Provenge results could be a shot in the arm for a struggling field.
A vaccine designed to fight prostate cancer significantly increased survival in a critical large clinical trial, investigators reported yesterday.
The vaccine, called Provenge (sipuleucel-T), trains the immune system to recognize and fight off prostate cancer cells. According to results presented at the American Urological Association meeting in Chicago, the vaccine reduced the risk of death by 22.5% in a clinical trial of 512 men with advanced prostate cancer. Three-year survival rates were 38% higher among men who received Provenge, compared with those who received the placebo.
"It's certainly a beautiful day for all of us," said James Gulley, director of clinical trials at the National Cancer Institute's (NCI) Laboratory of Tumor Immunology and Biology in Bethesda, Maryland. Gulley has not worked on Provenge, but is developing a different prostate cancer vaccine.
“It's certainly a beautiful day for all of us. James Gulley , NCI Laboratory of Tumor Immunology and Biology”
The results exceed goals laid out by the US Food and Drug Administration (FDA), announced Mitchell Gold, chief executive of Dendreon, the Seattle-based biotechnology company that developed Provenge.
The company intends to file for FDA approval by the end of the year, and the FDA will then have six months to respond to the application.
If the vaccine stands up to the FDA's detailed scrutiny, it would be the first therapeutic cancer vaccine to make it to market despite decades of research (see 'The cancer vaccine rollercoaster').
A controversial history
Provenge is created from the individual patient's own immune cells. Antigen-presenting cells, which display immune-stimulating molecules on their surface, are purified from the patient's blood and sent to Dendreon's laboratory. There they are exposed to an enzyme called 'prostatic acid phosphatase', which is produced by the prostate and present in large amounts in men with prostate cancer.
The cells take up the enzyme, and display bits of the protein on the cell surface. When these cells are reintroduced to the patient, they are ready to target the immune system against prostate cancer.
Earlier trials of Provenge measured the impact of the vaccine on the short-term spread of prostate cancer, and by these standards the vaccine failed. But men who received the vaccine lived 4.5 months longer than those who received the placebo1, and Dendreon used this result to petition the FDA for approval.
“What the field is finding — and unfortunately Dendreon had to find this out the hard way — is that the best clinical trial endpoint is survival. Jeffrey Schlom , NCI Laboratory of Tumor Immunology and Biology”
In a controversial decision that angered some prostate cancer patients and their advocates, the agency rejected Dendreon's application in 2007 even after an FDA advisory committee voted 13 to 4 in favor of the vaccine. The FDA then asked Dendreon to complete a larger trial explicitly designed to evaluate survival.
Meanwhile, Dendreon generated a little controversy of its own. The company announced last autumn that an analysis conducted while the trial was still going on showed that the vaccine had thus far reduced the risk of death by 20% — an unusually detailed statement for a company to make before a trial is completed. Then, on 14 April, Dendreon told investors that the trial had succeeded, but declined to release the data. "I think that oncologists have been somewhat sceptical because there have been so many press releases in comparison to actual data presentation," says Walter Stadler, an oncologist at the University of Chicago Medical Center. "Usually we prefer it the other way around."
Finding an endpoint
Nevertheless, the data presented yesterday seemed to be sound, says Gulley. The results were statistically significant and there were few side effects.
The results could be a boon to other cancer-vaccine companies, says Reni Benjamin, a biotechnology analyst at the investment bank Rodman & Renshaw in New York. "This shows investors that this technology has promise," he says. "But this doesn't mean there won't be other failures going forward."
Cancer vaccine researchers can learn from Dendreon's struggles, says Jeffrey Schlom, chief of the Laboratory of Tumor Immunology and Biology at the NCI. "What the field is finding — and unfortunately Dendreon had to find this out the hard way — is that the best clinical trial endpoint is survival," he says, adding that other vaccines may have failed in clinical trials because researchers elected to pursue a surrogate endpoint, such as disease progression, that yields results sooner.
Previous clinical trials also failed to consider how a cancer vaccine works, says Leisha Emens, an oncologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland. Trials typically enrolled patients that were in late stages of disease, when a vaccine is less likely to be effective. Endpoints sometimes failed to take into account the time it can take for the body to mount an effective immune response. And patients had often already been exposed to chemotherapy that weakened their immune systems, further reducing a vaccine's ability to stimulate immunity.
"We're still developing cancer vaccines the same way we develop traditional chemotherapies," says Emens. "It just doesn't take into account the science of it all."
Small, E. J. et al. J. Clin. Oncol. 24, 3089-3094 (2006).