Vaccine Boosts Immune System to Kill Brain Tumor Cells

A cancer vaccine developed by Duke University Comprehensive CancerCenter researchers is showing promise in mice for treating braintumors that had been thought "off limits" for the immunesystem.

The study, published in the September 17th issue of the Proceedingsof the National Academy of Science, shows that the immunesystem can combat brain tumors, and it appears to do so by a differentmechanism than in the rest of the body. The researchers say thefinding has important implications for designing future immunologicstrategies to combat brain cancer. The study was funded by theNational Institutes of Health, the American Association of NeurologicalSurgeons, and the American Brain Tumor Association.

"The finding shows that we can induce a successful immuneresponse against brain tumors and that we can apparently curepreexisting tumors in some of our animals," said Dr. JohnSampson, lead author of the study. "We believe it shows promisefor using cancer vaccines to cure brain tumors in people. "

The researchers said that human clinical trials could begin inabout a year.

Unlike conventional vaccines that prevent disease, cancer vaccinesare actually a type of therapy, said Sampson, a neurosurgicalresident. They are designed to stimulate the body's own naturaldefenses to seek out and destroy tumor cells.

Over the past several years, researchers at Duke and other institutionshave developed cancer vaccines consisting of tumor cells withgenes inserted in them to make them produce substances calledcytokines, which are known to stimulate the growth and developmentof the body's T-cells. The hope is that when the cytokine-stimulatedT-cells encounter tumor cells, they will treat the tumor cellsas "foreign" and destroy them, Sampson said.

Vaccine Studied in Metastatic Melanoma

The researchers studied a type of skin cancer called melanomathat 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 UnitedStates is increasing at a faster rate than that of any other cancer.It is estimated that 1in 75 white Americans born in the year 2000will develop malignant melanoma.

When still localized to the primary site where they initiallydevelop, most melanomas can be cured by surgical removal of theskin lesion. The 5-year survival of patients with localized diseaseis about 85%. But if the disease spreads to the brain, the prognosisfor long-term survival is poor. The 5-year survival rate for patientswith metastatic disease is 5%.

Sampson, Dr. Darell Bigner, Jones Cancer Research Professor ofPathology and Cancer Center investigator, and the Duke team designedsix vaccines that each produced a different cytokine. The teamwanted to determine which one, if any, would selectively activatethe immune system to kill tumors. To make the vaccines, Sampsonand his colleagues added a gene to cancer cells grown in the laboratory.The gene causes the cells to produce the cytokine. Then the researchersirradiated the cells to prevent them from growing further andinjected 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 stimulatingfactor, was the most powerful immunostimulant of the six moleculestested."

In the mouse model, GM-CSF boosted the immune system to rejecttumor cells subsequently implanted in the mice. Of the 23 micevaccinated with the GM-CSF vaccine, 8 survived for more than 100days and showed no sign of cancer cells. But more importantly,the researchers showed that vaccination with GM-CSF-producingcells could destroy small, preestablished tumors. Of mice withpreestablished tumors, 15% appeared to be cured. In contrast,the death rate for people with melanoma that has spread to thebrain is virtually 100%.

"We are beginning to amass evidence that the findings willalso hold true for tumors that originate in the brain," saidSampson.

The finding confirms previous cancer vaccine studies, in whichGM-CSF has been shown to produce a potent, long-lasting, and specificantitumor immunity in other parts of the body, Sampson said. Inthe Duke study, the cytokines interleukin-3 (IL-3) and IL-6 hada modest effect. Interleukin-4 and interferon-gamma had no effect.The research team also showed that IL-2 actually caused the animalsto die sooner than expected.

The second major finding is that the antitumor activity is dependenton CD8+ or "killer" T-cells, but not on CD4+, or "helper"T-cells, which had been shown necessary in other vaccine trialsoutside the brain. "This study suggests that the immune responseto tumors in the brain may be different from other areas of thebody," he said.

A Double Hit on Aggressive Brain Tumors

The researchers say a vaccine strategy that employs GM-CSF, combinedwith other strategies designed to inhibit transforming growthfactor-beta (TGF-B) might provide a potent double hit on aggressivebrain tumors. Transforming growth factor-beta is produced by somebrain tumors, and helps to hide them from the immune system.

"If TGF-B is knocked out and then a cancer vaccine that providesGM-CSF is administered, it might provide enough ammunition toknock out these tumors," Sampson said.

Drs. David Ashley, Herbert Fuch, Laura Hale, and Gerald Archerfrom Duke and Dr. Glenn Dranoff from Dana-Farber Cancer Institute,Boston, also contributed to the research.