Phase I clinical trial study results published June 26, 2018 in The New England Journal of Medicine outline how researchers used a novel recombinant poliovirus to treat glioblastoma.
Recurrent malignant glioma, or glioblastoma, at a late stage (World Health Organization grade IV), has a very poor prognosis. There is no currently accepted effective therapy and this type of malignancy is being seen more and more in the world. Treatments historically included surgical removal, radiotherapy, chemotherapy, and targeted therapies but have resulted in inconsistent results along with challenging central nervous system side effects.
The poliovirus is one of a small number of viruses known to infect and be brought into nerve cells. Once inside the cell, the virus, like other viral mechanisms of action, commandeers the cell’s replication assembly process to make copies of itself in a short span of time. Once replication is complete, the virus destroys the cell and goes on to infect other nerve cells. The reason this particular virus utilizes motor neurons, rather than other cell types, is still unknown.
In this study, the researchers engineered the poliovirus type 1 to include a ribosome entry site from a human rhinovirus type 2, to replace its original entry site (PVSRIPO). This non-native ribosome entry site does not allow the virus to recruit the cellular machinery required to translate the viral genome and further infect other neurons. Instead, the engineered virus has affinity for cluster of differentiation 155 (CD155), which is present on malignant cells. The infected glioma cells are destroyed, and the innate antiviral immune response ensues.
Results of this initial phase were promising. Overall survival rate for those treated with PVSRIPO was 21% at 24 and 36 months; the historical control overall survival rate was 14% at 24 months and 4% at 36 months. In a dose-expansion phase, some patients showed neurological side effects which the researchers speculated to be a result of treatment related peritumoral edema and were swiftly treated with bevacizumab to reduce edema and mitigate symptoms.
This group currently has a phase 2, randomized clinical trial underway using PVSRIPO in WHO grade IV glioblastoma.