A genetically engineered, nonpathogenic poliovirus vaccine appeared to improve survival time among patients with recurrent metastatic glioblastoma. That is the conclusion of investigators who conducted a noncontrolled, phase I dose-finding and dose-expansion study (ClinicalTrials.gov identifier: NCT01491893) at Duke University Medical Center (DUMC), Durham, North Carolina. The findings were published in the New England Journal of Medicine.
The 61 patients who received the intratumoral viral infusion had a 3-year survival rate of 21%, compared with a 4% rate in a historical control cohort of 104 patients who had received standard treatment at DUMC, reported Annick Desjardins, MD, and coauthors.
Among the patients who responded to treatment with the modified poliovirus, survival at 24 months was sustained through 36 months, the authors noted.
“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 stated in a press release “The big question is, how can we make sure that everybody responds?”
Immune checkpoint blockade is not viable in patients with malignant gliomas because of scant T-cell infiltration of the tumor and its microenvironment in the brain. Desjardins and colleagues engineered a recombinant live-attenuated nonpathogenic poliovirus-1-human rhinovirus type 2 chimera (PVSRIPO) that targets the CD155 receptor. CD155 receptor is “widely expressed” on solid tumor cell surfaces and in tumor microenvironments, the authors said.
PVSRIPO is infused directly into the brain tumor using a surgically implanted catheter. It is believed to work as a vaccine, first triggering a sustained but sublethal cytotoxic infection in cells, and subsequently activating an innate antiviral interferon immune response that triggers the release of proinflammatory cytokines.
“Tumor cytotoxic effects, interferon-dominant activation of antigen-presenting cells, and the profound inflammatory response to poliovirus may counter tumor-induced immune suppression and instigate antitumor immunity,” the authors explained.
Inflammation is believed to represent an important mechanism of action for PVSRIPO. To avoid the risk of side effects associated with long-term glucocorticoid administration, the study protocol for the dose-expansion phase was changed to limit the use of glucocorticoids, which suppress inflammation.
“PVSRIPO did not induce systemic autoimmune reactions; rather, patients had neurologic symptoms owing to what we think was peritumoral inflammation related to the location of the infused tumor,” the authors noted. “To mitigate this situation, we used bevacizumab to reverse edema rapidly and to treat symptoms. The role of bevacizumab in promoting immunotherapy mechanistically complicates preclinical evidence of PVSRIPO-instigated antitumor immunity.”
Between May 2012 and May 2017, the authors enrolled 61 patients with recurrent, histopathologically confirmed WHO (World Health Organization) grade IV malignant glioma. The patients had contrast-enhancing tumors at least 1 cm and no larger than 5.5 cm in maximal diameter. Patients received one of seven intratumoral-infusion PVSRIPO doses; the 5.0 × 107 tissue-culture infectious dose (TCID50) was identified as the one that will be used in the phase II study.
One patient died of a PVSRIPO-attributable seizure, and one patient had grade 4 cerebral edema attributable to PVSRIPO. A total of 9 patients (17%) had grade 3 PVSRIPO-related toxicities. Pyramidal tract syndrome (hemiparesis) occurred in 4 patients (8%). The investigators also reported adverse events including gait disturbance, dystonia, headache, seizure, confusion, and delusions (occurring in 1 patient each).