title: Complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques.
abstract: Oncolytic viruses (OVs) have shown promising clinical activity when administered by direct intratumoral injection. However, natural barriers in the blood, including antibodies and complement, are likely to limit the ability to repeatedly administer OVs by the intravenous route. We demonstrate here that for a prototype of the clinical vaccinia virus based product Pexa-Vec, the neutralizing activity of antibodies elicited by smallpox vaccination, as well as the anamnestic response in hyperimmune virus treated cancer patients, is strictly dependent on the activation of complement. In immunized rats, complement depletion stabilized vaccinia virus in the blood and led to improved delivery to tumors. Complement depletion also enhanced tumor infection when virus was directly injected into tumors in immunized animals. The feasibility and safety of using a complement inhibitor, CP40, in combination with vaccinia virus was tested in cynomolgus macaques. CP40 pretreatment elicited an average 10-fold increase in infectious titer in the blood early after the infusion and prolonged the time during which infectious virus was detectable in the blood of animals with preexisting immunity. Capitalizing on the complement dependence of antivaccinia antibody with adjunct complement inhibitors may increase the infectious dose of oncolytic vaccinia virus delivered to tumors in virus in immune hosts.
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors: Laura
authors: L
authors: Evgin
authors: Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors: Sergio A
authors: SA
authors: Acuna
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors: Christiano
authors: C
authors: Tanese de Souza
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors: Monique
authors: M
authors: Marguerie
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors: Chantal G
authors: CG
authors: Lemay
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors: Carolina S
authors: CS
authors: Ilkow
authors: Department of Biology, University of Ottawa, Ottawa, Ontario, Canada.
authors: C Scott
authors: CS
authors: Findlay
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors: Theresa
authors: T
authors: Falls
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors: Kelley A
authors: KA
authors: Parato
authors: Animal Resources Centre, University Health Network, Toronto, Ontario, Canada.
authors: David
authors: D
authors: Hanwell
authors: Animal Resources Centre, University Health Network, Toronto, Ontario, Canada.
authors: Alyssa
authors: A
authors: Goldstein
authors: Animal Resources Centre, University Health Network, Toronto, Ontario, Canada.
authors: Roberto
authors: R
authors: Lopez
authors: Animal Resources Centre, University Health Network, Toronto, Ontario, Canada.
authors: Sandra
authors: S
authors: Lafrance
authors: SillaJen Inc., Seoul, South Korea.
authors: Caroline J
authors: CJ
authors: Breitbach
authors: SillaJen Inc., Seoul, South Korea.
authors: David
authors: D
authors: Kirn
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors: Harold
authors: H
authors: Atkins
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors: Rebecca C
authors: RC
authors: Auer
authors: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors: Joshua M
authors: JM
authors: Thurman
authors: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts, USA.
authors: Gregory L
authors: GL
authors: Stahl
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: John D
authors: JD
authors: Lambris
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: jbell@ohri.ca.
authors: John C
authors: JC
authors: Bell
authors: Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.
authors: J Andrea
authors: JA
authors: McCart
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005240:Feasibility Studies; D005260:Female; D006367:HeLa Cells; D006801:Humans; D015552:Injections, Intralesional; D008252:Macaca fascicularis / Q000276:immunology; D008297:Male; D009369:Neoplasms / Q000097:blood / Q000628:therapy; D009500:Neutralization Tests; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000276:immunology*; D011728:Pyridones / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012900:Smallpox Vaccine / Q000097:blood / Q000276:immunology; D014611:Vaccination; D014616:Vaccinia virus / Q000276:immunology*; D014709:Vero Cells
chemical_list: D000914:Antibodies, Viral; D011728:Pyridones; D012900:Smallpox Vaccine; C098211:1-(ethan-1-ol)-2-methyl-3-hydroxypyridin-4-one