Unsatisfied with today's therapies, brain tumor scientists make new ones
June 8, 2015 | by David Levine
Clinicians and surgeons at City of Hope aren’t satisfied with current treatments for brain tumors, nor are they satisfied with focusing on only one avenue of research. Instead, they’re exploring many potential – and promising – options to help people with cancer in the brain.survival rates for malignant gliomas, the type of brain tumor that is the focus of research at City of Hope, is poor," said Behnam Badie, M.D., chief of neurosurgery and director of the Brain Tumor Program at City of Hope. In fact, the five-year survival rate for people age 45 to 64 is 6 percent; it's 4 percent for those age 55 to 64.
Glioblastoma is the most common type of primary brain tumor in adults (with “primary” meaning that it originated in the brain) and the most aggressive. Surgery is the treatment of choice, because radiation has its limits, and most chemotherapy drugs can't cross the blood-brain barrier. But surgery is not a perfect option. Removing all the tumor cells is virtually impossible due to the invasive nature of glioblastoma, and tumor recurrence is the norm. Most people live only 1.5 years after diagnosis.
Badie hopes that those numbers won’t be always be so grim. Here, he provides an overview of some of City of Hope’s most promising new treatments for brain tumors.
Creating chemotherapy at the tumor site
City of Hope is the first research institution in the world to directly administer neural stem cells into the brains of patients with recurrent glioblastoma. "The cells have been modified to carry a protein that converts a prodrug to an active chemotherapy agent at tumor sites in the brain," Badie said.
Here’s how the procedure works: During surgery, modified neural stem cells are injected into the tumor. The cells carry an enzyme that converts a safe antibiotic (specifically, Toca FC) into a toxic drug (specifically, 5-FU).
Then, Toca FC is given orally every few weeks, killing the tumor cells that have enough copies of the enzyme to convert the drug to 5-FU. The surgeon leaves a catheter tube in place so repeated injections can be given until the entire tumor is gone.
Already, Badie and his colleagues Karen Aboody, M.D., professor in the Department of Neurosciences and Division of Neurosurgery, and Jana Portnow, M.D., associate director of the Brain Tumor Program, have treated nine patients with this approach. They've also published a proof-of-concept paper demonstrating that neural stem cells produced chemotherapy locally at the sites of tumor in the brain while minimizing systemic toxicities.
CAR-T cell therapy could outwit brain tumors
"Tumors are very smart," Badie said. "We have to be smarter in order to outwit them." One way is through the use of immunotherapy – that is, using a patient’s own immune cells to recognize and attack tumors.
Many researchers at City of Hope are focused on a type of immunotherapy that uses chimeric antigen receptor-enhanced T-cells, or CAR-T. CAR-T uses engineered T cells, one type of immune system cell, that have on their surface a highly specific protein that recognizes another specific protein (antigen) on tumor cells. Shortly after injection into the tumors, and under the guidance of their engineered receptors, the CAR-T cells recognize and kill the cancer cells that have the antigen on their surfaces.
Already, CAR-T cells with specificity for the CD19 gene have shown promise in the treatment of chronic lymphocytic leukemia. Also, because between 30 to 40 percent of all brain tumors express the interleukin 13 gene (IL 13), CAR-T cells with specificity for IL 13 might show similar promise in treating brain tumors.
Badie and his colleague Christine Brown, Ph.D., plan to soon conduct a phase I trial to study the effects of CAR-T therapy against Stage 3 or Stage 4 malignant glioma.
How to build a better drug delivery system
"The human brain is a very confined space," Badie said. "The amount of space that you can inject medication into is limited." Although a breakthrough in device technology could be as important as the discovery of a new drug, it’s of little use if physicians can't deliver a drug in enough quantity to treat a tumor.
City of Hope researchers are looking into the use of nanoparticles that can bypass the challenges of the blood-brain barrier, and activate the immune system to attack tumor cells in the brain.
Jacob Berlin, Ph.D., assistant professor, Department of Molecular Medicine, is working with Badie to to enhance the immune system’s response to malignant gliomas and generate a more universal response to multiple tumor antigens. That work uses nanotubes, small structures that resemble a bacteria or virus in size, whose structure mimics those of invasive microorganisms.
The nanotubes contain CpG, small snippets of DNA molecules that, once safely transmitted across the blood-brain barrier, can stimulate a localized immune response. Badie has shown that the delivery of cancer drugs via nanotubes enhanced the activity of CpG, and eradicated GL261 gliomas in more than half of tumor-bearing mice.
Berlin is also working with Aboody to improve drug delivery to tumors by using nanoparticle-bearing neural stem cells that will release chemotherapy drugs at tumor interiors or be stimulated to use heat to destroy localized cancerous tissue.
As this and the other research avenues suggest, clinicians in the future will have more treatment options for glioma patients than they have today.
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