DURHAM, N.C. -- A cancer vaccine developed by Duke University Comprehensive
Cancer Center researchers is showing promise in mice of treating brain tumors
that had been thought "off limits" for the immune system.
The study, published in the Sept. 17 issue of the Proceedings of the National Academy of Science, shows that the immune system can combat brain tumors, and it appears to do so by a different mechanism than in the rest of the body. The researchers say the finding has important implications for designing future immunological strategies to combat brain cancer. The study was funded by the National Institutes of Health, the American Association of Neurological Surgeons and the American Brain Tumor Association.
"The finding shows that we can induce a successful immune response against brain tumors and that we can apparently cure pre-existing tumors in some of our animals," said Dr. John Sampson, first author of the study. "We believe it shows promise for using cancer vaccines to cure brain tumors in people."
The researchers said human clinical trials could begin in about a year.
Unlike conventional vaccines that prevent disease, cancer vaccines are actually a type of therapy, said Sampson, a neurosurgical resident. They are designed to stimulate the body's own natural defenses to seek out and destroy tumor cells.
Over the past several years, researchers at Duke and other institutions have developed cancer vaccines consisting of tumor cells with genes inserted in them to make them produce substances called cytokines, which are known to stimulate the growth and development of the body's T cells -- immune system cells that identify and destroy foreign or abnormal tissue. The hope is that when the cytokine-stimulated T cells encounter tumor cells, they will treat the tumor cells as "foreign" and destroy them, Sampson said.
The researchers studied a type of skin cancer called melanoma that can spread to the brain and form tumors there.
The need for better treatment for malignant melanoma is urgent, Sampson said, because the incidence of melanoma in the United States is increasing at a faster rate than that of any other cancer. It is estimated that one in 75 white Americans born in the year 2000 will develop malignant melanoma.
When still localized to the primary site where they initially develop, most melanomas can be cured by surgical removal of the skin lesion. The five-year survival of patients with localized disease is about 85 percent. But if the disease spreads to the brain, the prognosis for long-term survival is poor. The five-year survival rate for patients with metastatic disease is 5 percent.
Sampson, Dr. Darell Bigner, Jones Cancer Research Professor of Pathology and Cancer Center investigator, and the Duke team designed six vaccines that each produced a different cytokine. The team wanted to determine which one, if any, would selectively activate the immune system to kill tumors. To make the vaccines, Sampson and his colleagues added a gene to cancer cells grown in the laboratory. The gene causes the cells to produce the cytokine. Then the researchers irradiated the cells to prevent them from growing further and injected them back into the mice.
"Our study had two key findings," Sampson said. "First, we showed that GM-CSF, or granulocyte-macrophage colony stimulating factor, was the most powerful immunostimulant of the six molecules tested."
In the mouse model, GM-CSF boosted the immune system to reject tumor cells subsequently implanted in the mice. Eight of the 23 mice vaccinated with the GM-CSF vaccine survived for more than 100 days, and showed no sign of cancer cells. But more importantly, the researchers showed vaccination with GM-CSF-producing cells could destroy small, pre-established tumors. Fifteen percent of mice with pre-established tumors appeared cured. Comparatively, the mortality rate for people with melanoma that has spread to the brain is virtually 100 percent.
"We are beginning to amass evidence that the findings will also hold true for tumors that originate in the brain," said Sampson.
The finding confirms previous cancer vaccine studies, in which GM-CSF has been shown to produce a potent, long-lasting, and specific anti-tumor immunity in other parts of the body, Sampson said. In the Duke study, the cytokines IL-3 and IL-6 had a modest effect. IL-4 and gamma interferon had no effect. The research team also showed that a cytokine called IL-2 actually caused the animals to die sooner than expected.
The second major finding is that the anti-tumor activity is dependent on CD8+ or "killer" T cells, but not CD4+, or "helper" T cells, which had been shown necessary in other vaccine trials outside the brain. "This study suggests that the immune response to tumors in the brain may be different from other areas of the body," he said.
The researchers say a vaccine strategy that employs GM-CSF, combined with other strategies designed to inhibit transforming growth factor beta (TGF-B), might provide a potent double hit on aggressive brain tumors. TGF-B is produced by some brain tumors, and helps to hide them from the immune system.
"If TGF-B is knocked out and then a cancer vaccine that provides GM-CSF is administered, it might provide enough ammunition to knock out these tumors," Sampson said.
Drs. David Ashley, Herbert Fuch, Laura Hale, and Gerald Archer from Duke and Dr. Glenn Dranoff from Dana-Farber Cancer Institute, Boston, also contributed to the research.