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 anti-VEGF.
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.