title: Pre-clinical Assessment of C134, a Chimeric Oncolytic Herpes Simplex Virus, in Mice and Non-human Primates.
abstract: Oncolytic herpes simplex virus (oHSV) type I constructs are investigational anti-neoplastic agents for a variety of malignancies, including malignant glioma. Clinical trials to date have supported the safety of these agents even when directly administered in the CNS. Traditional pre-clinical US Food and Drug Administration (FDA) toxicity studies for these agents have included the use of two species, generally including murine and primate studies. Recently, the FDA has decreased its requirement of non-human primates as an animal model for ethical reasons, especially for established viral systems where there are good alternative model systems. Here we present data demonstrating the safety of C134, a chimeric oHSV construct, in CBA mice as well as in a limited number of the HSV-sensitive non-human primateAotus nancymaaeas a proposed agent for clinical trials. These data, along with the previously conducted clinical trials of oHSV constructs, support the use of the CBA mouse model as sufficient for the pre-clinical toxicity studies of this agent. We summarize our experience with different HSV recombinants and differences between them using multiple assays to assess neurovirulence, as well as our experience with C134 in a limited number ofA. nancymaae.
authors.affiliation: Department of Pediatrics, Research Institute Center for Childhood Cancer and Blood Disorders, Nationwide Children's Hospital, Columbus, OH 43212, USA; Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Cassady
authors.affiliation: Department of Neurosurgery, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Bauer
authors.affiliation: Department of Pediatrics, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Roth
authors.affiliation: Department of Neurosurgery, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Chambers
authors.affiliation: Department of Neurosurgery, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: Trent
authors.initials: T
authors.lastname: Shoeb
authors.affiliation: Department of Neurosurgery, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Coleman
authors.affiliation: Department of Pediatrics, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Prichard
authors.affiliation: Department of Neurosurgery, University of Alabama, Birmingham, AL 35294, USA; Department of Pediatrics, University of Alabama, Birmingham, AL 35294, USA; Department of Comparative Medicine, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: G Yancey
authors.initials: GY
authors.lastname: Gillespie
authors.affiliation: Department of Neurosurgery, University of Alabama, Birmingham, AL 35294, USA; Department of Pediatrics, University of Alabama, Birmingham, AL 35294, USA; Department of Comparative Medicine, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Markert
keywords: HSV; IRF3; IRS1; PKR; alpha US11; glioma; interferon; neurotoxicology; oncolytic virus; Δ; γ134.5