A genetically modified poliovirus therapy developed at Duke Cancer Institute shows significantly improved long-term survival for patients with recurrent glioblastoma, with a three-year survival rate of 21% in a phase 1 clinical trial. Comparatively, just 4% of patients at Duke with the same type of recurring brain tumours were alive at three years when undergoing the previously available standard treatment.
Phase 1 clinical trial results of the poliovirus therapy are being presented at the 22nd International Conference on Brain Tumor Research and Therapy in Norway.
“Glioblastoma remains a lethal and devastating disease, despite advances in surgical and radiation therapies, as well as new chemotherapy and targeted agents,” said Dr Darell D Bigner, emeritus director of The Preston Robert Tisch Brain Tumor Centre at Duke and senior author of the study.
“There is a tremendous need for fundamentally different approaches,” Bigner said. “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.”
Bigner and colleagues – including co-senior author Dr David Ashley, and co-lead authors Dr Annick Desjardins and Dr Matthias Gromeier, all in the department of neurosurgery – reported median follow-up of 27.6 months in the phase 1 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 therapy includes a genetically modified form of the poliovirus vaccine, which is infused directly into the brain tumour via a surgically implanted catheter. Developed by Gromeier in his lab at Duke, the modified virus preferentially zeroes in on tumour cells, igniting a targeted immune response.
An 18-year collaboration with the National Cancer Institute’s (NCI) Experimental Therapeutics (NExT) Programme, NCI, part of the National Institutes of Health, and the US Food and Drug Administration enabled the pre-clinical and translational phases of development of this novel therapy for glioblastoma.
“The Duke and NCI teams collaborated extensively on the preclinical work, which has culminated in these clinical trial results,” said Jim Dr Doroshow, 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.”
Initially in the phase 1 clinical trial, the Duke team planned to increase the dosage of the therapy infusion; a safe dose amount is a primary goal of phase 1 studies. But 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.
Study participants were selected according to strict guidelines based on the size of their recurring tumour, 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 enrolment criteria.
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,” Desjardins said. “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 at Duke to improve survival. A phase 2 study now underway combines the poliovirus therapy with the chemotherapy drug lomustine for patients with recurrent glioblastomas.
The authors reported that 69% of study patients had a mild or moderate adverse event attributed to poliovirus as their most severe side effect. Low dose bevacizumab was used to help control the localized inflammation of the tumour and its side effects.
The poliovirus therapy obtained “breakthrough therapy” designation in 2016 from the FDA.
New trials have already resulted. In addition to the phase 2 trial for glioblastoma, enrolment began this year to test the therapy in paediatric brain tumours. Some breast cancer and melanoma patients will soon be eligible to join clinical trials that expand the therapy beyond brain tumours.
Tumors thrive in an immunosuppressive microenvironment that impedes antitumor innate and adaptive immune responses. Thus, approaches that can overcome immunosuppression and engage antitumor immunity are needed. This study defines the adjuvant and cancer immunotherapy potential of the recombinant poliovirus/rhinovirus chimera PVSRIPO. PVSRIPO is currently in clinical trials against recurrent World Health Organization grade IV malignant glioma, a notoriously treatment-refractory cancer. Cytopathogenic infection of neoplastic cells releases the proteome and exposes pathogen- and damage-associated molecular patterns. At the same time, sublethal infection of antigen-presenting cells, such as dendritic cells and macrophages, yields potent, sustained type I interferon-dominant activation in an immunosuppressed microenvironment and promotes the development of tumor antigen–specific T cell responses in vitro and antitumor immunity in vivo. PVSRIPO’s immune adjuvancy stimulates canonical innate anti-pathogen inflammatory responses within the tumor microenvironment that culminate in dendritic cell and T cell infiltration. Our findings provide mechanistic evidence that PVSRIPO functions as a potent intratumor immune adjuvant that generates tumor antigen–specific cytotoxic T lymphocyte responses.
Michael C Brown, Eda K Holl, David Boczkowski, Elena Dobrikova, Mubeen Mosaheb, Vidya Chandramohan, Darell D Bigner, Matthias Gromeier, Smita K Nair