U Hospitals 1st to treat kidney-cancer patient with gene

University physicians last week made medical history by performing the first gene therapy treatment of a kidney-cancer patient. Their work also represents the first time a patient was treated in the Chicago area with gene therapy.

The treatment was administered to Edward Murphy, a 66-year-old law professor at Notre Dame, who has advanced kidney cancer that has spread throughout his body.

Nicholas Vogelzang, Professor in Medicine, is the leader of the Medical Center team conducting a trial of the promising new therapy.

"This trial is an early venture into a new field that, while still unproven, holds enormous promise for the treatment of many diseases," Vogelzang said. "Although gene therapy is still in its infancy, there is tremendous excitement about it, especially for the treatment of cancer."

The therapy is a radical new approach to battling cancer and other disorders. Doctors inject new genes directly into a patient's tumor tissue in an attempt to trick the body's immune system into recognizing the tumors as foreign, transplanted tissue and then launching an attack against them.

The new therapy is being tested first in patients whose disease has not responded to standard or investigational therapies.

Murphy was diagnosed with advanced kidney cancer in July 1992. Although his affected kidney was surgically removed soon after the tumor was detected, the cancer had already spread. He has since received standard and investigational therapies, but none has been effective.

The only previous trial of this approach, conducted by Gary Nabel at the University of Michigan, involved five patients with metastatic melanoma, a lethal skin cancer. The researchers found that the injected DNA was taken up and expressed by tumor cells in four of the five patients, and in one of the five the treatment produced a partial remission, causing several tumors to disappear entirely. This provided the first evidence that genes injected directly into human tumor cells can take hold, function and stimulate the immune system without toxic side effects.

In the wake of that work, three new trials, each involving 15 patients, are under way to test this approach against other types of cancer. Researchers at Chicago are testing the therapy against kidney cancer, researchers at the Mayo Clinic are testing it against colon cancer, and researchers at the Arizona Cancer Center are continuing the research on melanoma.

Treatment requires about 30 minutes, followed by overnight hospitalization for observation. Murphy is scheduled to return to the Hospitals two weeks after his June 1 treatment to assess whether the DNA was taken up by tumor cells, whether it generated an immune response and whether that response had any effect on the tumor. If his tumors decrease in size, Murphy will receive additional treatments.

In most previous gene-therapy experiments that have involved sending new genes into the body, researchers have used viruses to carry the DNA into the patient's tissues. But doctors have been concerned that even deactivated viruses, which are incapable of making new copies of themselves, could pose a risk.

In this trial, the therapeutic genes are transported within tiny fat bubbles, called liposomes, which can ooze through the cell membrane to deliver their genetic cargo. Although viruses are more efficient at introducing new genes into cells, liposomes appear to work well enough, ferrying the genes into about five percent of the targeted cells. Since the initial Michigan trial, the liposomal transport system -- developed by researchers at Vical, a San Diego-based biopharmaceutical company interested in gene therapy -- has been altered in ways that are expected to make it safer, more effective and easier to administer.

The injected DNA encodes a protein called HLA-B7 that can stimulate an immune-system attack against cells. HLA-B7 was chosen because it is known to play a crucial role in rejection of transplanted organs.

It is not necessary for all cancer cells to take up the foreign gene for the therapy to be effective. Studies in animals have shown that once the immune system responds to the foreign HLA gene, it can also begin to recognize other tumor-associated proteins that are produced only by cancerous cells and to attack those cells as well.

In each case, the therapy involves injection of about four cubic centimeters of a DNA mixture directly into the patient's tumors. Gary Sudakoff, Assistant Professor in Radiology and a collaborator in this trial, uses CT scans and ultrasound to guide the needle to several areas within a single tumor.

Technically, the procedure is similar to an ultrasound-guided biopsy. "We've performed nearly identical procedures thousands of times," said Sudakoff. "The difference this time is that we will be injecting DNA into the lesion, and we will monitor the effect on tumor size and vascularity using ultrasound and color Doppler imaging."