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Potential Treatment Breakthrough for Advanced Brain Cancer

  Potential Treatment Breakthrough for Advanced Brain Cancer
 

The Toca 511 virus selectively infects and spreads throughout brain-cancer cells and not healthy cells. Cancer cells infected with Toca 511 and programmed to produce an anticancer drug are pictured in brown (human tissue).
Image: Courtesy of Dr. Timothy Cloughesy

Doctors at UCLA and other institutions have achieved a milestone in the treatment for people with recurrent brain cancers. The development includes the treatment of glioblastoma, the most common and aggressive form of brain cancer, by successfully demonstrating that a modified virus can extend the lives of patients with this deadly disease.

If a glioblastoma tumor recurs following chemotherapy and radiation, there are few treatment options left, and patients have only months to live. In a phase I multicenter clinical trial, researchers found that, of the 43 participants who were given the investigational treatment Toca 511 and Toca FC, overall survival increased to 13.6 months compared to 7.1 months for an external control. For some patients, survival was extended to more than two years, with few side effects.

The findings were led by Timothy Cloughesy, MD (FEL ’92), a member of the UCLA Jonsson Comprehensive Cancer Center and director of the UCLA Neuro-Oncology Program, and Michael A. Vogelbaum, MD, PhD, professor of neurosurgery and associate director of the brain tumor neuro-oncology center at the Cleveland Clinic. Their work is the first publication of clinical data involving this new type of modified virus known as a retroviral replicating vector (RRV).

RRVs can deliver a therapeutic gene with a specific function to a cancer cell and insert it, thereby enabling cell killing. The use of RRVs holds promise in the development of innovative new therapies for many types of cancer, including brain cancers. “For the first time, these clinical data show that this treatment, used in combination with an antifungal drug, kills cancer cells and appears to activate the immune system against them while sparing healthy cells,” Dr. Cloughesy says.

During the first step of treatment, the patient is given an injection of Toca 511, which is a modified virus that selectively infects actively dividing cancer cells and delivers a gene for an enzyme called cytosine deaminase (CD) to the cancer cells. As it spreads through the tumor, Toca 511 programs the cancer cells to make CD. Next, the patient is prescribed oral cycles of Toca FC, an antifungal drug, for seven days, every four-to-eight weeks.

The genetic changes created by Toca 511 allow infected cancer cells to convert Toca FC into the U.S. Food and Drug Administration-approved anticancer drug 5-fluorouracil (5-FU). As a result, infected cancer cells and cells that help tumors hide from the immune system are selectively killed, subsequently activating the immune system to recognize and kill cancer cells, while leaving healthy cells unharmed.

An estimated 40 percent of study participants who received higher doses of the combo treatment during the phase I clinical trial were still living after two years. The researchers also noted that some study participants had partial or complete shrinkage of their tumor, which has lasted for a year or longer, and are still doing well. Additionally, Toca 511 & Toca FC demonstrated a favorable safety and tolerability profile. Based on the new clinical findings, the research has moved into a phase 2/3 international clinical trial, called Toca 5, for patients with recurrent glioblastoma or anaplastic astrocytoma.

“Phase 1 Trial of Vocimagene Amiretrorepvec and 5-fluorocytosine for Recurrent High-grade Glioma,” Science Translational Medicine, June 1, 2016

 





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