title: Efficacy and safety/toxicity study of recombinant vaccinia virus JX-594 in two immunocompetent animal models of glioma.
abstract: The purpose of this study was to investigate the oncolytic potential of the recombinant, granulocyte macrophage colony-stimulating factor (GM-CSF)-expressing vaccinia virus (VV) JX-594 in experimental malignant glioma (MGs) in vitro and in immunocompetent rodent models. We have found that JX-594 killed all MG cell lines tested in vitro. Intratumoral (i.t.) administration of JX-594 significantly inhibited tumor growth and prolonged survival in rats-bearing RG2 intracranial (i.c.) tumors and mice-bearing GL261 brain tumors. Combination therapy with JX-594 and rapamycin significantly increased viral replication and further prolonged survival in both immunocompetent i.c. MG models with several animals considered "cured" (three out of seven rats >120 days, terminated experiment). JX-594 infected and killed brain tumor-initiating cells (BTICs) from patient samples grown ex vivo, and did so more efficiently than other oncolytic viruses MYXV, Reovirus type-3, and VSV(ΔM51). Additional safety/toxicity studies in nontumor-bearing rodents treated with a supratherapeutic dose of JX-594 demonstrated GM-CSF-dependent inflammation and necrosis. These results suggest that i.c. administered JX-594 triggers a predictable GM-CSF-mediated inflammation in murine models. Before proceeding to clinical trials, JX-594 should be evaluated in the brains of nonhuman primates and optimized for the viral doses, delivery routes as well as the combination agents (e.g., mTOR inhibitors).
authors.affiliation: Department of Oncology, University of Calgary, Tom Baker Cancer Centre, Calgary, Alberta, Canada. xlun@ucalgary.ca
authors.forename: XueQing
authors.initials: X
authors.lastname: Lun
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chan
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Zhou
authors.forename: Beichen
authors.initials: B
authors.lastname: Sun
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kelly
authors.forename: Owen Owen
authors.initials: OO
authors.lastname: Stechishin
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: Kelley
authors.initials: K
authors.lastname: Parato
authors.forename: Kang
authors.initials: K
authors.lastname: Hu
authors.forename: Dominique
authors.initials: D
authors.lastname: Vaillant
authors.forename: Jiahu
authors.initials: J
authors.lastname: Wang
authors.forename: Ta-Chiang
authors.initials: TC
authors.lastname: Liu
authors.forename: Caroline
authors.initials: C
authors.lastname: Breitbach
authors.forename: David
authors.initials: D
authors.lastname: Kirn
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 / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors / Q000627:therapeutic use; D005910:Glioma / Q000235:genetics / Q000628:therapy*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000235:genetics*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050130:Oncolytic Virotherapy; D051381:Rats; D011916:Rats, Inbred F344; D020123:Sirolimus / Q000627:therapeutic use*; D015996:Survival Rate; D019076:Transgenes / Q000502:physiology; D014407:Tumor Cells, Cultured; D014614:Vaccines, Synthetic / Q000627:therapeutic use; D014616:Vaccinia virus / Q000235:genetics*; D014779:Virus Replication
chemical_list: D000903:Antibiotics, Antineoplastic; D014614:Vaccines, Synthetic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020123:Sirolimus
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