Ingenious Brain Tumor Therapy Found Safe and Effective in Early Trial

A Phase I dose-escalation trial, conducted at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and multiple sites nationwide, has shown that a new gene therapy treatment for high-grade gliomas — the most aggressive brain tumors — is safe and improves patient survival. Having passed this milestone, the treatment will move on to more advanced trials. The research was published in the journal Science Translational Medicine.

“Overall, 29 percent of our patients were still alive after two years,” said Noriyuki Kasahara, M.D., Ph.D., a gene therapy expert at Sylvester and professor of cell biology and pathology at the Miller School of Medicine, who originated the therapy in his lab. “If you take the higher dose cohorts, the number rises to 40 percent. Almost half of our patients are living more than two years with a disease that normally causes people to die after around seven months.”

The treatment, which has been licensed by San Diego-based biotech Tocagen, uses the engineered virus vocimagene amiretrorepvec (Toca 511) to selectively infect cancer cells with a gene for the yeast enzyme cytosine deaminase. Because Toca 511 is a retrovirus, a type of virus that embeds its genetic payload in tumor cell DNA as it spreads through the tumor, the trait is passed on to daughter cells.

After the virus has taken hold, patients are given 5-fluorocytosine (Toca FC), an FDA-approved anti-fungal treatment, which readily crosses the blood-brain barrier. As Toca FC encounters tumor cells expressing cytosine deaminase, it is converted into the potent, FDA-approved chemotherapeutic 5-fluorouracil (5-FU), which kills the infected tumor cells from within.

“We are outfitting a virus with a suicide gene,” said Kasahara, a Sylvester member. “It forces cancer cells to make an enzyme that converts a non-toxic compound into an active cancer drug, generating that drug right inside the cancer cell itself.”

Because any remaining tumor cells are still infected with the Toca 511 virus embedded in their DNA, patients can receive additional doses of 5-FC to continue fighting their cancer.

In the trial, which studied 43 patients with recurrent brain cancer, 82.2 percent of subjects had glioblastoma, the most aggressive form of the disease. Median survival was 13.6 months, compared with 7.1 months in an external control group treated with chemotherapy. Patients with glioblastoma had an overall survival of 54.8 percent at 1 year and 29.1 percent at 2 years, compared with 26.4 percent and 9.1 percent in the control group. The median survival for patients receiving higher doses of Toca 511 was 14.4 months, and the 2-year survival rate was 40 percent.

The treatment was extremely well tolerated, with few major side effects. Most of these were relatively mild, grade 1 or 2. There were two grade 3 events, one of which was unrelated to treatment.

“We’re not seeing any of these side effects because we’re not giving the drug itself, we’re giving the precursor compound,” said Kasahara. “And that doesn’t do anything until it hits the tumor cells, which transform it into the drug.”

In addition to killing tumor cells, the therapy also unleashes the immune system. Because the chemotherapy drug generated by the “suicide” gene is localized to the tumor itself, it does not destroy immune cell-producing bone marrow like standard chemotherapy does. But even more important, 5-FU destroys bystander cells called myeloid-derived suppressor cells (MDSCs), which help tumors escape the immune system. In addition, the remnants of dead cancer cells and virus fragments attract more immune attention, triggering an anti-tumor rejection response. Basically, “suicide” gene therapy with this tumor-infiltrating retrovirus also acts as immunotherapy.

As effective as the treatment was, it’s possible that researchers have not yet seen its therapeutic ceiling, as no maximum-tolerated dose was reached in the trial.

“The more virus we gave, the better the survival results,” said Kasahara. “That’s a promising sign because it indicates there’s a real treatment effect.”

Based on these encouraging results, Sylvester neuro-oncologists Deborah Heros, M.D., and Macarena de la Fuente, M.D., along with neurosurgeons Ricardo Komotar, M.D., and Michael Ivan, M.D., all Sylvester members, have just launched an advanced trial using this gene therapy strategy to treat patients with recurrent high-grade glioma.

“This is a highly collaborative effort,” said Kasahara. “It is a platform technology that has the potential to be widely applicable to several types of cancer.”

In fact, two additional Sylvester oncologist-members will be exploring other therapeutic applications for the virus. Jaime Merchan, M.D., will be the first in the nation to begin another early-stage clinical trial using the virus in metastatic renal, colorectal, pancreatic, lung, and breast cancer and melanoma, and Brian Slomovitz, M.D., is conducting translational studies to validate the use of the virus in ovarian cancer.

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