Complement Inhibition Prevents Oncolytic Vaccinia Virus Neutralization in Immune Humans and Cynomolgus Macaques

Mol Ther. 2015 Jun;23(6):1066-1076. doi: 10.1038/mt.2015.49. Epub 2015 Mar 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Viral / blood
  • Antibodies, Viral / immunology
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Drug Delivery Systems
  • Feasibility Studies
  • Female
  • HeLa Cells
  • Humans
  • Injections, Intralesional
  • Macaca fascicularis / immunology
  • Male
  • Neoplasms / blood
  • Neoplasms / therapy
  • Neutralization Tests
  • Oncolytic Virotherapy / methods*
  • Oncolytic Viruses / immunology*
  • Pyridones / immunology
  • Pyridones / pharmacology
  • Rats
  • Rats, Inbred F344
  • Smallpox Vaccine / blood
  • Smallpox Vaccine / immunology
  • Vaccination
  • Vaccinia virus / immunology*
  • Vero Cells

Substances

  • Antibodies, Viral
  • Pyridones
  • Smallpox Vaccine
  • 1-(ethan-1-ol)-2-methyl-3-hydroxypyridin-4-one