title: Preclinical evaluation of a genetically engineered herpes simplex virus expressing interleukin-12.
abstract: Herpes simplex virus 1 (HSV-1) mutants that lack the γ(1)34.5 gene are unable to replicate in the central nervous system but maintain replication competence in dividing cell populations, such as those found in brain tumors. We have previously demonstrated that a γ(1)34.5-deleted HSV-1 expressing murine interleukin-12 (IL-12; M002) prolonged survival of immunocompetent mice in intracranial models of brain tumors. We hypothesized that M002 would be suitable for use in clinical trials for patients with malignant glioma. To test this hypothesis, we (i) compared the efficacy of M002 to three other HSV-1 mutants, R3659, R8306, and G207, in murine models of brain tumors, (ii) examined the safety and biodistribution of M002 in the HSV-1-sensitive primate Aotus nancymae following intracerebral inoculation, and (iii) determined whether murine IL-12 produced by M002 was capable of activating primate lymphocytes. Results are summarized as follows: (i) M002 demonstrated superior antitumor activity in two different murine brain tumor models compared to three other genetically engineered HSV-1 mutants; (ii) no significant clinical or magnetic resonance imaging evidence of toxicity was observed following direct inoculation of M002 into the right frontal lobes of A. nancymae; (iii) there was no histopathologic evidence of disease in A. nancymae 1 month or 5.5 years following direct inoculation; and (iv) murine IL-12 produced by M002 activates A. nancymae lymphocytes in vitro. We conclude that the safety and preclinical efficacy of M002 warrants the advancement of a Δγ(1)34.5 virus expressing IL-12 to phase I clinical trials for patients with recurrent malignant glioma.
authors.affiliation: Department of Surgery, Division of Neurosurgery, The University of Alabama at Birmingham, Birmingham, Alabama, USA. jmarkert@uabmc.edu
authors.forename: James M
authors.initials: JM
authors.lastname: Markert
authors.forename: James J
authors.initials: JJ
authors.lastname: Cody
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Parker
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Coleman
authors.forename: Kathleen H
authors.initials: KH
authors.lastname: Price
authors.forename: Earl R
authors.initials: ER
authors.lastname: Kern
authors.forename: Debra C
authors.initials: DC
authors.lastname: Quenelle
authors.forename: Alfred D
authors.initials: AD
authors.lastname: Lakeman
authors.forename: Trenton R
authors.initials: TR
authors.lastname: Schoeb
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Palmer
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Cartner
authors.forename: G Yancey
authors.initials: GY
authors.lastname: Gillespie
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Whitley
mesh_terms: D000212:Acyclovir / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D016645:Aotidae; D001921:Brain / Q000473:pathology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics*; D005910:Glioma / Q000235:genetics / Q000401:mortality / Q000628:therapy; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018139:Simplexvirus / Q000187:drug effects / Q000235:genetics*; D016019:Survival Analysis; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000998:Antiviral Agents; D018664:Interleukin-12; D000212:Acyclovir