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

Abstract

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.

• Authors: Jeong Heo, Caroline J Breitbach, Anne Moon, Chang Won Kim, Rick Patt, Mi Kyung Kim, Yu Kyung Lee, Sung Yong Oh, Hyun Young Woo, Kelley Parato, Julia Rintoul, Theresa Falls, Theresa Hickman, Byung-Geon Rhee, John C Bell, David H Kirn, Tae-Ho Hwang
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 19 Issue 6 Pg. 1170-9 (Jun 2011) ISSN: 1525-0024 [Electronic] United States
• PMID: 21427706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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