The U.S. Food and Drug Administration has allowed City of Hope researchers to conduct the first-in-human study of a neural stem cell-based therapy targeting recurrent high-grade glioma, the most aggressive type of brain tumors.

Karen S. Aboody, M.D., associate professor in City of Hope’s Department of Neurosciences and Division of Neurosurgery, leads the research team that developed the treatment strategy. Jana Portnow, M.D., assistant professor and assistant director of the Brain Tumor Program at City of Hope, is principal investigator for the clinical trial.

Karen Aboody (Photo by Markie Ramirez)

Each year, about 22,500 Americans are diagnosed with malignant primary brain tumors and more than 12,900 die from the disease. While survival rates vary with the type of brain tumor, median survival for glioblastoma, the most common type of glioma in adults, is only about 15 months.

These tumors are highly invasive and resistant to surgery, radiation and chemotherapy. One significant obstacle to curing brain tumors is the blood-brain barrier, which can prevent chemotherapy agents from entering the brain and reaching effective concentrations at tumor sites.

In 2000, Aboody and her colleagues were the first to demonstrate neural stem cells’ tendency to home in on invasive tumor cells, a characteristic known as tropism. Neural stem cells can even migrate toward tumors from the opposite side of the brain — or through the blood-brain barrier if delivered intravenously. Aboody’s research team has since harnessed the tumor-tropism of neural stem cells to deliver therapeutic agents to tumors and showed the technique’s effectiveness in laboratory testing.

The investigational therapy in the clinical trial uses a genetically modified human neural stem cell line generated by Seung U. Kim, M.D., Ph.D., professor in the Division of Neurology at the University of British Columbia, to deliver an enzyme called cytosine deaminase to brain tumor sites. Physicians then treat patients with 5-fluorocytosine, a relatively nontoxic “prodrug.” Cytosine deaminase then converts the prodrug to an active cancer-fighting drug (5-fluorouracil).

The strategy allows for activation of the anticancer drug only in the area of the tumor, minimizing exposure of surrounding healthy tissue.

“This novel tumor-selective treatment has the potential to overcome many obstacles that limit the success of currently available treatments for malignant brain tumors and other invasive cancers,” said Aboody. “Using neural stem cells as delivery vehicles for therapy may allow us to target concentrated therapeutics specifically to tumor sites while reducing the undesirable side effects of current chemotherapy regimens, including toxicity to normally dividing bone marrow, gastrointestinal tract, skin and hair cells.”

The pilot feasibility study, which is supported by a grant from the National Cancer Institute, will assess a range of neural stem cell doses to determine the starting dose to be used in future studies of the new treatment strategy.