Possible New Treatment Strategy for Deadly Brain Tumors

In spite of advances in neurosurgery and radiation techniques, the prognosis for patients with intracranial glioma remains devastating. Now, researchers have identified a possible new treatment strategy for this common type of malignant brain tumor.

Two studies funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) show that, in a mouse model, neural stem cells (NSCs) can be used to deliver therapeutic agents capable of killing glioma cells and their migrating tumor cells.

“It’s definitely a big leap from mice to humans, but we think these studies offer patients real hope for a future treatment for glioma,” says senior author John S. Yu, M.D., co-director of the Comprehensive Brain Tumor Program at the Cedars-Sinai Maxine Dunitz Neurosurgical Institute in Los Angeles, California. The studies appear in the October 15 and December 15, 2002, issues of Cancer Research.

Gliomas are particularly difficult to treat because the tumor cells tend to migrate far from the original tumor mass, forming deposits for future tumor growth. The resulting “satellite” tumor cells tend to disperse within normal brain, making surgery and radiation therapy extremely risky and even impossible in some cases. The median survival time for the most common and severe type of glioma is 9 months to a year for both adults and children.

The first study shows that NSCs can deliver an immune system protein called interleukin 12 (IL-12) to gliomas and their migrating tumor cells. Previous studies have shown that IL-12 can stimulate an immune response against tumor cells. In this study, Dr. Yu and colleagues prepared IL-12-secreting fetal mouse NSCs and injected them into the brains of mice with advanced gliomas.

Compared with treatments of saline and NSCs alone, the NSCs producing IL-12 prolonged survival and induced long-term immunity against future tumor growth in mice, the researchers found. Tissue analyses from the study showed that the NSCs actively tracked tumor outgrowths that were deeply entangled in normal brain tissue and that the IL-12 secreted by the NSCs induced a strong T-cell immune response against tumors and tumor satellites.

About 30 percent of the treated mice survived about seven times longer than the control mice, which all died within 30 days. Treated mice that survived beyond 60 days were able to suppress new tumor growth for up to 90 days.

“These results are very encouraging,” says Dr. Yu. “But we have many challenges ahead of us before we can apply this approach to humans.” There is a vast size difference between a mouse and a human brain, and the tumor-tracking ability of NSCs may not work as well in a large area. Also, the mouse model has only one type of glioma, while human patients have a wide variety of tumor types, Dr. Yu adds.

The second study also demonstrates the tumor-tracking ability of NSCs. The researchers used genetically engineered NSCs carrying a cancer-fighting protein known as tumor necrosis factor related apoptosis-inducing ligand (TRAIL) to kill human glioma cells implanted in mice. TRAIL causes cell death in several types of cancers without killing normal cells. Within a week, the TRAIL-treated tumors decreased significantly in size, compared with controls.

Many research teams are now working to develop a reliable and plentiful source of NSCs. Dr. Yu says he believes a patient’s own bone marrow would be an ideal source, but isolating a supply of NSCs from bone marrow has proven to be difficult. “This immunologic approach is just one of many possible treatment strategies,” says Dr. Yu. “This is a relentless disease, but with so many people working on this, we’re approaching the threshold of being able to effectively treat patients who have it.”

Reference:
>Ehtesham M, Kabos P, Kabosova A, Neuman T, Black K, and Yu J. “The Use of Interleukin 12-secreting Neural Stem Cells for the Treatment of Intracranial Glioma.” Cancer Research, Vol. 62, October 15, 2002, pp. 5657-5663.

Ehtesham M, Kabos P, Kabosova A, Neuman T, Black K, and Yu J. “The Use of Interleukin 12-secreting Neural Stem Cells for the Treatment of Intracranial Glioma.” Cancer Research, Vol. 62, October 15, 2002, pp. 5657-5663.