Efficacy and safety/toxicity study of recombinant vaccinia virus JX-594 in two immunocompetent animal models of glioma

Mol Ther. 2010 Nov;18(11):1927-36. doi: 10.1038/mt.2010.183. Epub 2010 Aug 31.


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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / therapeutic use
  • Brain Neoplasms / genetics
  • Brain Neoplasms / therapy*
  • Combined Modality Therapy
  • Disease Models, Animal*
  • Female
  • Genetic Vectors / therapeutic use
  • Glioma / genetics
  • Glioma / therapy*
  • Granulocyte-Macrophage Colony-Stimulating Factor / analysis
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
  • Immunoenzyme Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oncolytic Virotherapy*
  • Rats
  • Rats, Inbred F344
  • Sirolimus / therapeutic use*
  • Survival Rate
  • Transgenes / physiology
  • Tumor Cells, Cultured
  • Vaccines, Synthetic / therapeutic use
  • Vaccinia virus / genetics*
  • Virus Replication


  • Antibiotics, Antineoplastic
  • Vaccines, Synthetic
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Sirolimus