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 University of California, San Francisco
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
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
Dendreon funded this study and is funding the Phase III trial.