Engineered poliovirus shows potential for treatment of recurrent glioma
medwireNews: A recombinant nonpathogenic polio–rhinovirus chimera (PVSRIPO) has demonstrated promising tolerability and efficacy in patients with recurrent malignant glioma in a phase I trial.
PVSRIPO is “a live attenuated poliovirus type 1 (Sabin) vaccine with its cognate internal ribosome entry site replaced with that of human rhinovirus type 2,” which modification “causes neuronal incompetence […] and ablates neurovirulence,” the researchers explain.
Sixty-one patients with recurrent, supratentorial, World Health Organization grade IV malignant glioma received an intratumoral infusion of PVSRIPO at doses ranging from 107 to 1010 50% tissue-culture infectious doses (TCID50), initially in a dose-escalation phase, followed by a dose-expansion phase.
As reported in The New England Journal of Medicine by Darell Bigner (Duke University Medical Center, Durham, North Carolina, USA) and co-investigators, the majority of adverse events in the dose-escalation and dose-expansion phases were of grade 1 or 2.
But one patient who received the engineered poliovirus at the highest dose experienced a dose-limiting toxicity, a grade 4 intracranial hemorrhage that occurred immediately after the catheter was removed.
Nineteen percent of the 52 patients in the dose-expansion phase experienced a PVSRIPO treatment-related toxicity of at least grade 3, with grade 3 pyramidal tract syndrome (hemiparesis) the most common event.
Two participants died during the course of the trial, one due to grade 4 cerebral edema and grade 5 seizure, which may or may not have been related to PVSRIPO infusion, and the other as a result of intracranial hemorrhage-related complications that were attributed to bevacizumab treatment, which was ongoing at the time.
Of note, there was no evidence of viral neuropathogenicity (ie, encephalomyelitis, poliomyelitis, meningitis, or systemic autoimmune reactions) or virus shedding in any patient, attesting to “the absence of neurovirulent potential,” say the study authors.
Based on these results, they recommend the 5.0×107 TCID50 dose for the phase II trial.
With regard to efficacy, PVSRIPO treatment was associated with a median overall survival (OS) of 12.5 months over a median follow-up of 27.6 months.
This compared with a median OS time of 11.3 months for a group of 114 historical controls, who were patients treated at Duke University Medical Center and would have met the eligibility criteria for PVSRIPO had the option been available then.
At the 24-month mark, 21% of PVSRIPO-treated patients were alive; the same proportion as at 36 months. By contrast, the OS rates for the historical controls at these time points were 14% and 4%, respectively.
Dan Longo and Lindsey Baden, both from Brigham and Women's Hospital in Boston, Massachusetts, USA, say in an accompanying editorial that “[a] number of questions and problems remain for these viral approaches to cancer treatment.”
For instance, “[h]ow will local administration interact with systemic immunity such that lesions that are remote from the injection site will be recognized and eliminated?” ask the editorialists. Also questions pertaining to safety, including whether there are risks associated with the restoration of viral pathogenicity or replication competence in vivo, and whether engineering viruses with a destruct gene could be a way to control unanticipated viral expansion.
Although the editorial authors say that “[m]uch more needs to be learned,” they believe “the clinical results to date encourage further exploration of this new treatment approach.”
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