Barbara Derenowski had just finished packing for a trip to Hawaii last May when she walked into her kitchen and found she was unable to speak. The 68-year-old retired nurse assumed she'd had a stroke, and she remained calm as her husband John drove her to the local hospital in Surprise, Ariz. There she got the tragic news. Multiple brain scans revealed Barbara had the deadliest form of brain tumor, a glioblastoma, which kills most victims within a year. After undergoing surgery, Barbara was told she had about six months to live, and she knew from experience the doctor wasn't being overly negative. Her mother had died of a brain tumor at age 45, five months after the disease was diagnosed.
Beyond surgery, there are no effective treatments available for glioblastomas. But Barbara's daughter, a TV news producer, knew about an experimental approach being tested at the University of Texas M.D. Anderson Cancer Center in Houston, a cancer vaccine designed to train the body's immune system to attack the tumor. It is different from Merck & Co.'s (MRK) Gardasil vaccine, approved last year to block a virus that causes cervical cancer. M.D. Anderson's vaccine alerts the body's own defenses that cancer cells have taken root, essentially prodding the body to heal itself.
Such therapeutic cancer vaccines have been the dream of oncologists for more than a century, but the theory, though elegant, has yet to prove itself. None of the dozens of vaccines in development has won approval from regulators, and there have been several high-profile failures in the past few years. One of the nation's leading cancer researchers, Dr. Steven A. Rosenberg of the National Cancer Institute, insists that "there are no therapeutic vaccines that have been shown to be effective."
It's true. There is no confirmation that vaccines can shrink tumors, a standard measure of a cancer drug's effectiveness. There are mounting signals these treatments can keep patients alive far longer than anyone thought possible without major side effects, but no data proving the point. What's more, researchers are not sure how to interpret the available survival data.
Many point out that there are no drugs known to prolong life without shrinking the tumor. But medicine is an uncertain science--and vaccine research is especially murky because much of the immune system's inner workings remain an enigma. A host of oncologists now argue that a treatment deserves serious consideration if it allows patients with no other alternatives to live longer, without hampering their quality of life.
The experience of Antigenics Inc. (AGEN) shows how this ambiguity plays out in the market and in patient care. Last year the company reported that its cancer vaccine, Oncophage, did not prevent recurrences of kidney cancer in a late-stage trial, a devastating blow to a drug some expected to win Food & Drug Administration approval this year. But on Apr. 16 researchers from the University of California at San Francisco reported that Oncophage produced a strong immune reaction in all 12 glioblastoma patients in a clinical trial, and they were living on average four months longer than normal. Lead researcher Dr. Andrew Parsa, a neurosurgeon at UCSF, says the earlier Antigenic trial should be reconsidered: "There is no doubt in my mind there are kidney cancer patients alive because of that vaccine."
Like Parsa, scientists and companies in this field are beginning to sound less circumspect. The measured optimism is bolstered by sheer numbers: More than 60 vaccines are being tested in humans, and at least a dozen are in late-stage clinical trials (table, page 60). On Apr. 3, Cell Genesys Inc. (CEGE) reported that 22 patients taking its prostate cancer vaccine, GVAX, lived a median of 35 months after treatment, compared with 19 months on standard therapy. And an important milestone is looming: The FDA is slated to reach a decision by May 15 on the first therapeutic cancer vaccine up for approval, Dendreon Corp.'s (DNDN) Provenge, also for prostate cancer.
Barbara Derenowski is one of the patients raising the credibility of cancer vaccines. At M.D. Anderson she participated in a clinical trial of a vaccine developed by Celldex Therapeutics Inc. that is meant to seek out and destroy an aberrant bit of protein found only on cancer cells. She received her first shot in August, followed five days later by a large dose of chemotherapy, and has been going back for another injection every month since. "My latest MRI showed there was still no growth of any tumor," she says with obvious joy. "I can do just about everything I did before, though I still have a little trouble with my talking." "Everything" includes that long-delayed trip to Hawaii. She and her husband are booked to leave in May.
