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.