NDLI: ONCOLYTIC POLIOVIRUS IMMUNOTHERAPY OF GLIOBLASTOMA

Content Provider	PubMed Central
Author	Matthias, Gromeier Elena, Dobrikova Mikhail, Dobrikov Brown, Michael Bryant, Jeffrey Threatt, Stevie Boulton, Susan Carter, Karen Herndon, James Desjardins, Annick Friedman, Henry Sampson, John Friedman, Alan Bigner, Darell
Copyright Year	2014
Abstract	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 their use, oncolytic viruses such as PVSRIPO may induce tumor-cytotoxic, immune-modulatory and immune-stimulatory effects with an extent and biological range that are difficult to achieve with any other type of anti-cancer agent. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.
Related Links	http://dx.doi.org/10.1093/neuonc/nou208.69
Starting Page	41
File Format	PDF
ISSN	15228517
e-ISSN	15235866
Journal	Neuro-Oncology
Issue Number	Suppl 3
Volume Number	16
Language	English
Publisher	Oxford University Press
Publisher Date	2014-07-01
Access Restriction	Open
Rights Holder	Oxford University Press
Subject Keyword	Cancer Research Oncology Clinical Neurology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Neurology (clinical) Oncology

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

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