Gene therapy for kidney cancer

June 1, 1994

Gene therapy comes to Chicago

At 11 a.m., on Wednesday, June 1, Edward Murphy--a 66-year-old Osceola, IN, man who suffers from advanced kidney cancer that has spread throughout his body--became the first patient ever to be treated in the Chicago-area with gene therapy. He is the first kidney cancer patient to be treated with in vivo gene therapy.

The therapy involves injection of new genes directly into a patient's tumor tissue, a radical new approach to battling cancer and other disorders. The injected gene is designed to trick the body's immune system into launching an attack against the tumors as if they were foreign, transplanted tissue.

"Although gene therapy is still in its infancy, there is tremendous excitement about it," said Nicholas J. Vogelzang, MD, professor of medicine at the University of Chicago Medical Center and leader of the team conducting this trial.

"One of the most appealing areas for gene therapy research has been in the treatment of cancer," added Vogelzang. "This trial is an early venture into a new field that, while still unproven, holds enormous promise for the treatment of many diseases."

Like most phase-I trials, this therapy will be tested first in patients with disease that has not responded to standard or other investigational therapies. Although there are no effective chemotherapies for metastatic kidney cancer, about 20 percent of patients treated with high doses of an immune system stimulant called interleukin-2, have a full or partial regression.

Murphy, a law professor at Notre Dame University, was diagnosed with advanced kidney cancer in July 1992. He has since received standard and several investigational therapies. His affected kidney was surgically removed soon after the tumor was detected, but the cancer had already spread beyond the kidney.

Murphy underwent outpatient treatment with an investigational therapy--a newer agent called interleukin-4--but had to stop treatment because of side effects. He came to the University of Chicago Hospitals for inpatient treatment with interleukin-2 in the summer of 1993, but that was not effective. He also had radiation therapy last February for a tumor near his ear.

Despite his illness, Professor Murphy has continued to teach with occasional medical leaves for treatment. A specialist in contracts and jurisprudence, he has taught at Notre Dame since 1958.

The only previous trial of this approach, conducted by Dr. Gary Nabel and colleagues 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.

None of the initial patients reported any harmful or unpleasant side effects from the therapy, except for the mild discomfort associated with biopsy of their tumors. Although the treatment did not cure the disease, 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 toxicity.

Consequently, three new trials, each involving 15 patients, are getting underway to test this approach against other types of cancer. Researchers at the University of Chicago are studying kidney cancer, researchers at the Mayo Clinic are testing this therapy against colon cancer, and researchers at the Arizona Cancer Center are continuing the research on melanoma. These tumor types were selected because a biologically enhanced immune response has induced regression of all three.

Therapy involves injection of about four cubic centimeters of a lipid/DNA mixture directly into the patient's tumors. Gary Sudakoff, MD, assistant professor of radiology at the University of Chicago and a collaborator in this trial, will use CT scans and ultrasound to guide the needle to several areas within a single nodule. In Murphy's case, the target nodule is just beneath the skin of his chest wall.

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."

Treatment requires about 30 minutes. Patients will initially be hospitalized overnight for observation. Murphy will return in two weeks to assess whether the DNA was taken up by tumor cells, whether it generated an immune response and if that response had any effect on the tumor.

If his tumors show a response, Murphy will receive additional treatments. The research protocol allows the treatment to be repeated twice, after two-week intervals. As in most phase-I trial, the protocol allows for increases in dose or frequency in subsequent patients.

The injected DNA encodes a protein called HLA-B7 that can stimulate an immune system attack against cells that produce the protein. 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 animal models 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 attack those cells as well.

In most previous in vivo gene therapy experiments, researchers have used viruses to carry the DNA into the patient's tissues. But there has long been a concern 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 goal of phase-I trials is to determine the safety and toxicity of a new therapy. This trial will measure the ability of the liposomal delivery system to transport the gene and confirm expression of the HLA-B7 gene in tumor cells. It will also measure the immune response to tumor cells and characterize the therapeutic consequences of escalating doses of the study drug.

Murphy reports no particular excitement or concerns about his role in this trial. "I've been through so many treatments," he says. "This is one more step. The theory makes sense; it's a plausible idea and probably the least toxic of any treatment I've had so far."

Murphy is married and has nine children. He has remained active despite his disease and has just retired from teaching after 37 years.

The Recombinant Advisory Committee of the U.S. National Institutes of Health unanimously approved the gene therapy protocol--submitted by Vogelzang and Vical--on March 4, 1994.