When Provenge vaccine for prostate cancer is approved by the FDA, as most likely it will be on or by May 15, this decision to make this new therapy available immediately to any patient who can afford or whose insurance covers it — rather than to delay approval until the results are in from a larger clinical trial — will be due to Michael Milken. In Cora Daniels’ blockbuster article for Fortune Magazine (November 2004), The Man Who Changed Medicine, reprinted at Cptech.com, Milken said:

I believe the person who waits for 110% of the facts to be in and all the information is a person who is probably not alive — because it’s too late for him. A lot of businesspeople have been forced to make decisions without 100% or perfect information but based on what they know. I worked in a field where ten seconds was a long decision process. Either you’re buying the securities or you’re not. Either you’re selling them or you’re not. Now people said, ‘Well, gosh, that’s a short period of time,’ and I say, ‘No, it’s not.’ I’ve prepared my entire life to make that decision. I think getting off that inertia of making a decision qualifies well in building something.

“Inertia,” Daniels wrote in 2004, “is exactly what Milken found with the cancer community in the early 1990s: Researchers were swimming in data and theories, but nobody acted. Milken traced much of the paralysis to the government-funding mechanisms that fuel scientific discovery. The process of getting research grants is convoluted and counterproductive. Just gathering enough data and background research to apply for an NCI grant can take a year or more. (The applications and supporting data often run hundreds of pages.) Add another year for the government’s review process. And throw in another year, perhaps — depending on the federal budget cycle — to allocate the money. At the end of the ordeal, funded researchers are locked into their proposed study topic. Trouble is, in three years science has often passed the ideas by.”

This is the situation Dendreon found itself in despite Milken’s shake-up of prostate cancer research. In 1999 they initiated a clinical trial designed to show that Sipuleucal-T vaccine, injected into men with advanced though symptom-free hormone refractory prostate cancer spread to bone and/or soft tissue, would extend median time to disease progression from 8 to 16 weeks. It didn’t happen that way. By the time the first round of bone and CT scans were taken 8 weeks into the trial, roughly 50% of the patients, those who took the vaccine and those who did not, showed tumors grown larger.

Seeing that the study had failed, Dendreon did not want its researchers to be, as Daniels had put it in 2004, “locked into their proposed study topic.” In 2006, when the dismal results of the two, small Phase 3 studies were out in the open, Eric Small M. D. presented a new analysis of the data at ASCO and Daniel Petrylak M.D. presented another re-analysis at the Michael Milken annual scientific retreat. These re-analyses indicated that men who took the vaccine lived longer than men who did not. This became the new basis of Dendreon’s approval application at the FDA.

“Great ‘investment’ opportunities—investments in science that could pay off in lives saved—were being lost,” Daniels wrote in 2004. “Milken, who’d already donated millions of dollars since 1982 through his medical and educational philanthropy, the Milken Family Foundation, realized that ‘just giving money was no longer enough.’ What the cancer establishment really needed was a completely different approach for generating promising research.”

This “completely different” approach approached fruition March 29 when the FDA’s hearing on Dendreon’s Sipuleucal-T took an end run around the FDA Oncologic Drugs Advisory Committee, chaired by oncologist Maha Hussain M.D.. Instead, the hearing was held before the FDA Center for Biologics Evaluation and Review’s Cellular, Tissue and Gene Therapies Advisory Committee, chaired by James J. Mulé Ph.D, with Dr. Hussain as one of the panel members. In many ways this looks like an appropriate venue. Dr. Mulé’s research group is involved in vaccine strategies and other approaches to stimulate the immune system to recognize and destroy tumors. According to a bio of his online at the Hasumi Foundation’s web site, his work in these areas has helped to develop new treatments for advanced cancer patients. Yet somehow his research interests seem closer to the lab than to the patients themselves.
Dr. Mulé was one of the organizers of a conference this past January on Molecular Targets in Cancer Therapy: Mechanism & Therapeutic Reversal of Immune Suppression in Cancer. That conference addressed problems with vaccines that the Dendreon approval process is striving to rush past:

Despite high promise, cancer immunotherapy so far has not delivered tangible clinical benefits. It is now clear that without understanding the mechanisms of tumor induced immune suppression, further progress in this area will not be possible. By this time, a large number of possible mechanisms of immune suppression in cancer have been proposed. They form a foundation for current and future clinical trials; however, this wealth of information has created a very convoluted picture. Proposed mechanisms compete with each other. There is a pressing need for the entire field to discuss already described and new emerging mechanisms to see how they can be put together in more or less cohesive structure. Special emphasis will be placed on new approaches to therapeutic correction of observed abnormalities.

In April an International Cancer Vaccine Symposium took place in Vienna, Austria organized by The Austrian Academy of Sciences & Hasumi International Research Foundation to answer the question “Can we cure only mice?” Speakers included James P. Allison, Ph.D, , chair of Memorial Sloan-Kettering Cancer Center’s cancer immunology program. Allison recently teamed with a lead investigator for Dendreon’s Provenge clinical trials, Eric Small M.D. of UCSF, on a pilot study on how to overcome hormone-refractory prostate cancer’s resistance to therapeutic vaccine activity (A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer, Clin Cancer Res. 2007 Mar 15; see also A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy, Clin Cancer Res. 2007 Feb 1.) Allison and Small’s research with Ipilimumab is designed to overcome problems arising with cancer vaccines — like Provenge — that use dendritic cells. Dendritic cells can be used to present a cancer tumor antigen to the immune system’s T-cells, but dendritric cells also can turn the T-cells off so that they don’t attack the cancer cells. To switch the cells off they bind to CTLA-4 protein. (see illustration, middle panel.

In the 1990s, Michael Milken, with all the understandable frustration of a man diagnosed with a deadly cancer and all the courage of his determination to beat it, blamed US government sponsorship of cancer research for lack of progress. A decade and a half later, with Taxotere, a commercial outcome of government research, as the only new drug approved for prostate cancer, Dendreon’s vaccine received FDA’s fast track status. At this point Dendreon faced the likelihood that if their vaccine went before the Oncologic Drugs Advisory Committee, they would be asked to complete their 500-man Phase III trial, which might delay approval for 2 or 3 years. A lot can happen in three years. “Trouble is,” Milken told Daniels, “in three years science has often passed the ideas by.” As Allison’s and Small’s work on hormone-refractory prostate cancer’s resistance to therapeutic vaccine activity shows, that’s already happened for dendritic cell vaccines, which complicates the dream.

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