Intratumoral Recombinant Poliovirus in Grade IV Glioblastoma
In a study reported in The New England Journal of Medicine, Desjardins and colleagues found that convection-enhanced intratumoral delivery of a recombinant nonpathogenic polio–rhinovirus chimera (PVSRIPO) was not associated with neurovirulence in patients with recurrent grade IV glioma and appeared to produce survival outcomes that compare favorably with historical controls.
PVSRIPO recognizes the poliovirus receptor CD155, widely expressed in neoplastic cells of solid tumors and in components of the tumor microenvironment. Studies in vitro have shown that PVSRIPO infection of neoplastic cells results in lethal cytotoxic effects and activates antitumor immunity.
Study Details
The phase I/dose-expansion study enrolled consecutive adult patients at Duke University between May 2012 and May 2017 who had recurrent supratentorial World Health Organization (WHO) grade IV malignant glioma with measurable disease. The study evaluated 7 dose levels of PVSRIPO, ranging from 107 to 1010 50% tissue-culture infectious doses (TCID50) in a dose-escalation phase followed by a dose-expansion phase.
In total, 61 patients were enrolled and received a dose of PVSRIPO. A dose level of 5.0 × 107 TCID50 was identified as the phase II dose. A dose-limiting toxicity occurred in a patient receiving a dose of 1010 TCID50, who had a grade 4 intracranial hemorrhage immediately after catheter removal.
Among 52 patients in the dose-expansion phase, 6 received 3.3 × 108 TCID50, 31 received 5.0 × 107 TCID50, and 15 received 107 TCID50. The most common adverse events in these patients were headache (52%), pyramidal tract syndrome (hemiparesis; 50%), seizure (45%), dysphasia (28%), and cognitive disturbance (25%). Treatment-related adverse events of grade ≥ 3 occurred in 19%.
Two deaths occurred during the trial. One patient had a seizure related to cerebral edema considered likely related to autopsy-confirmed tumor progression at 4.8 months after PVSRIPO infusion; the events were attributed to PVSRIPO as grade 4 cerebral edema and grade 5 seizure. Another patient, noted above, died 10.5 months after PVSRIPO infusion due to complications of an intracranial hemorrhage while receiving anticoagulation and bevacizumab (Avastin).
Median overall survival among all 61 patients who received a PVSRIPO dose was 12.5 months, compared with 11.3 months in a historical control group of 104 patients previously treated at Duke University Medical Center who would have met the eligibility criteria for PVSRIPO. Overall survival among PVSRIPO patients reached a plateau of 21% at 24 months that was maintained at 36 months and beyond, whereas survival in the historical control group declined from 14% at 24 months to 4% at 36 months.
The investigators concluded, “Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls.”
The study was funded by the Brain Tumor Research Charity and others.
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