Synergistic interaction between oncolytic viruses augments tumor killing

Mol Ther. 2010 May;18(5):888-95. doi: 10.1038/mt.2010.44. Epub 2010 Mar 16.


A major barrier to all oncolytic viruses (OVs) in clinical development is cellular innate immunity, which is variably active in a spectrum of human malignancies. To overcome the heterogeneity of tumor response, we combined complementary OVs that attack cancers in distinct ways to improve therapeutic outcome. Two genetically distinct viruses, vesicular stomatitis virus (VSV) and vaccinia virus (VV), were used to eliminate the risk of recombination. The combination was tested in a variety of tumor types in vitro, in immunodeficient and immunocompetent mouse tumor models, and ex vivo, in a panel of primary human cancer samples. We found that VV synergistically enhanced VSV antitumor activity, dependent in large part on the activity of the VV B18R gene product. A recombinant version of VSV expressing the fusion-associated small-transmembrane (p14FAST) protein also further enhanced the ability of VV to spread through an infected monolayer, resulting in a "ping pong" oncolytic effect wherein each virus enhanced the ability of the other to replicate and/or spread in tumor cells. Our strategy is the first example where OVs are rationally combined to utilize attributes of different OVs to overcome the heterogeneity of malignancies and demonstrates the feasibility of combining complementary OVs to improve therapeutic outcome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorocebus aethiops
  • Female
  • Genetic Therapy / adverse effects
  • Genetic Therapy / methods
  • Genetic Vectors / genetics
  • HT29 Cells
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Nude
  • Neoplasms / therapy*
  • Oncolytic Virotherapy / adverse effects*
  • Oncolytic Virotherapy / methods*
  • Oncolytic Viruses / genetics
  • Oncolytic Viruses / physiology*
  • Vaccinia virus / genetics
  • Vaccinia virus / physiology
  • Vero Cells
  • Vesiculovirus / genetics
  • Vesiculovirus / physiology