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.

Progress in clinical oncolytic virus-based therapy for hepatocellular carcinoma

“…In addition to the role played by OV-induced inflammation, JX-594 has been shown to directly infect and kill tumourassociated vascular endothelial cells in mice following intravenous (IV) delivery (Breitbach et al, 2013). These findings have been confirmed in human HCC trials, demonstrating disruption of tumour perfusion following JX-594 therapy Heo et al, 2011).…”

Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

“…Clinically, profound tumor vascular ablation and subsequent durable tumor necrosis and long-term survival have been induced by JX-594 followed by small-molecule inhibitors of VEGFR in hypervascular HCC and renal cell cancers (both VEGF-rich; ref. 44). Of note, this potential synergy was reported even in patients who had failed previous therapy with sorafenib.…”

The impact of hypoxia on oncolytic virotherapy

“…The virus, either alone or in combination with sorafenib, a small molecule inhibitor of B-Raf and vascular endothelial growth factor (VEGF) receptor, was well-tolerated and displayed objective tumor response in a small number of patients with hepatocellular carcinoma. 14 In a recent study, Breitbach et al showed in a clinical trial that JX-594 selectively infects, replicates, and expresses transgene products in cancer tissue after intravenous infusion in a dose-related fashion in human cancer patients. 15 China approved the world's first OV (H101) for cancer treatment in 2005, showcasing the potential of OVs as a new class of pharmaceutical drugs for cancer patients.…”