BETHESDA, MdProstate cancer researchers at the
University of California, San Francisco (UCSF) are focusing on GM-CSF,
dendritic cells, and anti-VEGF antibodies, Eric Small, MD, said at a conference
sponsored by the National Cancer Institute and the Society of Urologic
Oncology. Dr. Small is associate professor of medicine and of urology and
co-director of the UCSF/Mt. Zion Urologic Oncology Program.
Granulocyte-macrophage colony stimulating factor (GM-CSF) can
make use of principal cell-cell interactions to elicit immune responses to
cancer, Dr. Small said. He and his colleagues at UCSF hypothesized that using
GM-CSF in patients with hormone-refractory prostate cancer might
nonspecifically activate dendritic cells.
"GM-CSF is a very interesting molecule and quite easy to
administer," he said. For example, one man given the treatment saw his PSA
level drop from 80 to 0.1 ng/mL. The effect was real, Dr. Small said, but it
was still too soon to know if it was clinically significant.
Potentially, combining GM-CSF with other antigen-presenting
cell techniques or cytotoxics might increase efficacy, he added.
In a related area, Dr. Small reported on antigen-loading
dendritic cell immunotherapy. His group used standard leukapheresis for 3 or 4
hours to isolate dendritic cells. Then the dendritic cells were pulsed with a
fusion protein, PA2024. The process was tested using prostatic acid phosphatase
(PAP) dendritic cellsPAP is expressed in 90% of prostate cancer patients.
Patients were infused once a month for 3 months.
The first endpoint of the test was immunologic, he said.
Normally, there is no human response to PA2024, but after even one treatment,
every patient had brisk leukocyte proliferation.
"Prior to treatment, leukocytes don’t recognize
PAP," he said. "Post-treatment, 38% of patients broke tolerance.
There was also an indication of TH-1 response, a cellular response that was
more important in terms of cancer therapy."
Clinically, patients had an average drop in PSA of 20%. More
interestingly, Dr. Small said, there was a significant difference in objective
disease progression between the patients who responded to PAP and those who did
not. There was also a dose-response curve.
"There certainly is immunologic activitytolerance can
be broken," he said. "We think there’s early evidence of antitumor
activity." A pivotal phase III, multicenter trial is underway in patients
with asymptomatic hormone-refractory cancer.
Studies of Anti-VEGF
Dr. Small also reported work at UCSF based on the premise that
vascular endothelial growth factor (VEGF) inhibits dendritic cell function, in
addition to its better-known role as an antiangiogenic.
In animal models, anti-VEGF antibodies enhance dendritic cell
production, function, and differentiation. He said that while phase II trials
have shown only minor activity against advanced metastatic hormone-refractory
prostate cancer, it is nevertheless possible to get sustained plasma levels of
He has proposed a trial for patients who have had radical
prostatectomy but who also have declining PSA levels, using anti-VEGF at 10
µg/kg every 2 weeks, with T-cell activity as the biologic endpoint.