Immunotherapy has enjoyed much-deserved adulations over the past several years, as scientists have proven that the basic biology is sound and drugs developed to modulate the human immune system contain an immense therapeutic value. Yet, aggressive cancers such as those residing within the brain have been particularly difficult to treat and require some “outside the box” thinking. Now, a team of investigators at Duke University and the National Cancer Institute (NCI) are showing how a genetically modified poliovirus therapy significantly improved long-term survival for patients with recurrent glioblastoma, with a three-year survival rate of 21%. Findings from the new study were published today in The New England Journal of Medicine, in an article entitled “Recurrent Glioblastoma Treated with Recombinant Poliovirus.”

“Glioblastoma remains a lethal and devastating disease, despite advances in surgical and radiation therapies, as well as new chemotherapy and targeted agents,” explained senior study investigator Darell Bigner, M.D., Ph.D., emeritus director of The Preston Robert Tisch Brain Tumor Center at Duke. “There is a tremendous need for fundamentally different approaches. With the survival rates in this early phase of the poliovirus therapy, we are encouraged and eager to continue with the additional studies that are already underway or planned.”

Currently, just 4% of patients at Duke with the same type of recurring brain tumors were alive at three years when undergoing the previously available standard treatment.

In the current study, the Duke team reported the median follow-up of 27.6 months in the Phase I trial, which was launched in 2012 with a young patient who was just entering nursing school. She has since married and works as a registered nurse.

The newly developed therapy includes a genetically modified form of the poliovirus vaccine, which is infused directly into the brain tumor via a surgically implanted catheter. Developed by co-lead study investigator Matthias Gromeier, M.D., in his lab at Duke, the modified virus preferentially zeroes in on tumor cells, igniting a targeted immune response. Dr. Gromeier and his co-authors recently published a study in Science Translational Medicine describing the mechanism of action for the poliovirus therapy.

“The Duke and NCI teams collaborated extensively on the preclinical work, which has culminated in these clinical trial results,” commented Jim Doroshow, M.D., deputy director for Clinical and Translational Research at NCI. “This promising approach in glioblastoma therapy exemplifies the strategic investment made by the NCI to support the development of new therapies such as this one from research discovery into clinical trials.”

Study participants were selected according to strict guidelines based on the size of their recurring tumor, its location in the brain, and other factors designed for patient protection. A comparison group of patients was drawn from historical cases at Duke involving patients who would have matched the poliovirus enrollment criteria.

Initially, the Duke team planned to increase the dosage of the therapy infusion—a safe dose amount is a primary goal of Phase I studies. However, at higher dosages, some patients experienced too much inflammation, resulting in seizures, cognitive disturbances, and other adverse events, so the amount infused was reduced. All but 15 of the 61 patients enrolled in the study had one of the lower dosages.

For all 61 poliovirus patients, the median overall survival was 12.5 months, compared to 11.3 months for the historical control group. Starting at two years after treatment, the survival curves in the two groups diverged.

The rate of overall survival of poliovirus patients at 24 months was 21%, compared to 14% for the historical controls. At three years, the gap widened further, with a survival rate of 21% for poliovirus patients, compared to 4% in the control group.

“Similar to many immunotherapies, it appears that some patients don't respond for one reason or another, but if they respond, they often become long-term survivors,” noted co-lead study investigator Annick Desjardins, M.D., an associate professor of neurosurgery at Duke. “The big question is, how can we make sure that everybody responds?”

Combining the poliovirus with other approved therapies is one approach already being tested to improve survival. A Phase II study now underway combines the poliovirus therapy with the chemotherapy drug lomustine for patients with recurrent glioblastomas.

The poliovirus therapy obtained “breakthrough therapy” designation in 2016 from the U.S. Food and Drug Administration.

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