title: Myxoma virus virotherapy for glioma in immunocompetent animal models: optimizing administration routes and synergy with rapamycin.
abstract: Oncolytic myxoma virus (MYXV) is being developed as a novel virotherapeutic against human brain cancer and has promising activity against human brain tumor models in immunocompromised hosts. Because an intact immune system could reduce its efficacy, the purpose of this study was to evaluate the oncolytic potential of MYXV in immunocompetent racine glioma models. Here, we report that MYXV infects and kills all racine cell glioma lines and that its effects are enhanced by rapamycin. Intratumoral administration of MYXV with rapamycin improved viral replication in the tumor and significantly prolonged host survival. Similarly, coadministration via a method of convection-enhanced delivery (CED) enhanced viral replication and efficacy in vivo. Mechanisms by which rapamycin improved MYXV oncolysis included an inhibition of type I IFN production in vitro and a reduction of intratumoral infiltration of CD68(+) microglia/macrophages and CD163(+) macrophages in vivo. Our findings define a method to improve MYXV efficacy against gliomas by rapamycin coadministration, which acts to promote immune responses engaged by viral delivery.
authors.affiliation: Department of Oncology, University of Calgary, Tom Baker Cancer Centre, Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: XueQing
authors.initials: X
authors.lastname: Lun
authors.forename: Tommy
authors.initials: T
authors.lastname: Alain
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Zemp
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Zhou
authors.forename: Masmudur M
authors.initials: MM
authors.lastname: Rahman
authors.forename: Mark G
authors.initials: MG
authors.lastname: Hamilton
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.forename: John
authors.initials: J
authors.lastname: Bell
authors.forename: Donna L
authors.initials: DL
authors.lastname: Senger
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005910:Glioma / Q000628:therapy* / Q000821:virology; D007121:Immunocompetence; D051379:Mice; D009233:Myxoma virus / Q000502:physiology*; D041681:NIH 3T3 Cells; D050130:Oncolytic Virotherapy / Q000379:methods*; D051381:Rats; D011916:Rats, Inbred F344; D020123:Sirolimus / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D020123:Sirolimus