UCSF Oncologist Led Early Clinical Trials of Provenge

Prostate cancer patients who have advanced disease that no longer responds to hormone-blocking therapy might become the first to benefit from a new type of cancer drug.

Eric Small

With these new immunotherapies, the patients’ own immune cells are supercharged to better fight the disease, says a UCSF oncologist who has led some of the first clinical trials on immunotherapies for prostate cancer. Eric Small, MD, director of investigational therapeutics and leader of the Prostate Cancer Program at the UCSF Helen Diller Family Comprehensive Cancer Center, has helped to design and implement clinical trials on a few different immunotherapies. One may soon be under review for approval by the Food and Drug Administration (FDA). The drug, called sipuleucel-T, is made by Dendreon Corp., a Seattle-based biotech firm. Its brand name is Provenge. Dendreon earlier announced that new clinical trial data – to be presented today (April 28) in Chicago at the annual meeting of the American Urological Association (AUA) – indicate that study patients treated with Provenge survived longer. “This confirms our earlier results,” Small says. “This trial represents the second set of phase III data to demonstrate improved survival with Provenge treatment.” Provenge is made from a patient’s own immune cells. The cells are called dendritic cells. Like a bounty hunter displaying a culprit’s article of clothing to the hounds, a dendritic cell grabs onto a foreign target molecule, or antigen, and displays it to other cells of the immune system. The cells that detect the antigen target are thereby primed to expand their ranks and to attack any tumor that displays the same antigen. The dendritic cells are obtained through a process called leukapheresis. The cells are exposed to and attach to an antigen called prostatic acid phosphatase (PAP). PAP normally is found on most prostate cancer cells as well as on normal, noncancerous prostate cells, but not on cells from the body’s other tissues. After the dendritic cells are labeled with PAP, they are returned to the patient. The patient receives a total of three, hourlong infusions – one every two weeks. Once infused, the dendritic cells prime the immune system to attack cells that express PAP. Small helped design and led early phase I and phase II clinical trials to evaluate Provenge. He also led design and implementation of the first phase III trial, called D9901. That study of 127 patients aimed to detect significant differences in how long it took advanced prostate cancer tumors to begin growing again despite treatment. Patients who received Provenge were compared with patients treated with untargeted dendritic cells. Although patients treated with Provenge during the trial lived significantly longer – four months on average – the difference between the two groups in the time it took for tumors to start growing again was not quite statistically significant. In the July 1, 2006, issue of the Journal of Clinical Oncology, Small and colleagues reported that 34 percent of Provenge patients were alive after three years, compared with just 11 percent of the placebo patients. In 2007, the set of clinical trial data that Dendreon submitted to the FDA did not gain the company FDA approval to market Provenge. The company’s application was based on combined results from D9901 and a smaller, second phase III study. The FDA asked for more data from more patients. Now data from a new phase III study are being presented at the Chicago AUA meeting. The 2007 FDA decision disappointed many, in part because chemotherapy is the only other treatment option for men whose prostate tumors continue to grow despite hormone-blocking therapy, according to Small. Chemotherapy has significant side effects, while Provenge has few, he says. “The toxicity of this drug approaches zero,” Small says. “I think the benefit-to-risk ratio clearly favors patients.” Provenge is not intended to replace chemotherapy, but rather to add to the cancer-fighting armamentarium, he adds. “This is an additional weapon against prostate cancer.” Small and fellow UCSF oncologists continue to investigate Provenge and other immunotherapies. Small earlier worked on clinical trials of an immunotherapy called GVAX, made by Cell Genesys, Inc. GVAX consists of lethally irradiated cancer cells that are genetically engineered to make a molecule called GM-CSF. GM-CSF stimulates the immune system to attack similar cancer cells from the patient’s tumor. Cell Genesys lost its drug development partner, Takeda Oncology Co., after setbacks in recent phase III trials to treat prostate cancer. Small also led the first clinical trials to treat advanced prostate cancer with a human antibody manufactured by Medarex, Inc. The antibody is called ipilimumab. The Medarex drug boosts immune responses by targeting a molecule called CTLA-4. CTLA-4 normally acts as a molecular braking mechanism to hold the immune system in check. None of these immunotherapy drugs has yet passed muster with the FDA. Still, Small believes immune-priming strategies continue to hold great promise for patients with prostate cancer. “For regulatory reasons, most drugs in development are first evaluated in patients with fairly advanced prostate cancer that resists hormonal treatment,” Small says. “The problem is that many of these patients may be somewhat immunosuppressed due to the extent of their disease. Immunotherapy works better when there is less cancer on board. “The data presented today confirm our prior observations and suggest that immunotherapy is a viable therapeutic option for patients with advanced prostate cancer.”

Placebo-Controlled Phase III Trial of Immunologic Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone Refractory Prostate Cancer

Eric J. Small, Paul F. Schellhammer, Celestia S. Higano, Charles H. Redfern, John J. Nemunaitis, Frank H. Valone, Suleman S. Verjee, Lori A. Jones and Robert M. Hershberg

Journal of Clinical Oncology (Published online July 1, 2006, 24(19):3089-3094

Abstract | Full Text

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