Cancer vaccines in final test phase The drugs are not preventive, but provoke the body to fight cancer cells.

Posted: June 12, 2005

More than a dozen cancer vaccines are now in the final phase of human testing, the last step before Food and Drug Administration approval is sought for marketing.

Provenge, a prostate-cancer vaccine, may be the first to be approved, possibly this year. Vaccines for skin, kidney and lung cancers are on the horizon. Not far behind are versions for leukemia and myeloma as well as breast, ovarian, pancreatic, colorectal and brain cancers.

Unlike conventional disease-preventing vaccines, the new ones are designed to work after cancer develops by provoking a heightened immune response.

Within four years, the market for such products could be $2 billion, analysts predict.

"Cancer vaccines have finally come of age," said Yvonne Paterson, a University of Pennsylvania microbiologist and scientific founder of Advaxis Inc. The company is about to begin human testing of a therapeutic cervical-cancer vaccine that produced stunning results in mice.

Paterson and two other vaccine pioneers will talk about their infant industry on June 20 at the Biotechnology Industry Organization's annual gathering, this year at the Pennsylvania Convention Center.

Olivera Finn, a University of Pittsburgh immunologist, will make the provocative argument that treatment vaccines will not do much to reduce the toll of cancer unless they are also used in a traditional way: to prevent the disease in high-risk patients.

"If we diagnose a pre-malignant lesion - for example, in the lungs - right now that person is watched until he develops cancer, or he's given a cytotoxic therapy," she said. "Why not vaccinate that person?"

Conventional immunizations, familiar around the world, are synonymous with prevention.

Vaccines such as those that ward off measles, polio, and flu work by forewarning the body's natural defenses to attack an invading virus. The vaccine primes the immune system to watch for the invader's unique proteins, called antigens.

With cancer, this preemptive approach is effective only for the few malignancies known to be caused by infectious invaders. The one cancer vaccine already on the market prevents infection with hepatitis B virus, a cause of liver cancer. Two new vaccines, both racing toward FDA approval, avert infection with human papillomavirus, which causes cervical cancer.

But for most cancers, jump-starting the immune system is complicated by the fact that the disease starts with enemies from within - the body's own cells that turn malignant due to genetic or environmental forces. In effect, vaccines that fight established cancer must trick the body into a self-attack.

This is no easy feat. Cancer cells have antigens that are unique or unusually abundant, but the immune system is very tolerant of these abnormal cells, like the parent of a troubled child. Tumors also shed or change antigens to stay under the immune radar.

Even though researchers began isolating cancer antigens in 1991 - the breakthrough was with melanoma cells - they have had difficulty presenting these antigens to the body in ways that prompt an immune response.

Paradoxically, even though the immune system does not like to kill its own cancerous cells, most therapeutic vaccines are tailor-made, using the patient's own cancer-cell antigens. Among exceptions is Canvaxin, a melanoma vaccine made from three lab-engineered cell lines containing many known melanoma antigens.

"Five years ago, it seemed to be possible to use generic vaccines, but many of those immune responses had no effect on the patient's outcome," said Thomas Jefferson University oncologist David Berd, medical chief of Avax Technologies Inc., which is developing M-Vax, a melanoma vaccine tailor-made from the patient's cells. "It underscored the idea that tumor antigens for one patient are not exactly the same for another."

A number of strategies have worked to get the body to go after its own renegade cells.

Paterson, for example, has engineered the common listeria bacteria to be a "vector," or carrier, of the cervical-cancer antigen. The body's first-line immune cells gobble up the listeria and simultaneously release chemical signals, called cytokines, that call in the big immune guns - cytotoxic T cells.

These killer cells go looking for anything bearing the antigen carried by listeria and wind up destroying cervical-cancer tumors - at least, in experiments with mice.

Listeria is a cause of serious food-borne illness, so Paterson weakens, or attenuates, it before using it as a carrier. Still, she is keenly aware that vectors can be risky; the death of Jesse Gelsinger, a volunteer in a Penn gene-therapy experiment, was linked to a viral vector.

"But that's another reason we like Listeria," Paterson said. "Suppose someone spikes a fever when we do a clinical trial. Penicillin can kill this bacteria."

