Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy

Mol Ther. 2011 Jun;19(6):1170-9. doi: 10.1038/mt.2011.39. Epub 2011 Mar 22.


JX-594 is a targeted and granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In a phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, decreased tumor perfusion, and tumor necrosis. We hypothesized that JX-594 and sorafenib, a small molecule inhibitor of B-raf and vascular endothelial growth factor receptor (VEGFR) approved for HCC, would have clinical benefit in combination given their demonstrated efficacy in HCC patients and their complementary mechanisms-of-action. HCC cell lines were uniformly sensitive to JX-594. Anti-raf kinase effects of concurrent sorafenib inhibited JX-594 replication in vitro, whereas sequential therapy was superior to either agent alone in murine tumor models. We therefore explored pilot safety and efficacy of JX-594 followed by sorafenib in three HCC patients. In all three patients, sequential treatment was (i) well-tolerated, (ii) associated with significantly decreased tumor perfusion, and (iii) associated with objective tumor responses (Choi criteria; up to 100% necrosis). HCC historical control patients on sorafenib alone at the same institutions had no objective tumor responses (0 of 15). Treatment of HCC with JX-594 followed by sorafenib has antitumoral activity, and JX-594 may sensitize tumors to subsequent therapy with VEGF/VEGFR inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Benzenesulfonates / therapeutic use*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / therapy*
  • Cell Line, Tumor
  • Female
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / therapy
  • Melanoma / drug therapy
  • Melanoma / therapy
  • Mice
  • Mice, SCID
  • Niacinamide / analogs & derivatives
  • Oncolytic Virotherapy / methods
  • Phenylurea Compounds
  • Pyridines / therapeutic use*
  • Sorafenib
  • Vaccinia virus / genetics
  • Vaccinia virus / physiology*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Benzenesulfonates
  • Phenylurea Compounds
  • Pyridines
  • Niacinamide
  • Sorafenib