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 

. 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&mdash;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.”

	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 (

). 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 (

). 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.

Frohlich said prior to releasing the Provengetreated cells for reinfusion, the company measures CD54 upregulation, which is considered a marker of potency for the antigen-presenting cells. Clinical data show significant correlation between the degree of cumulative CD54 upregulation prior to infusion and clinical outcomes with Provenge. Patients whose dendritic cells demonstrate greater activation prior to administration tend to survive longer than those whose cells are less active. According to Frohlich, this is in line with how Provenge is designed to work. It also adds another layer of personalization, helping to individualize prognosis. “It’s been one of the holy grails, to personalize treatments to individual patients. I think this is a major step in that direction,” said Frohlich.

	To support FDA licensure, Dendreon submitted data from 3 phase III studies involving 737 patients. The pivotal study was the randomized, placebo-controlled IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial. IMPACT enrolled 512 patients with asymptomatic or minimally symptomatic metastatic CRPC at multiple centers. In the study, Provenge extended median survival beyond 2 years, with patients in the treatment arm surviving a median of 4.1 months longer than patients in the placebo arm (25.8 mo vs 21.7 mo, respectively). Overall, Provenge reduced the risk of death by 22.5% compared with placebo.

	“Those are meaningful, clinical benefits,” said Philip Kantoff , MD, principal investigator of the IMPACT study. Kantoff is a director at the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. “Statistically, at any point in time, there’s a 23% improvement in your likelihood of being alive.”

	Jim White, a 76-year-old New Jersey resident, said he is happy with those odds. Aft er battling stage IV prostate cancer for nearly 12 years, White enrolled in one of the phase III Provenge trials and said he has been in remission for the last 2½ years. “I’ve noticed a major change in my outlook on life,” White said. “It went from storm clouds on the horizon to a beautiful day.”

	Len Lichtenfeld, MD, is deputy chief medical officer of the American Cancer Society (ACS). He said despite the enthusiasm over Provenge’s approval and stories like White’s, it is important to keep expectations in line with what study results have shown. “Most of the men [in the Provenge trials] did not go into remission…their disease progressed just as it would in comparison to men who did not receive this treatment,” Lichtenfeld noted. “Whether it be Provenge or any other targeted therapy, there are clearly cases where some subsets of people respond extraordinarily and some will not have any benefit at all,” he said.

	Jill O’Donnell Tormey, PhD, executive director of the Cancer Research Institute echoed Lichtenfeld’s call for caution. Tormey pointed out that the entire field of cancer immunotherapy has “a spotted history,” with new treatments hailed as a magic bullet against cancer then failing to pan out. “Hopefully, we have learned from our past.”

	Lichtenfeld said physicians now face a major challenge in talking with their patients about Provenge, many of whom have bought into the excitement in the headlines. He said that while 4.1 months was the median improved survival and more than half of the men who participated in the clinical trials saw their lives extended by several months, the treatment was given to a select group of men.

	“[Provenge] is not for men who, unfortunately, have had difficult progression and are in terrible pain. This is not a medicine that’s going to help them, and it’s not a medicine for men who have just been newly diagnosed with prostate cancer,” Lichtenfeld said. “My major concern, and a concern shared by my colleagues with whom I’ve spoken, is that people not have false expectations of what this drug is going to accomplish.”

	Kantoff said the concept of setting expectations correctly with patients is not a new one. He suggested physicians start by talking with patients about the IMPACT study, explaining the results in lay language. “People do understand what it means to have a 38% greater likelihood of being alive in 3 years.” He said they also need to know that patients treated with Provenge do not feel better afterward and their tumors do not decrease appreciably in size. “That’s an important expectation-setting tool. Because if people are thinking, this is going to make my cancer go away, it needs to be stated up front that is not what’s going to happen,” said Kantoff.

	Dendreon’s Frohlich said he understands these cautious perspectives. Because Provenge is a first-in- class therapy, Frohlich said physicians and patients will require educational support on its use and benefits. In addition, they need to have conversations on what Provenge is, how it works, whether or not it is the right product for a particular patient, and what the patient can expect after treatment.

	Dendreon plans to provide physicians with the information they need to hold those discussions. “We have a large team that we’ve hired, both from the sales and medical affairs perspective, that will be educating physicians in their offices,” Frohlich said. “And we’ll be doing educational activities at the major medical meetings across the country in the next few months.”

	The price for Provenge has been pegged at $93,000 per patient, a figure that has raised quite a few eyebrows. Frohlich said from the company’s perspective, Provenge offers a good value proposition to physicians and patients. It has been shown to prolong life significantly and has a favorable adverse event profile, which Frohlich said stands in stark contrast with many other anticancer agents, such as chemotherapy. He anticipates that Medicare and private payers will off er coverage for treatment with Provenge, reducing the burden on the patient.

