Early Trial Finds Ingenious Brain Tumour Therapy Safe and Effective
A new gene therapy treatment for high-grade gliomas — the most aggressive brain tumours — has been found to be safe and to improve patient survival.
The Phase I dose-escalation trial was conducted at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and multiple other sites and published in the journal, Science Translational Medicine.
“Overall, 29% 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%. 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 tumour cell DNA as it spreads through the tumour, 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 tumour cells expressing cytosine deaminase, it is converted into the potent, FDAapproved chemotherapeutic 5-fluorouracil (5-FU), which kills the infected tumour 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 % at 1 year and 29.1 % at 2 years, compared with 26.4 % and 9.1 % 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 %.
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.
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 given, the better the survival results were. That’s a promising sign because it indicates there’s a real treatment effect.
Source: Health Canal