“A uniformly dismal prognosis.” That’s how Children’s of Alabama neurosurgeon James M. Johnston, Jr., M.D., describes what children with recurrent malignant brain tumors face, with an average lifespan of six months given a lack of effective treatments.
Now Johnston, in collaboration with Greg Friedman, M.D., associate professor of pediatric oncology and director of Developmental Therapeutics at Children’s, is leading groundbreaking studies designed to shift that trajectory. The team recently completed a Phase 1 immunotherapy clinical trial of genetically re-engineered herpes virus G207 to treat pediatric high-grade gliomas. Their work builds on adult research on the viral treatment pioneered by James Markert, M.D., MPH, who chairs the Department of Neurosurgery at the University of Alabama at Birmingham (UAB), as well as Friedman’s laboratory work, which showed the virus was more effective against pediatric brain tumors than adult tumors.
In the past three years, 11 patients with high-grade gliomas have traveled to Children’s from throughout the country, Mexico and Canada to participate in the study. They receive special screening to pinpoint the tumor location, which is then biopsied. Johnston then places three to four catheters in the tumor. The next day, Friedman and his team infuse the genetically-modified virus into the brain through the catheters.
“We think the virus works by directly killing the tumor cells,” Johnston said, as well as activating the immune system to destroy any remaining cells. “Brain tumors have a way to hide from the immune system by making themselves immunologically ‘cold,’” he explained. The herpes virus turns a “cold” tumor into a “hot” tumor and generates the immune response. Indeed, months after the surgery tests show that immune cells have infiltrated the tumor and continue killing tumor cells.
The initial phase 1 trial in patients with high-grade gliomas was designed to demonstrate safety and wasn’t powered to show efficacy. Nonetheless, Johnston said, “our median survival was significantly longer than the historical six months,” with several children now long-term responders.
In late December 2019, the team received a three-year, $750,000 R01 grant from the U.S. Food and Drug Administration for a Phase 1 trial in malignant cerebellar brain tumors, which may be even more sensitive to the virotherapy than the gliomas. At the same time, they are submitting grants for a Phase 2 multicenter trial of the virus therapy for recurrent malignant supratentorial tumors.
Johnston stresses that the research is a team effort, involving basic scientists, oncologists, surgeons, nurses and intensivists. “It’s an ‘all-hands-on-deck’ kind of thing,” he said.