期刊
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
卷 17, 期 -, 页码 871-893出版社
CELL PRESS
DOI: 10.1016/j.omtm.2020.03.028
关键词
-
资金
- NIH [U01NS061811, P01CA163205, R01NS110942, P01CA236749]
- Alliance for Cancer Gene Therapy (Greenwich, CT)
rQNestin34.5v.2 is an oncolytic herpes simplex virus 1 (oHSV) that retains expression of the neurovirulent ICP34.5 gene under glioma-selective transcriptional regulation. To prepare an investigational new drug (IND) application, we performed toxicology and efficacy studies of rQNestin34.5v.2 in mice in the presence or absence of the immunomodulating drug cyclophosphamide (CPA). ICP34.5 allowsHSV1 to survive interferon and improves viral replication by dephosphorylation of the eIF-2 alpha translation factor. rQNestin34.5v.2 dephosphorylated eIF-2 alpha in human glioma cells, but not in human normal cells, resulting in significantly higher cytotoxicity and viral replication in the former compared to the latter. In vivo toxicity of rQNestin34.5v.2 was compared with that of wild-type F strain in immunocompetent BALB/cmice and athymicmice bymultiple routes of administration in the presence or absence of CPA. A likely no observed adverse effect level (NOAEL) dose for intracranial rQNestin34.5v.2 was estimated, justifying a phase 1 clinical trial in recurrent glioma patients (ClinicalTrials.gov: NCT03152318), after successful submission of an IND.
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