Experts cross fingers on cancer experiment Many hope Hopkins will produce vaccine

April 16, 1997|By Jonathan Bor | Jonathan Bor,SUN STAFF

A day after reporting the early promise of an experimental cancer vaccine, Johns Hopkins scientists spoke yesterday of excitement and a gnawing awareness that one of life's most feared diseases might win in the end.

"When I get up in the morning and get into my car and drive to work, I think about what today's experiments are going to show and where the next improvements are going to come from," said Dr. Hyam Levitsky, an oncologist who is part of the vaccine development team.

"But I've been around a long time and know that cancer got there because it evaded a number of different mechanisms that would have prevented it in the first place. We celebrate our successes, then worry about how we're going to make the next transition."

The story of how a group of young scientists began their quest for a therapeutic vaccine started a decade ago with experiments on laboratory mice. The search has progressed through bolder tests on humans, and will unfold in years to come as the vaccine is tried on larger groups of patients at different stages of cancer.

On Monday, Dr. Jonathan Simons of the Johns Hopkins Oncology Center told a national gathering of cancer researchers that an experimental vaccine had stimulated the immune systems of patients in the late stages of kidney cancer. The Hopkins team is one of several around the country pursuing a vaccine strategy, with targets ranging from melanoma to brain cancer.

Hopkins doctors had removed the tumors of 18 patients, then returned them in three injections spaced several months apart. Before receiving the injections, however, half of the patients had their tumor cells engineered to secrete proteins known as immune-system stimulators.

Patients receiving the altered cells generated immune responses that looked suspiciously like soldiers gathering for a fight. What this means is both thrilling and limited.

It means that the immune system can be coaxed to mobilize against cancer in a manner that resembles the body's initial reaction to invading bacteria and viruses. But it will take years before scientists learn if the response is powerful enough to cure anyone.

In the 1980s, a few researchers under the tutelage of Hopkins oncologist Bert Vogelstein started veering in the direction of cancer vaccines.

Dr. Vogelstein was well into groundbreaking studies that would establish the genetic basis for colon cancer -- the way that a cascade of genetic mutations transforms normal cells to abnormal ones that multiply out of control.

Dr. Eric Fearon, a graduate student who later moved to the University of Michigan, was the first at Hopkins to tweak the immune system with a vaccine. He was joined by Dr. Drew Pardoll, who had returned from a fellowship at the National Institutes of Health.

For reasons that remain elusive, cancers spread without alerting the immune system the way infections do. So the scientists, experimenting on mice, inserted a flu virus into the tumor cells and then waited to see if the vaccine would fool the immune system into attacking the cancer as well as the virus.

"That looked promising," said Vogelstein, but the researchers moved to newer approaches that might offer better results.

By 1989, Pardoll had become the senior scientist on a team that would carry the work to the present day. He was joined by Simons, Levitsky and Dr. Elizabeth Jaffee.

Each was about 30.

They focused on altering tumors with genes that secrete cytokines -- proteins that are key players in the body's response to infection, summoning other parts of the immune system to a well-orchestrated attack.

"The idea was to educate the immune system to the idea that the tumor had something it could recognize," said Jaffee.

But which cytokine was best?

For the answer, they enlisted Dr. Richard Mulligan and Dr. Glenn Dranoff of MIT, who had developed an efficient method of transferring genes into tumors. They implanted genes into a virus, then let the virus deliver the genes to tumor cells that had been harvested from a mouse.

With this method, the MIT researchers tried one cytokine gene after another to see which did the best job of waking the immune system from its slumber. "They put the gene for every possible cytokine into tumors and tested them head-to-head in every tumor model," said Jaffee.

The contest was won by a gene called GM-CSF (for granulocyte-macrophage colony stimulating factor), which melted away cancers of the colon, kidney, lung and bone. For most of the mice, the vaccine was an outright cure.

Jaffee and her colleagues are the first to admit that a mouse

cure doesn't necessarily translate into a human cure.

Mice cannot be counted on to develop tumors on their own, so the disease is given to them through injections or caused by exposure to carcinogens. Also, mouse tumors double in size every 24 to 48 hours, compared with an average of three months for humans.

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