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Novel suicide gene therapy combined with standard treatment is safe to treat malignant brain tumors

Houston, TX - 8/18/2011

A form of gene therapy is safe for treating one of the deadliest types of brain cancer, according to research to be published in an upcoming issue of the Journal of Clinical Oncology.

Only two locations in the nation, including the Methodist Neurological Institute in Houston, conducted the phase 1b trial. Physicians and researchers at Methodist and The Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, studied the use of a novel combination of radiation and suicide gene therapy to treat typically stubborn malignant brain tumors. Suicide gene therapy recognizes cancer cells and specifically introduces genetic material to make those cells die by a process called apoptosis, or programmed cell death.

"In addition to improved overall survival of 25 percent at three years, research showed the therapy may stimulate an immune response against the malignant gliomas, which are the most common form of brain tumor," said Dr. Pamela New, a neuro-oncologist and the principal investigator on this study at Methodist. "This significant rise in the number of T-lymphocytes in the tumors suggests that the gene therapy stimulated an immune response against the tumor, producing an immunogene therapy effect."

In the study, the common cold virus was used as a "cargo ship" to carry the herpes virus gene into the tumor. During surgery, a neurosurgeon would inject this gene agent, known as AdV-tk, into the edges of the cavity where the brain tumor was removed. Following the procedure, study patients were given the drug Valtrex orally, which is the medication used to attack the herpes virus gene, and is often used to treat common cold sores, which are a form of a herpes infection.

"When the drug killed the herpes, it also attacked the cancer cells, making them self-destruct," said Dr. David S. Baskin, a Methodist NI neurosurgeon specializing in brain and spine tumor surgery and who was involved in the study. "This particular therapy is exciting because it not only kills cancer cells that are directly infected with the herpes gene, but it also produces an immune response causing cells that are not infected with the herpes gene to die. Cells died beyond the margin of the injection because of this vaccine-like effect. Patients with glioblastoma multiforme typically survive 15 months after diagnosis. Several of our study patients are now alive three to four years after treatment and living a good life."

Malignant gliomas account for more than half of the more than 18,000 primary malignant brain tumors diagnosed annually in the United States. These tumors are the second-most common cause of cancer death in the 15 to 44 age group, and are unique in their ability to grow uncontrollably and aggressively invade and destroy neighboring areas of the brain.

Cancer immunogene therapy refers to genetically manipulating cancer cells to stimulate an immune response against a tumor. This differs from "immunotherapy," which attempts to stimulate the immune system directly against tumor cells.

The combination of radiation and gene therapy is already a treatment option for eradicating localized prostate cancer. Methodist is also studying gene therapy in other cancer sites including pancreas. In addition, several other novel treatments for brain cancer are in development at the Methodist NI involving the use of nanotechnology and precise targeting of molecules inside the cancer cells.

Funding from the National Cancer Institute and Advantagene, Inc. supported this gene therapy research.

Other Methodist Neurological Institute researchers involved in this study were Robert G. Grossman, M.D., chairman of neurosurgery and Todd W. Trask, M.D. Participants from Ohio State University included Dr. E. Antonio Chiocca, professor and chair of neurological surgery; Susan D. Bell; Balveen Kaur, Ph.D.; Jayson Hardcastle; Robert Cavaliere, M.D.; John McGregor, M.D.; Simon Lo, M.D.; Abhik Ray Chaudhuri, M.D.; Arnab Chakarvarti, M.D.; John Grecula, M.D.; and Herbert Newton, M.D. Advantagene's researchers included Laura K. Aguilar, Carissa M. Monterroso, Andrea G. Manzanera, and Estuardo Aguilar-Cordova.

About the study

After tumor removal, the neurosurgeon injects the tumor bed with 1 milliliter (1/30th oz) of a solution containing the AdV-tk vector. The vector carries a gene from the herpes simplex virus for an enzyme called thymidine kinase (the '-tk' in AdV-tk). Cancer cells infected with the vector begin making the enzyme.

Patients take the anti-herpes virus drug valacyclovir for two weeks. During this timeframe, the herpes thymidine kinase enzyme converts valacyclovir into DNA building blocks that the cancer cells cannot use to make DNA, and this kills them.

Radiation therapy begins halfway through the course of valacyclovir. The radiation damages the DNA in the cancer cells, which then try to repair it, using the toxic valacyclovir building blocks.

For more on the Methodist Neurological Institute, visit our website or call 713-790-3333.

 

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