	Frohlich said it is important to remember that the cost of the therapy does not necessarily equate with the price of the therapy. Again referring to chemotherapy, Frohlich said there are costs that arise from managing adverse events that are not included in the price or administration of the drugs. Because Provenge is well tolerated, with minimal adverse events and few hospitalizations, Frohlich said there is little variation between its cost and its end price. When looking at overall costs related to treatment with a specific drug, Frohlich said Provenge is in the same ballpark as other commonly used cancer drugs. Dendreon weighed Provenge against various biologics with a similar degree of benefit that have been approved to treat cancer and concluded that the price for Provenge was “comparable.”

Kantoff , who admits he is not an economist, said the price emphasizes the importance of only using Provenge in those patients physicians believe are most likely to benefit. This, he said, means adhering to the FDA label. Kantoff said it may be the most desperate patients—those with few options available&mdash;who will want the treatment the most, but they are unfortunately the least likely to benefit from it. “I think that physicians need to be very careful about that,” he added.

	Alter at John Theurer acknowledged there is concern about whether a 4.1-month improvement in overall survival justifi es the cost. “To that end, I think every patient is diff erent…everyone has different concerns about [his] disease.” Alter said cost must be part of the discussion physicians have with patients when considering Provenge, and the likely benefit should be weighed against the out-of-pocket costs. For now, how much of the cost commercial insurers will cover remains a mystery.

	ACS’s Lichtenfeld suspects that “quite a few” men with CRPC in the Medicare population will be candidates for Provenge. He also believes that as the medication becomes more available and the number of patients treated with Provenge ramps up, the financial burden on Medicare will be noticeable. “Does that mean that Medicare won’t cover it? I can’t answer that. They generally do cover treatments that are approved by the FDA, but it’s an open question remaining to be answered,” he said.

	Don McLeod, a spokesman for the Center for Medicare and Medicaid Services (CMS), told several media outlets that the agency is almost certain to cover Provenge. McLeod said cost is currently not a factor in Medicare’s coverage decisions and once the FDA has approved a drug for cancer, it is generally covered. Dendreon has received word from CMS that Provenge is being issued a temporary J code, which will be replaced with a permanent J code in January 2011. Provenge has not yet been approved for use in the European Union, where the regulatory agencies do weigh cost as a factor in reimbursement decisions.

	Dendreon estimates approximately 103,000 men in the United States are candidates for treatment with Provenge and that there are an even greater number of suitable patients in Europe. This has led the company to give careful consideration to product availability.

	“We do anticipate that there is going to be strong demand from physicians and patients,” Frohlich said. “When we got the positive news of the trial, and before we had FDA approval, in fact, we began making substantial eff orts to build out 2 new manufacturing facilities—1 in Atlanta, and 1 in Seal Beach, California.” This is in addition to Dendreon’s facility in New Jersey, which the company continues to expand. “By the middle of 2011, we anticipate having full capacity at all 3 of those manufacturing facilities, which we anticipate should be able to meet the demands substantially,” he said.

	Despite Dendreon's efforts to increase manufacturing capacity during the coming year, Frohlich acknowledges that demand for Provenge may outstrip what the company is able to deliver. The company has been transparent in communicating this to physicians and patients, announcing that it anticipates being able to treat approximately 2000 patients over the next year. “Our initial launch is with approximately 50 clinical sites…that had previous involvement in our clinical trials,” Frohlich said.

	Dendreon met with trial physicians, oncology organizations, and patient advocacy groups to determine how best to distribute the limited supply of Provenge. Frohlich said the overwhelming consensus was to leave the decision making as to which patients receive treatment up to the physician.

Provenge Just the First Step for Dendreon

	Lichtenfeld said until now, there was healthy skepticism as to whether immunotherapy vaccines would ever be successful in treating cancer. Over the years, there were rays of hope, but nothing that achieved what Dendreon has with Provenge.

	“What [the FDA approval of Provenge] has done is taken that healthy skepticism and made it a little more enthusiastic that the same or perhaps similar technology can be used to approach other diseases,” Lichtenfeld said. “It certainly gives vindication to the company, to the researchers, and to the patients in the clinical trials who were up against tremendous odds and barriers to get this drug to the approval stage.” For some companies and organizations, the approval of Provenge helps justify investing resources toward the development of other anticancer immunotherapy vaccines.

	Those sentiments resonate at Dendreon. With the Provenge delivery platform validated, Frohlich said the company is interested in putting other tumor antigens into the same antigen delivery cassette to target other cancers. A program is already in place targeting HER-2, a protein overexpressed in several cancer types, including breast, colorectal, ovarian, and bladder, and Dendreon is planning new trials. Said Frohlich, “I think it’s really going to open the floodgates in terms of new and different approaches to try and expand on what we’ve been able to demonstrate.”

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