Duke Medical Center to Begin Breast Cancer Gene Therapy Trials
DURHAM, N.C. -- A group of 20 women with incurable breast cancer soon will be treated with gene therapy at Duke University Medical Center. The experiment is not expected to save the lives of these pioneering patients but may prove crucial in helping future generations of women for whom all other therapy has failed, Duke researchers say.
The trial is the first of its kind supported scientifically and financially by the National Cancer Institute (NCI). Federal approval for the trial was received last year by the National Institutes of Health and in late October by the Food and Drug Administration.
The effort to develop a new therapy for breast cancer signals the launch of a spate of gene therapy trials at Duke, including ones for ovarian and prostate cancer, and AIDS. Several of those trials have received the blessing of the National Institutes of Health, and are awaiting FDA approval.
The difference between Duke's breast cancer gene therapy trial and several others underway across the country is two-fold, according to team leader, Dr. Kim Lyerly. One is that Duke's novel strategy has already stopped tumor progression in animals with cancer. Secondly, the researchers' method of modifying human cancer cells has been optimized in the test tube and the strong results have already been published, Lyerly said.
"Some gene therapy trials were started with little evidence that the tumor cells were indeed gene modified, and others began without extensive optimization of conditions," he said in an interview. "We have worked our conditions over and over again until we felt certain that it was possible to produce gene modified human tumor cells capable of eliciting the good responses we've seen in animal experiments."
Lyerly said this slow and careful approach won the approval of the NCI. "As was shown recently in several early gene therapy approaches that did not demonstrate benefit or little active gene delivery, the field may have suffered because a few were pursuing gene therapy before the groundwork was established and the trials justified," he said. "We undertook a methodical and systematic approach that focused on effective gene delivery."
Lyerly co-directs the Molecular Therapeutics Program, along with molecular biologist Dr. Eli Gilboa. Key members on the breast cancer trial include Drs. Kathleen Havlin, George Leight and Dirk Iglehart.
Dr. Michael Colvin, director of the Comprehensive Cancer Center, said he sees Duke's emerging gene therapy program as a promising new avenue to treat intractable cancer. "These scientists are using techniques no one put together before," Colvin said. "While we know that effective gene therapy is a distant goal, given all that we don't yet understand about how best to use it, the center can't help but be excited about the start of this ambitious program."
Duke's experimental therapy is designed to prevent metastasis, or spreading, of breast cancer tumors by bolstering the body's natural immune response to the cancer. Current therapeutic strategies, such as chemotherapy or hormonal therapy, reduce the risk of metastasis in only a fraction of women with breast cancer. As a result, more than 40,000 women die each year from tumor cells that have moved beyond breast tissue.
If successful, the therapy may have two roles for women with breast cancer, Lyerly said. It may be given to women with early stage breast cancer immediately after surgical removal of the primary tumor to prevent recurrences. The therapy could also be given to women with advanced disease in combination with conventional forms of therapy. The team will remove cancer cells from a woman and alter the genetic material within the cells by adding additional genes. Then they will inject the re-engineered cells back into her body. The new genes direct the cells to secrete a substance called interleukin-2 (IL-2), one of the body's natural immune system boosters. IL-2 causes the immune system to expand populations of "killer" immune cells known as T lymphocytes that will attack the tumor. Many therapeutic protocols have tested IL-2 delivered to the whole body to alert and alarm the immune system, but the Duke protocol stimulates the production of IL-2 that will specifically target the tumor. This different approach may eliminate side effects that have been associated with other interleukin protocols, Lyerly said. In addition, the Duke therapy does not use deactivated virus "vectors" to deliver the genes, which most other gene therapy trials have used, and from which many difficulties have arisen. Instead, Duke's system uses liposomes, hollow spheres of fat, to transfer genes across cell membranes and into the cell's nucleus. The modified genes are contained within the sphere, and cells readily take in such liposome molecules to maintain their membranes. This liposome technology is regarded as a promising wave in gene therapy, according to Lyerly. Collaborating with Duke in the application of this technique to breast cancer is Applied Immune Sciences of Santa Clara, Calif.