Provenge, made by Dendreon Corp. of Seattle, harvests the patient's dendritic cells - another first-line immune cell - then uses them to deliver a prostate cancer antigen found on 95 percent of prostate cancer cells. Dendreon is also developing a breast-cancer vaccine.

The M-Vax melanoma vaccine - a 17-year development odyssey for Berd - is based on yet another strategy, one that also seems promising for ovarian and lung cancers. M-Vax combines the patient's tumor cells with a "hapten," a molecule that acts like an antigen when coupled with a carrier.

The vaccine is injected along with a skin-prick test that serves as an indicator of success; if itchy, sore bumps rise at the site, the patient is mounting an immune response.

In theory, M-Vax and other vaccines could send the immune system into a harmful overreaction.

"Scientists and regulators always raise that issue: If you get too much response, theoretically you could get an autoimmune response," said Berd. "We have to monitor for it. But in our patients, we've never seen it."

One of those patients, Bruce Godfriaux, 62, of Mertztown, Berks County, opted to be a guinea pig for M-Vax after having surgeries to remove a melanoma and diseased lymph nodes.

Without the vaccine, he had about a one in three chance of surviving five years. An 18-month course of interferon might have slightly improved those odds, but the drug has toxic, flu-like side effects.

Now, seven years later, Godfriaux is fine - apparently cured.

"Dr. Berd and his vaccine are phenomenal," said the retired zoologist.

Godfriaux's dramatic case notwithstanding, only about half of patients in M-Vax trials have responded, Berd said. Their five-year survival has been 45 percent, compared with 25 percent for those who only had surgery.

Putting such results in perspective is tricky - and goes to the heart of Finn's rationale for extending treatment vaccines to prevention.

Consider data from testing of some promising vaccines.

The median survival of men treated with Provenge was 26 months, just 4.5 months more than patients who received a dummy vaccine. The drug did not achieve one of its primary goals of delaying disease progression. Yet Provenge's survival benefit of 4.5 months was almost double that of Taxotere, the next best treatment for advanced-stage prostate cancer.

Canvaxin, the melanoma vaccine made by CancerVax Corp., kept patients with stage 3 cancer alive a median of 55 months, compared with 31 months for untreated patients. But Canvaxin offered no survival benefit for stage 4 melanoma patients.

Two years ago, a final trial of Theratope, a vaccine for breast cancer that has spread, showed no benefit. Biomira, a Canadian-based biotech company, says it is currently "seeking partners" to continue development of the product.

Finn, for one, is not surprised by such results.

"Therapeutic-vaccine success is marginal for many reasons," she said. "One reason is that most patients are older, so their immune system is older. Then, you're dealing with a disease that suppresses the immune system because the cancer has . . . learned how to avoid the immune system. Finally, because therapeutic vaccines are considered by the Food and Drug Administration to be experimental, you can only give them after regular therapy - chemotherapy and radiation - that destroys the immune system."

She advocates vaccinating patients with known cancer-risk factors, such as colon polyps or premalignant abnormal cells that have formed in the milk ducts of the breast.

"We know from animal models, prophylaxis [prevention] works," Finn said. "In a preventive setting, the vaccine would have a qualitatively and quantitatively better response."

"I would agree that we need to change the paradigm for approval of therapies like this," said Dendreon CEO Mitchell Gold. "These drugs have very low side effects, so their safety profile is appealing."

But CancerVax CEO David Hale, who will be on the panel with Finn and Paterson, thinks such talk is premature.

So does Paterson: "I don't think it will be in my lifetime that we can predict who will get cancer. Nobody comes to you and says: 'I think I'm going to get prostate cancer in 30 years. Give me a shot.' "

On the other hand, Paterson can't wait to turn cancer - diagnosed in 11 million more people worldwide each year - from a terrifying plague into a manageable illness.

"I'm at an age where I seem to be losing people to cancer all the time," said Paterson, 64, herself a breast-cancer survivor. "It's time to stop curing cancer in mice and start curing it in humans."

Contact staff writer Marie McCullough at 215-854-2720 or mmccullough@phillynews.com.

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