The virus enters into the brain without the immune system even recognizing it. That's because the genetically engineered bug doesn't normally infect humans. But when rapidly dividing cells — such as cancer cells associated with brain tumors — are present, the virus known as Toca 511 starts churning out an enzyme that is a precursor to the battle to come and an advance that could transform how aggressive brain tumors are treated.
"I was looking to attack a very difficult clinical problem, and there are few diseases that have been as difficult as malignant brain tumors," explains Dr. Michael Vogelbaum, a neurosurgeon in the Cleveland Clinic's Burkhardt Brain Tumor and Neuro-Oncology Center since 1999. "This is the perfect match of my research and clinical interests."
Vogelbaum is currently participating in the first in-human trial to treat gliobastoma — a malignant and aggressive brain tumor — by way of gene therapy conducted in collaboration with the California-based biopharmaceutical firm Tocagen. Previous lab tests yielded positive results in mice, with the therapy resulting in tumor shrinkage and improved survival rates. In the past, researchers tried to engineer treatments that would be delivered via cold or herpes viruses, but they proved ineffective so far.
"We have been trying gene therapy for brain tumors for a couple of decades," Vogelbaum says. "The point of introducing a gene is to create a virus that will only replicate in tumor cells."
Such an approach is necessary because standard chemotherapy treatments aren't successful against brain cancer because of the network of capillaries that supply blood to the brain and prevent toxic substances, including chemotherapy drugs, from entering.
Cleveland Clinic brain tumor physicians saw more than 800 new brain tumor patients in 2012. Of those patients, approximately 40 percent of the tumors were malignant.
The gene therapy Vogelbaum is working on bypasses the barrier with an injection of the Toca 511 virus that delivers a therapeutic gene directly into the tumor, causing infected cells to produce an enzyme. Approximately four weeks after the virus has been allowed to spread, patients receive the oral drug Toca 5FC. The enzymes that have spread throughout the tumor cells covert Toca 5FC into a chemotherapylike drug. The newly created drug attacks the rapidly multiplying cancer cells, killing them and stopping their growth. One of the greatest benefits of the treatment is that the process doesn't affect the patient's normal brain cells. In addition, the grueling side effects normally associated with chemotherapy drugs aren't present.
"What we are doing is introducing a gene into tumor cells which converts a nontoxic molecule into a toxic molecule," says Vogelbaum. "In the past it has not been easy to get a virus to spread because of the body's immune system. What we're doing now is turning these tumor cells into virus factories."
The Toca 511 treatments are unique in that the virus produced is not endemic in humans and is not recognized by the
immune system, which would normally fight it. As a consequence, the engineered virus is able to spread freely through the tumor cells.
The trial initially began two years ago at the Cleveland Clinic, UCLA and the University of California at San Francisco and has now spread to other treatment centers throughout the country.
Vogelbaum says this revolutionary approach to the treatment of primary and metastatic brain tumors is an important advance in combating one of the most deadly types of cancer, which has a typical survival rate of just one to two years and claims more than 20,000 lives annually.
"This is experimental and a lot of our initial experience has been focused on safety and looking for evidence it's working," he says. "It's still very early but the results are encouraging."