title: The oncolytic poxvirus JX-594 selectively replicates in and destroys cancer cells driven by genetic pathways commonly activated in cancers.
abstract: Oncolytic viruses are generally designed to be cancer selective on the basis of a single genetic mutation. JX-594 is a thymidine kinase (TK) gene-inactivated oncolytic vaccinia virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and lac-Z transgenes that is designed to destroy cancer cells through replication-dependent cell lysis and stimulation of antitumoral immunity. JX-594 has demonstrated a favorable safety profile and reproducible tumor necrosis in a variety of solid cancer types in clinical trials. However, the mechanism(s) responsible for its cancer-selectivity have not yet been well described. We analyzed the replication of JX-594 in three model systems: primary normal and cancer cells, surgical explants, and murine tumor models. JX-594 replication, transgene expression, and cytopathic effects were highly cancer-selective, and broad spectrum activity was demonstrated. JX-594 cancer-selectivity was multi-mechanistic; replication was activated by epidermal growth factor receptor (EGFR)/Ras pathway signaling, cellular TK levels, and cancer cell resistance to type-I interferons (IFNs). These findings confirm a large therapeutic index for JX-594 that is driven by common genetic abnormalities in human solid tumors. This appears to be the first description of multiple selectivity mechanisms, both inherent and engineered, for an oncolytic virus. These findings have implications for oncolytic viruses in general, and suggest that their cancer targeting is a complex and multifactorial process.
authors.affiliation: Ottawa Hospital Research Institute, Centre for Innovative Cancer Research, Ottawa, Ontario, Canada.
authors.forename: Kelley A
authors.initials: KA
authors.lastname: Parato
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Breitbach
authors.forename: Fabrice
authors.initials: F
authors.lastname: Le Boeuf
authors.forename: Jiahu
authors.initials: J
authors.lastname: Wang
authors.forename: Chris
authors.initials: C
authors.lastname: Storbeck
authors.forename: Carolina
authors.initials: C
authors.lastname: Ilkow
authors.forename: Jean-Simon
authors.initials: JS
authors.lastname: Diallo
authors.forename: Theresa
authors.initials: T
authors.lastname: Falls
authors.forename: Joseph
authors.initials: J
authors.lastname: Burns
authors.forename: Vanessa
authors.initials: V
authors.lastname: Garcia
authors.forename: Femina
authors.initials: F
authors.lastname: Kanji
authors.forename: Laura
authors.initials: L
authors.lastname: Evgin
authors.forename: Kang
authors.initials: K
authors.lastname: Hu
authors.forename: Francois
authors.initials: F
authors.lastname: Paradis
authors.forename: Shane
authors.initials: S
authors.lastname: Knowles
authors.forename: Tae-Ho
authors.initials: TH
authors.lastname: Hwang
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Vanderhyden
authors.forename: Rebecca
authors.initials: R
authors.lastname: Auer
authors.forename: David H
authors.initials: DH
authors.lastname: Kirn
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D011212:Poxviridae / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication / Q000235:genetics / Q000502:physiology*
chemical_list: D066246:ErbB Receptors