There are hundreds of patients like Derenowski, with a broad range of cancers, who say they owe their survival to a vaccine. They usually get through the treatment without the dire side effects linked to radiation and chemotherapy. As a result, analysts have come up with annual sales projections for this sector five years out ranging anywhere from $600 million to $6 billion.
But first, the drugs have to reach the market, and that will probably require data that show vaccines can extend life. Proving survival in the kind of large, lengthy, and well-designed clinical trial preferred by the FDA is challenging for the small biotech firms that dominate this field, although some are in the works. Cell Genesys is enrolling 1,200 patients in two Phase 3 clinical trials aimed at proving survival for its GVAX vaccine, but the results won't be in until 2009.
Meanwhile, the lack of such a trial for Dendreon's Provenge is causing a rift in the cancer community. A midstage trial of the vaccine in 127 patients with late-stage prostate cancer failed to reach its stated goal of slowing the disease's spread, usually a death knell for a new drug facing the FDA. But when Dendreon dug into the data it discovered patients on Provenge lived an average of 4 1/2 months longer than those receiving the standard chemotherapy, Taxotere. To gain four months in such sick patients is considered significant, if it's real. But since the trial wasn't meant to prove survival, there is a chance something else could be prolonging these patients' lives. "This trial wasn't well-designed, so it leaves plenty of ambiguities," says Dr. Howard I. Scher, an expert in prostate cancer at Memorial Sloan-Kettering Cancer Center in New York. "It doesn't mean the drug isn't working, but it needs more study."
'A NEW FIELD'
Scher was one of the naysayers on an FDA advisory panel that voted 13 to 4 on Mar. 28 to recommend approval of Provenge. He complains that the FDA may be lowering its standards for this drug. Others in the field insist vaccines are so novel and so well-tolerated that they must be evaluated by a different standard. (All 17 members of the FDA panel concluded that Provenge was safe.) "We are opening a new field," argued panel member Dr. Francesco Marincola, director of the Immunogenetics Laboratory at the National Institutes of Health. "There is much to learn by starting to see patients being treated with this."
The roots of this controversy lie in the immune system's strange relationship with cancer. Immune cells usually mount an inflammatory response the instant disease-causing invaders such as viruses or bacteria enter the body. Yet the body's sentries ignore mutant cancer cells, because they assume anything homegrown belongs in the body.
The idea that the immune system could be reprogrammed to fight cancer was first tested in the late 1800s by Dr. William B. Coley, a New York surgeon. He infected patients with a vaccine made from benign bacteria in an attempt to set off an anti-tumor response. Some patients experienced complete remissions, but the results were inconsistent and Coley's treatment never caught on.
A cancer vaccine renaissance started about a decade ago when a number of scientists and biotech firms came up with a better approach. They isolate various protein triggers found only on the surface of cancer cells. Technicians remove some of these proteins, or clone them in a lab, and combine them with various immune-system activators. That might be an inactive virus, or something altogether different. In the case of Genitope Corp.'s (GTOP) MyVax, a promising vaccine for lymphoma, the cancer protein is combined with a cloned piece of a giant sea mollusk, the keyhole limpet, which triggers a strong immune reaction because it is so alien to the human body.
So why, in trial after clinical trial, doesn't this reaction eliminate the tumor? Dr. Glenn Dranoff, a vaccine expert at Boston's Dana-Farber Cancer Institute, says there is evidence immune cells infiltrate the tumor and kill it from within, leaving a ball of scar tissue the same size as the malignant growth. "You don't see a visible change in the size of the tumor, but the composition has been dramatically altered."
Oncologists believe vaccines will work best at stopping cancer recurrences after initial surgery. These metastases are what usually kill the patient. Consequently, a growing cadre of oncologists say patients who have failed other treatments should have a chance to try these drugs. Dr. David F. Penson, a urologist at the University of Southern California's Norris Cancer Center who has consulted for Dendreon, is convinced Provenge has extended the lives of his prostate cancer patients. "I don't know what else could be doing it." Equally important, he says, is the quality-of-life issue. "These are guys who have one or two years to live, and their only treatment option is Taxotere," a chemotherapy so toxic that many men refuse treatment. With Provenge, "patients get infused on Thursday and play golf over the weekend," says Penson.
By Catherine Arnst