VUMC Researchers Report BRCA1 Clinical Trial Results.

November 10, 1997

The first gene therapy trial using the BRCA1 "breast cancer gene" in patients with ovarian cancer demonstrated minimal side effects and prompted little immune response, Vanderbilt Cancer Center researchers and their colleagues report today.

The promising results are reported in the November issue of the journal Clinical Cancer Research.

Whether the body will thwart attempts at gene therapy by building immunity against the treatment is one of the concerns facing scientists working on this emerging field of medicine.

"It's been very surprising to me that many of the women didn't produce antibodies because that differs from what we saw in the animal studies," said Dr. Jeffrey T. Holt, professor of Cell Biology.

"We had assumed that patients would make antibodies against the gene or the 'vector' carrying the gene into the cells, and those antibodies would attack the vector if you tried subsequent treatments. We had thought it would be pointless to treat people again, that we'd only get one shot."

The Phase 1 study of BRCA1, one of the genes linked to the development of breast and ovarian cancer, is a collaboration between Vanderbilt Cancer Center researchers and investigators at the University of Washington in Seattle.

The researchers have now moved into a Phase 2 study of women with earlier stage disease.

The Phase 1 study was the first dose escalation gene therapy trial. It was designed to evaluate -- at gradually increasing doses -- any side effects, whether the BRCA1 gene was taken up and expressed by cancer cells, and the stability of the vector inside the body.

Antibody production occurred only at the highest dose tested.

The trial evaluated much larger doses than in other studies thus far, and the researchers noted the first observed side effects provoked by gene therapy. Three of the 12 women experienced an allergy-like reaction that caused severe abdominal pain that went away on its own within 48 hours.

"But all the patients told me that they felt better on this than on traditional chemotherapy," said Dr. David L. Tait, assistant professor of Obstetrics and Gynecology, division of Gynecologic Oncology.

The researchers found that the vector was not immediately destroyed by the body's immune system and that it transferred the BRCA1 gene into cancer cells, which then expressed the vector.

Tumor reduction was observed in three of the 12 participants in the study. However, the researchers noted that a Phase 1 trial is not designed to determine efficacy, and any suggestion of effectiveness must be evaluated in a larger, Phase 2 study.

The development of gene therapy is in its infancy, but many scientists hope that it ultimately will provide breakthroughs in treatment for many diseases, including cancer. Researchers are looking for new ways to get potentially therapeutic genes inside cells, to control those genes' activity and to target specific cells while sparing others from the genes' effects.

In this Phase 1 trial, the normal BRCA1 gene was tucked inside an inactivated retrovirus. In earlier work, researchers at the VCC have demonstrated that the BRCA1 gene is a tumor suppressor gene -- - one of its normal functions is to act as a brake on cell growth -- and that it can halt and, in some cases, reverse ovarian and breast tumors in animals.

Researchers evaluated five dose levels ranging from 100 million viruses suspended in one milliliter of fluid (less than a fluid ounce) to 10 billion viruses suspended in 300 milliliters of fluid (about the equivalent of a can of soda).

The participants, all with recurrent or persistent metastatic ovarian cancer that had not responded to other treatment, were admitted to Vanderbilt's Clinical Research Center for the study.

Each patient received daily infusions of vector through an abdominal catheter for four consecutive days and was evaluated a month later to determine whether her disease had progressed.

If there was no progression, she could be treated again at four-week intervals. Three patients were treated at each dose level before the next dose level was evaluated. Some individual patients received as many as three cycles of treatments.

Researchers could evaluate much larger doses than other gene therapy trials because the study was conducted inside the abdominal cavity, where there is room to deliver more vector. The vector was also followed with more than a liter of saline, which helped distribute the dose through the cavity.

Ovarian cancer tends to spread like the seeds of a dandelion, with malignant cells shedding from the free-floating ovaries and landing anywhere in the abdominal cavity, Tait said.

"Patients can have literally hundreds of seedlike tumors where these tumor cells have landed throughout the cavity," he said. "That's where we've seen some reduction in tumors. It makes sense because we can more completely bathe the small tumors in the virus. It's much harder to penetrate the mass of a larger tumor."

From the Phase 1 trial, the researchers have been able to determine a potentially effective dose, Tait said.

"This will be the first efficacy trial of BRCA1 gene therapy in ovarian cancer. Very few gene therapy trials have moved into Phase 2, where you begin to test whether it really works in people."

The Phase 2 trial will be conducted in about 40 women with early recurrent disease who have previously completed standard front-line chemotherapy. They must have small tumors less than three centimeters in diameter.

The patients will be evaluated surgically with laparoscopy to determine the size of their tumors before they receive six injections of the BRCA1-carrying virus. They will then be examined again to determine whether the tumors' size has changed.

"With typical ovarian cancer treatment, you may win the battle but you often don't win the war because you can't get rid of these tiny tumors, which then grow back," Holt said. "If gene therapy ultimately works to stop these little tumors, that would be really important because it's what's missing now. We are pretty good at shrinking tumors to a certain point, but we often can't go beyond that."

Other VCC co-investigators in the Phase 1 trial were Patrice S. Obermiller, manager of VCC's Gene Therapy Core Laboratory; Sheryl Redlin-Frazier, clinical research specialist in Obstetrics-Gynecology; Dr. Roy A. Jensen, associate professor of Pathology; and Dr. David H. Johnson, Cornelius Abernathy Craig Professor of Oncology and director of clinical programs for the Vanderbilt Cancer Center. The UW researchers are Dr. Mary-Claire King, Piri Welcsh, and Jamie Dann.

The research was supported by the Vanderbilt Clinical Research Center, the National Institutes of Health, the Frances Williams Preston Laboratories of the T.J. Martell Foundation, the Susan G. Komen Foundation, the Ingram Charitable Fund, the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation, and the American Cancer Society.

Vanderbilt University Medical Center

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