A cancer vaccine developed by Duke University Comprehensive Cancer
Center researchers is showing promise in mice for treating brain
tumors that had been thought "off limits" for the immune
The study, published in the September 17th 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 immunologic
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
preexisting tumors in some of our animals," said Dr. John
Sampson, lead author of the study. "We believe it shows promise
for using cancer vaccines to cure brain tumors in people. "
The researchers said that 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. 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.
Vaccine Studied in Metastatic Melanoma
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 1in 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 5-year survival of patients with localized disease
is about 85%. But if the disease spreads to the brain, the prognosis
for long-term survival is poor. The 5-year survival rate for patients
with metastatic disease is 5%.
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.
Two Key Findings
"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
In the mouse model, GM-CSF boosted the immune system to reject
tumor cells subsequently implanted in the mice. Of the 23 mice
vaccinated with the GM-CSF vaccine, 8 survived for more than 100
days and showed no sign of cancer cells. But more importantly,
the researchers showed that vaccination with GM-CSF-producing
cells could destroy small, preestablished tumors. Of mice with
preestablished tumors, 15% appeared to be cured. In contrast,
the death rate for people with melanoma that has spread to the
brain is virtually 100%.
"We are beginning to amass evidence that the findings will
also hold true for tumors that originate in the brain," said
The finding confirms previous cancer vaccine studies, in which
GM-CSF has been shown to produce a potent, long-lasting, and specific
antitumor immunity in other parts of the body, Sampson said. In
the Duke study, the cytokines interleukin-3 (IL-3) and IL-6 had
a modest effect. Interleukin-4 and interferon-gamma had no effect.
The research team also showed that IL-2 actually caused the animals
to die sooner than expected.
The second major finding is that the antitumor activity is dependent
on CD8+ or "killer" T-cells, but not on 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.
A Double Hit on Aggressive Brain Tumors
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. Transforming growth factor-beta 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.