Dec. 13, 2000 A novel therapy that employs the immune system to attack and kill prostate cancer cells has been found to slow disease progression in some men and decrease levels of prostate specific antigen (PSA), a protein in the blood that often indicates prostate cancer, a UCSF study has found.
The study of 31 men involved collecting patients' dendritic cells from their bloodstream and mixing them in a test tube with a synthetic version of prostatic acid phosphatase (PAP), an antigen found on the surface of most prostate cancer cells. Dendreon Corporation in Seattle Washington prepared the therapy, called Provenge, made of synthetic PAP combined with dendritic cells. The modified dendritic cells were then infused back into the patient with the hope that they would help trigger the patient's immune system to kill prostate cancer cells throughout the body, said study author Eric Small, MD, associate professor of medicine and member of the UCSF Comprehensive Cancer Center's Urologic Oncology program.
The results will be published in the December 1 issue of the Journal of Clinical Oncology.
Dendritic cells are an integral part of the immune system. They scavenge foreign material, such as bacteria and viruses, and then interact with another important component of the immune system, lymphocytes, bringing this foreign material to the lymphocytes' attention. The lymphocytes then jump into action and circulate through the body, destroying the foreign substance. The goal of the study was to see if these modified dendritic cells would be able to train the lymphocytes to recognize cells with PAP on their surface as a foreign substance and kill those cells. The men in the study received an infusion of dendritic cells once a month for three months.
The Phase I/II study enrolled men with advanced prostate cancer --defined as tumors spreading beyond the prostate to other parts of the body and no longer responding to conventional hormone therapies. The median age of the participants was 69 years old, with a range from 48 to 83. Twenty of the men had a strong immune response to PAP after treatment. For these men, time until their disease progressed, or became worse, was 34 weeks compared to 13 weeks for those patients who had weaker immune responses. In addition, three patients had a greater than 50 percent decrease in PSA. Three more patients had a 25 percent to 49 percent decrease in PSA. A PSA decrease of more than 50 percent has been accepted by most researchers as a reasonable indication of anticancer activity, according to the study.
Small said the results of this study were encouraging. "It really shows the immune system can be manipulated and made to recognize prostate cancer," he said. "This trial shows we can break tolerance to the antigen. Immunologically, we always thought we couldn't do that in prostate cancer."
While other studies have shown immunotherapy to have some benefit in melanoma and kidney cancer, this study is one of the first to demonstrate an effect in prostate cancer, Small said.
"Immune therapy for prostate cancer has not historically been viewed with much enthusiasm. This is because it was believed that the immune system, for whatever reason, did not recognize prostate tumors as foreign and therefore they did not illicit an immune response," Small said. "As it turns out, that isn't the case. Apparently, the immune system was just not being adequately stimulated to attack the cancer."
The therapy was well tolerated by patients, with mild fever being the most common side effect.
The trial lays the groundwork for future research of this therapy, including using it in patients with less extensive disease and possibly in combination with other therapeutic agents. Small is principal investigator of a Phase III trial of Provenge that is enrolling about 240 men with advance disease at multiple sites nationwide. "This trial opens up an huge arena of further study," Small said.
Prostate cancer is the most common cancer, excluding nonmelanoma skin cancers, in American men, according to the American Cancer Society. It is the second leading cause of cancer deaths in men, exceeded only by lung cancer. Physicians initially treat advanced disease by prescribing hormones to deprive a man's body of testosterone, which fuels prostate cancer growth. However, all patients ultimately develop hormone independent disease, meaning the cancer progresses despite lowering testosterone. The median survival for this group of patients is about a year, according to the study. The American Cancer Society estimates 180,400 new cases of prostate cancer will be diagnosed this year in the U.S. and about 31,900 men will die of this disease.
Other UCSF study authors are David M. Reese, MD, assistant clinical professor of medicine and Paige Fratesi, research assistant. Authors from Dendreon are George Strang, clinical data systems management analyst; Reiner Laus, MD, vice president, immunology; Madhusudan V. Peshwa, PhD, vice president, process science and Frank H. Valone, MD, senior vice president, medical & regulatory affairs
Dendreon funded this study and is funding the Phase III trial.
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