Vaccine turns cancer on itself Altered tumor cells spur immune system


Using an experimental cancer vaccine, researchers at the Johns Hopkins Oncology Center say they have spurred the immune system to rise up against cancer in a manner that resembles the body's fight against infection.

The trial, described yesterday at a national meeting of cancer researchers in San Diego, showed that the vaccine is capable of waking a person's immune system from the slumber that allows cancer to spread. The treatment involves injections of altered tumor cells back into the patient.

Coming after eight years of laboratory, animal and human studies, the report represents an early but crucial step in the development of a new strategy against cancer.

Future experiments will determine whether the immune response is sufficient to cure anyone, a result this study was not designed to measure.

"The chapter isn't written yet," said Dr. Jonathan Simons, an oncologist and principal investigator. "We're about to ask the good questions."

The experiment involved 18 patients who were in advanced stages of kidney cancer. Their tumors were removed and then given back to them in three injections spaced several months apart.

Half the patients received tumor cells that had been genetically altered to produce proteins that, in effect, served as red flags to the immune system.

Following the rules of human experimentation, researchers chose patients for the so-called phase-1 trial whose conditions were too advanced to be cured.

The purpose was to judge the vaccine's safety and its ability to generate an immune response.

One patient did experience a sudden remission marked by shrinkage of his tumor, although that person and many others eventually died of their cancers.

Researchers are hoping the vaccines will bring about reversals in patients whose cancers haven't progressed nearly as far.

In an experiment scheduled to begin later this year in Japan, the vaccine will be given to a larger group of patients who have millions -- rather than billions -- of cancer cells.

"If you made a vaccine for these kinds of patients where the immune system is taking on a number of cells they can handle, you might make a big difference," Simons said.

Although much work remains to be done, the researchers hope that cancer vaccines will become an effective adjuvant therapy to accompany surgery and other conventional approaches.

Cancer vaccines are being tried elsewhere against other types of cancers, including melanoma and brain cancer.

The concept is an outgrowth of gene therapy, an experimental approach in which normal genes are delivered to tissues in hopes of correcting inherited abnormalities such as cystic fibrosis.

Similarly, cancer vaccines carry genes that serve as factories for proteins helpful to humans.

But these proteins are used to fool the immune system into mounting a defense -- not to correct a defect by themselves.

In the Hopkins experiment, urologist Fray Marshall removed kidney tumors from all 18 patients. The tumors were then chopped up and expanded in laboratory culture dishes.

Half of the tumors were turned into cancer vaccines. This was done by inserting copies of an "immune system activating gene" -- so named because the gene produces proteins that help the immune system recognize the presence of a foreign invader. The gene is known as GM-CSF (for granulocyte-macrophage colony stimulating factor.)

The researchers irradiated all of the tumor cells to render them incapable of spreading once they had been returned to the body.

The injections sparked an immune response in both groups, but it was more powerful among people receiving the altered cells.

"Probably what happens in the crudest sense is that the body's immune system is blinded in some way to cancer, possibly by substances created by the tumor," Marshall said.

"Putting the GM-CSF cells is probably like putting a little red light in the cells. The body's immune system can now recognize the tumor as foreign and bad, and the immune system can go attack it."

Simons presented the study results yesterday at the annual meeting of the American Association for Cancer Research.

"This is absolutely a pioneering study," said Dr. Donald Coffey, the association's incoming president and a leading cancer researcher at Hopkins.

The Hopkins team worked in relative quiet at a time when many gene therapy trials were generating hoopla followed by disappointment. In many experiments, researchers were unable to deliver genes to enough cells to trigger the desired responses.

"There were too many studies of gene therapy where everybody got excited and then everybody said nothing happened," Simons said. "Maybe they were able to get the gene into only 1 percent of the cells."

In contrast, the Hopkins team delivered the gene to well over half the cells in most cases -- and to virtually all the cells in a few.

The vaccine was developed and tested on animals in 1989 by Dr. Drew Pardoll, Dr. Elizabeth Jaffe and Dr. Hyam Levitsky at Hopkins along with collaborators at MIT. In those tests, scientists gave mice a lethal dose of cancer, then cured them with injections of altered tumor cells.

"That work was basically a series of experiments trying to find the best gene to introduce in tumor cells to stimulate the immune response," said Dr. Glenn Dranoff, formerly of MIT and now an assistant professor of medicine at Harvard. "From that work, GM-CSF popped out as the best."

Dranoff is trying the same vaccine approach for melanoma and plans to begin a lung cancer study this year. The Hopkins group recently began giving a vaccine to prostate cancer patients.

"At this point, all you can really say is that the approach clearly shows the generation of an immune response against tumors, which in and of itself is exciting," he said. "But it's premature to know how strong the overall strategy is and whether it's powerful enough to make a difference in the outcome of cancers for people."

Pub Date: 4/15/97

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