A Shot In The Arm For The Fight Against Cancer?

Last October, Dr. Steven A. Rosenberg, chief mf surgery at the National Cancer Institute in Bethesda, Md., began injecting five melanoma patients with a revolutionary vaccine. It contained the patients' own tumor cells, which had been genetically altered and reintroduced in hopes of stimulating their immune systems to fight their skin cancer more fiercely. While Rosenberg awaits results, Memorial Sloan-Kettering Cancer Center in New York is about to try something similar. Dr. Bernd Gansbacher, an oncologist, will inject melanoma and kidney cancer patients with a vaccine made from lab-grown, gene-altered tumor cells. The goal: "Prevent the spread of cancer throughout their bodies," says Dr. Bernadine Healy, director of the National Institutes of Health.

After decades of work, scientists are drawing close to such a breakthrough. Their model is vaccines for infectious diseases such as smallpox, which work by using injections of killed virus to prime the immune system so it responds when the live virus shows up. In cancer, such a vaccine would be used therapeutically, to boost the immune systems of patients already afflicted. This should avoid the nasty side effects of chemotherapy and radiation. Even better, a pumped-up immune system might react early to recurrence of the cancer. "The most important goal of cancer treatment is to get patients, through their immune systems, to fight cancer themselves," says Dr. Hilary Koprowski, a professor at the Wistar Institute of Anatomy & Biology in Philadelphia.

`OUT OF MY FACE.' For 50 years, researchers have debated whether the body produces an immune response to tumor cells. But it wasn't until the 1970s that scientists at the National Cancer Institute and elsewhere began large-scale trials. They injected solutions of cancer cells and adjuvants--immune-system boosters--into patients suffering from advanced melanoma, ovarian cancer, and other malignancies. The results weren't especially encouraging: "It was a 'gemisch' a mixture that they were injecting," says Samuel D. Waksal, president and CEO of ImClone Systems, Inc., a New York biotech company.

Cancer vaccine work went underground after that. "The financial community said: `Cancer vaccines, get out of my face,' " says Matthew F. Heil, an immunologist and partner at Delphi Group Ltd., a consultant in White Plains, N.Y. But now, biotech is changing attitudes. Its tools make it possible to dissect cancer cells and antibodies, helping scientists understand how the immune system reacts against tumors and how to design a vaccine. This has spawned new activity (table) at universities, the NCI, and at biotech startups, including ImClone, Idec Pharmaceuticals in La Jolla, Calif., and Biomira Inc. in Edmonton, Alta. Cancer vaccines are also a major goal for companies such as Cell Genesys in Cambridge, Mass., and Genetic Therapy Inc. in Gaithersburg, Md., which are experimenting with slipping new genes into human cells. Across the U.S., there are at least three dozen vaccine trials--the majority for melanoma.

The reason the body fails to fight off cancer is that it doesn't see the diseased cells as foreign. Scientists aren't sure why, though they think cancerous cells may be so similar to normal ones that they don't stand out. And they may grow too slowly at first for immune cells to spot them, or may release compounds that suppress the immune system.

FOREIGN ATTACK. The latest attempts to grapple with this began in the mid-1980s, when researchers infected tumor cells with influenza or other viruses and injected them into patients suffering from melanoma and other cancers. The hope was that the virus would produce antigens--proteins or sugars--that would bud out of the cancer cell's membrane. The body would see them as foreign and attack. "The vaccines showed modest results in the clinic," says Dr. Ralph S. Freedman, chief of experimental gynecology at M.D. Anderson Cancer Center in Houston. But it was hard to tell exactly what caused an immune response.

That's where biotech comes in. Using tools of molecular biology, researchers are beginning to identify antigens, located either on the outer coating of cancer cells or hidden inside, that may be unique to tumors. The idea is that formulations of these may be more effective than the messy concoctions used in experiments just a few years ago.

Some human trials using such antigens have already started. Dr. Jean-Claude Bystryn at New York University is using a vaccine made from a mixture of several proteins removed from melanoma cell cultures. He has seen immune responses in about one-third of the patients given the vaccine after melanoma was surgically removed from their lymph nodes, and he is starting trials to see if the vaccine prevents recurrence. Ribi ImmunoChem Research Inc. in Hamilton, Mont., is testing its melanoma vaccine--made from a mixture of tumor-associated antigens with a proprietary adjuvant called Detox--in 27 research centers in the U.S. According to the In early vaccine tests,

survival for late-stage melanoma patients doubled, to nearly two years

company, survival in late-stage melanoma patients has doubled, to nearly two years, compared with those receiving chemotherapy. Biomira is using synthetic carbohydrate molecules--modeled after those found on the surface of certain solid tumor cells--in a similar vaccine.

CUSTOM CLONES. Some companies are trying to increase the effect of antigens--mainly complex fats--that normally would provoke weak immune responses. The concept is complicated, but basically, researchers use mice to manufacture synthetic versions of tumor-associated antigens. These anti-ids, as they are called, may arouse more of an immune response than the original substance, partially because they are more foreign. Vaccines using anti-ids might do the most good in stalling recurring cancers, says ImClone's Waksal, who imagines boosters every six months or so: "If you have a strong immune response there all the time, that would keep the cancer from growing." Idec and ImClone are testing anti-id vaccines in postsurgery melanoma patients.

Still, most cancer antigens identified so far can't provoke a strong response from T-lymphocytes, white cells that are key in destroying cancer. The best vaccine, say researchers, will employ a tumor-specific antigen that also has this effect. Last December, Thierry Boon, director of the Ludwig Institute for Cancer Research in Brussels, located the first such antigen--called MAGE-1--in melanoma and lung cancer cells. He also cloned the gene that produces this protein. Dr. Malcolm S. Mitchell, professor of medicine and microbiology at the University of Southern California's School of Medicine, has found nine genes that might produce antigens unique to melanoma. "To make a synthetic vaccine with a mixture of these antigens shouldn't be impossible," says Mitchell.

There are several ideas about how to administer these antigens, and gene therapy is high on everyone's list. Rosenberg thinks T-lymphocytes don't recognize cancer antigens if they aren't presented right. He uses the analogy of a diamond that may not be recognized by its owner when placed in a different setting. For T-cells to see them as intruders, cancer antigens must be displayed by so-called HLA-molecules--cellular diamond settings--that vary among individuals. That's why in his vaccine, Rosenberg uses a patient's own tumor cells. By year's end, he plans to slip the gene for MAGE-1 into patients' melanoma cells in hopes of provoking a strong cancer defense.

Critics say it's hard to commercialize such individualized treatments. And some patients' altered tumor cells stop growing before enough can be harvested to make a vaccine. Gansbacher's vaccine at Sloan Kettering may offer a partial solution: He uses lab-grown melanoma cells that he says can provoke a response in 40% of white melanoma sufferers who have similar HLA molecules.

In the end, researchers agree, just as there are 100 or more cancers, there will be dozens of cancer vaccines, based on more than one technology. And one day, perhaps relatively soon, more cancer patients may have a fighting chance.