Targeted For Destruction
By Christine Deriso
Note: This article first appeared in the Summer 1997 issue of GHSU Today Magazine.
A virus' ability to infect a cell has doctors at the Georgia Health Sciences University
using a genetically engineered virus to target deadly brai
n tumor cells for destruction.
"We are investigating the potential for a whole new way of delivering medication that makes use of gene transfer technology to selectively target tumor cells for destruction," said Dr. James Fick, GHSU neurosurgeon and researcher specializing in brain tumors.
In the brain, more than any other organ, location can limit conventional treatment of tumors because different areas of the brain have different functions, Dr. Fick said. Depending on location, a surgeon might not be able remove the tumor without creating major deficits such as loss of sight, movement or speech. Clinicians also are limited in the amount of radiation they can give without injuring the brain or chemotherapy they can administer without producing harmful side effects.
GHSU is one of 40 centers worldwide investigating a new approach to treating newly diagnosed glioblastoma multiforme, the most malignant tumor that arises from glial cells that support neurons in the brain.
For some unknown reason these glial cells, found throughout the brain and the spinal cord, sometimes go awry. "Think of them as cells with unregulated growth that begin to replicate quickly and as they do so, they spread and invade into the surrounding brain," Dr. Fick said.
The result is a rapidly growing, durable tumor that often rebounds from the conventional therapies of surgery, radiation and chemotherapy; the median survival is 50 weeks and victims tend to be in their 40s and 50s. Even when surgery is considered successful and the patient does well afterward, most of these tumors recur near their original location, Dr. Fick said.
"A complete removal of this tumor can result in an excellent postoperative brain scan, yet the tumor has a propensity to recur within two inches of where it was originally located," Dr. Fick said. "In these cases, we fail because we cannot control the local growth of tumor."
In the study, GHSU is helping investigate whether a virus capable of seeking rapidly dividing brain tumor cells and rendering them susceptible to an antiviral drug can improve quality of life for these patients and prolong their survival by preventing local tumor recurrence.
A virus requires a living cell to replicate; that's how the cold virus multiplies and spreads. For this therapy, mouse skin cells are used to manufacture a genetically engineered virus that has been disabled so it cannot replicate, but it can infect tumor cells, Dr. Fick said.
A specific characteristic of this genetically engineered virus, known as a retroviral vector, is that it carries with it the thymidine kinase gene from a second virus, the herpes simplex virus. This gene can only be transferred into rapidly dividing cells where it turns an antiviral drug patients will get later--called a prodrug--into a toxin that destroys the cell.
What happens is that patients have surgery to remove the tumor, then surgeons inject 1 billion of these retroviral vectors into the surgery site. Two weeks later, when the virus has had time to carry the gene into the tumor cells, patients begin receiving the prodrug, ganciclovir, intravenously. Afterward they receive radiation therapy.
"This particular type of virus has the potential to be used to transfer genes into brain tumor cells because they are the primary cells in the brain replicating," Dr. Fick said. "It is believed that even if the virus infects all the cells, it can only transfer genes into the replicating or tumor cells." Dr. Fick said.
In the international trial, half the patients get the gene therapy and half get today's standard treatment of surgery followed by radiation therapy. However, this is a crossover trial which means if standard therapy fails, and it always does with these tumors, patients also will be eligible for gene therapy, Dr. Fick said.