title: Increased efficacy of an interleukin-12-secreting herpes simplex virus in a syngeneic intracranial murine glioma model.
abstract: Long-term survivors of glioblastoma multiforme, the most common form of primary intracranial malignancy in adults, are extremely rare. Experimental animal models that more closely resemble human disease are essential for the identification of effective novel therapies. We report here an extensive analysis of the 4C8 glioma model to assess its suitability for evaluating novel type 1 herpes simplex virus (HSV-1) therapies of malignant glioma. We first determined that expression of major histocompatibility complex I and II and of alphavbeta3 in the 4C8 model was comparable to that seen in human glioma cells. Next, using a panel of Delta(gamma1)34.5 HSVs, we demonstrated that, in vitro, 4C8 cells were as sensitive as human glioma cells to both infection and lysis and that the 4C8 cells supported the production of foreign gene products. Replication competence of HSV was demonstrated in vitro. Finally, 4C8 intracranial gliomas were established in immunologically competent syngeneic B6D2F1 mice, treated by intratumoral injection of selected engineered HSVs, including the interleukin-12-expressing virus, M002. Survival data from these studies demonstrated that 4C8 cells in vivo are sensitive to both direct oncolysis and HSV-mediated interleukin-12 expression. Fluorescence-activated cell sorting analyses of immune-related infiltrating cells supported the concept that survival was prolonged in part because of antitumor actions of these cells. We conclude that the 4C8/B6D2F1 syngeneic glioma model is suitable for preclinical evaluation of HSV-based therapies and that M002 is a superior virus for the treatment of murine glioma in this model.
authors.affiliation: Brain Tumor Research Laboratories, Division of Neurosurgery, Department of Surgery, University of Alabama School of Medicine, Birmingham AL 35294, USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Hellums
authors.forename: James M
authors.initials: JM
authors.lastname: Markert
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Parker
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Bernard
authors.initials: B
authors.lastname: Perbal
authors.forename: Bernard
authors.initials: B
authors.lastname: Roizman
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Whitley
authors.forename: Catherine P
authors.initials: CP
authors.lastname: Langford
authors.forename: Suman
authors.initials: S
authors.lastname: Bharara
authors.forename: G Yancey
authors.initials: GY
authors.lastname: Gillespie
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy / Q000821:virology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015316:Genetic Therapy; D005910:Glioma / Q000378:metabolism / Q000628:therapy / Q000821:virology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism*; D051379:Mice; D018139:Simplexvirus / Q000502:physiology*; D014185:Transplantation, Isogeneic
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D018664:Interleukin-12