients with metastatic prostate cancer who have failed prior androgen ablation and docetaxel. OX40 is a costimulatory molecule expressed after T cell activation that enhances T cell survival and anti-cancer effector function. In a phase I trial of the treatment in multiple cancer types (), investigators showed that treatment with the anti-OX40 antibody augmented the cell-killing ability of cancer-specific T cells and led to enhanced anti-tumor immunity.

Cancer Research Institute and Prostate Cancer

Since 1996, CRI has made 88 grants in support of projects and initiatives with relevance for prostate cancer, totaling nearly $18 million in pledged funds. 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:

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 undergo 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 has initiated a pre-surgical clinical trial of anti-CTLA-4 in patients with localized prostate cancer. For more information, go to the trial record at ClinicalTrials.gov.

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., are also conducting 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. They plan to enroll 48 patients. 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. See the trial record at ClinicalTrials.gov for more information.

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 through its patient support program.

Sources: National Cancer Institute; National Cancer Institute Physician Data Query (PDQ); American Cancer Society Facts & Figures 2012; 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.

[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)
- See more at: http://www.cancerresearch.org/prostate-cancer#sthash.PX7OifBj.dpuf




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