ONCOLYTIC POLIOVIRUS IMMUNOTHERAPY OF GLIOBLASTOMA

BACKGROUND: With the exception of Burkitt lymphoma, almost all solid cancers are susceptible to infection with poliovirus, due to widespread ectopic expression of the poliovirus receptor, the onco-fetal cell adhesion molecule Necl5/CD155. We engineered a profoundly CNS-incompetent and genetically stable variant of polio through recombination of the cognate internal ribosomal entry site (IRES) with its counterpart from human rhinovirus type 2. The resulting PVSRIPO chimera is incapable of causing poliomyelitis or encephalitis in non-human primates or human subjects, even after high-dose intracerebral inoculation, but retains excellent cytotoxic properties in malignant cells. This is due to constitutively active signal transduction pathways via Raf-Erk MAPKs to the MAPK-interacting kinase, Mnk, and the translation apparatus. METHODS: Raf-Erk-Mnk signals favor translation of mRNAs with highly structured, encumbered 5' untranslated regions, typical for mRNAs encoding potent biological response modifiers, survival factors, growth factors or oncogenes. They afford an enormous advantage to PVSRIPO translation, causing irreversible lethal cytotoxicity as early as 60 min after infection. PVSRIPO infection of GBM produces drastic, violent cytotoxicity and a wide range of pro-inflammatory and immunogenic host responses. These are due to virally-induced 'immunogenic cell death', forceful activation of innate antiviral type 1 interferon responses, non-lethal infection and pro-inflammatory stimulation of tumor-associated macrophages/dendritic cells and stimulation of cytotoxic T-cell responses directed against the tumor. RESULTS: A currently accruing Phase-1 clinical trial of PVSRIPO with intratumoral, CED-mediated infusion in recurrent GBM is showing promise with the first patients experiencing durable complete clinical and near-complete radiographic responses >20 months post PVSRIPO infusion. The key to PVSRIPO oncolytic immunotherapy is the early acute phase of viral cytotoxicity after intratumoral infusion. Unhinged translation control, enabling unfettered viral, IRES-mediated initiation, is independent of the notorious intratumoral and inter-individual heterogeneity of advanced, treatment-refractory cancers. To define the molecular mechanism of PVSRIPO-mediated immunogenic cell death, we unraveled a signaling network centered on Raf-Erk-Mnk signals and their control over the Ser-Arg-rich protein kinase. CONCLUSIONS: Provided a solid mechanistic rationale exists for