April was a watershed month for anticancer vaccines. On April 29, the FDA approved Provenge (sipuleucel-T), an autologous cellular immunotherapy, for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (CRPC). Manufactured by Dendreon Corporation in Seattle, Washington, Provenge becomes the first immunotherapy vaccine against cancer to win FDA approval.
The challenge of harnessing the human body’s immune system to fi ght cancer has been around for more than a century. In the literature, it starts with William B. Coley, MD, a bone surgeon at New York Cancer Hospital. In 1893, Coley administered the first anticancer vaccine to a 16-year-old boy who presented with a large abdominal mass. He injected a cocktail of dead toxins, including Streptococcus progenies
and Serratia marcescens
. A series of these shots triggered an immune response followed by substantial tumor regression until the mass was no longer evident. Reportedly, the patient never received any additional anticancer therapy and succumbed to a heart attack 26 years later.
Physicians and hospitals used Coley’s treatment well into the 1950s, with anecdotal accounts of success. Coley’s daughter, Helen Coley Nauts, cofounded the Cancer Research Institute in 1953 with the express mission of pursuing her father’s research and the role of immunotherapy in cancer. Use of “Coley’s toxins,” as the vaccine therapy came to be known, was discontinued in 1962, when the FDA established a regulatory process for approving drugs similar to the one used today.
Since then, there have been many promising starts followed by just as many dashed expectations. With the FDA denial of Dendreon’s application for approval of Provenge in 2007—a decision that contradicted the recommendation of an FDA advisory panel—some were concerned Provenge would go on record as yet another failure in the drive to develop an immunotherapy vaccine. Instead, aft er additional trials demonstrated the safety and effectiveness of Provenge, it now claims the title of the first success story in a decades-long quest.
“I think it’s a vast breakthrough,” said Robert Alter, MD, co-chief, Urologic Oncology, John Theurer Cancer Center at Hackensack University Medical Center, who enrolled 24 patients in 2 Provenge clinical trials. “It now off ers the FDA the opportunity to see that immunotherapy may be a cornerstone in therapies for other conditions.” It is a feeling shared by executives at Dendreon. “Everyone feels like they’ve been trying to push a boulder uphill for so long, and it’s been rolling back so many times that a lot of people didn’t believe [an immunotherapy for cancer] was possible,” said Mark Frohlich, MD, senior vice president of clinical affairs and chief medical officer for Dendreon. “I think that’s why this is such a milestone event, and why there’s been so much enthusiasm by people in the immunology field.”Provenge Takes Personalization to a New Level
Every dose of Provenge must be developed specifically for each individual patient. Treatment begins with harvesting dendritic cells from the patient’s blood using leukapheresis (Figure 1
). This process takes approximately 3 hours. The cells are then shipped to a Dendreon manufacturing facility where they are exposed to Provenge, a drug combining prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The recombinant protein PAP is expressed in 95% of prostate cancer cases. GM-CSF is an immune cell activator.
The dendritic cells soak in this brew for several days and proliferate until eventually the prostatecancer- associated antigen can be found on the cell surface (Figure 2
). The cells are then returned to the physician to be reinfused in the patient. Each patient receives 3 infusions, administered at 2-week intervals. Inside the patient, the activated dendritic cells display the antigen to armies of T cells, priming them to seek out and attack all prostate cancer cells bearing the target protein. The treatment generally spares healthy cells, and adverse effects are minimal. The most common are mild-to-moderate chills, pyrexia, and headache. Other patients have reported fatigue, back pain, and joint aches.