The Wyeth vaccinia backbone of JX-594 is inherently

The Wyeth vaccinia backbone of JX-594 is inherently selleck bio tumor-selective due to endothelial growth factor receptor (EGFR)-ras pathway dependency (activated in cancer cells)5,6 and resistance to interferon induction and effects in tumors.7 The inherent therapeutic index is amplified by the deletion of the vaccinia thymidine kinase (TK) gene. As a result, JX-594 replication is also dependent on high levels of cellular TK which is driven by cell cycle abnormalities in cancer.8 Results from a phase 1 clinical trial of intratumoral JX-594 in patients with refractory liver tumors demonstrated safety, antitumor efficacy and mechanistic proof-of-concept for JX-594 replication, systemic dissemination to distant tumors and expression of biologically active GM-CSF.

9 In this trial, hepatocellular carcinoma (HCC) were found to be highly sensitive to JX-594, resulting in acute vascular shutdown and necrotic (Choi) tumor responses.10 Noninjected tumors also demonstrated infection and necrosis following trafficking of JX-594 through the blood to distant tumor sites. No liver toxicity was reported. Phase 2 development of JX-594 in patients with advanced HCC was therefore indicated. The only approved systemic therapy for HCC to date is sorafenib (Nexavar, and Bayer, Leverkusen, Germany). Sorafenib is an oral small molecule multi-kinase inhibitor that has both antiproliferative (via B-raf kinase inhibition) and antiangiogenic effects [via inhibition of vascular EGFR (VEGFR)] in mice and humans.11 Sorafenib was evaluated in two phase 3 randomized clinical trials of patients with advanced HCC.

12,13 In both of these trials, objective tumor responses were rare (1�C2% objective partial Response Evaluation Criteria In Solid Tumors (RECIST) responses). The median survival duration was increased by ~3 months. Sorafenib toxicities include rash (hand-foot syndrome), diarrhea, and fatigue; dose reductions and/or discontinuation are common. Therefore, novel therapies are needed for patients with HCC, both as single agents and in combination with sorafenib therapy. We hypothesized that the combination of the oncolytic poxvirus JX-594 and the small molecule sorafenib could result in superior efficacy to that achievable with sorafenib alone in HCC. These agents have differing and complementary mechanisms-of-action. JX-594 induces acute tumor cell cytolysis, tumor vascular disruption, and necrosis followed by long-term antitumor immunity.

In contrast, sorafenib is antiangiogenic and inhibits tumor progression. In addition, the toxicity profiles are not over-lapping, and therefore the combination was predicted to have an acceptable toxicity profile. Cilengitide A potential problem with this combination, if given simultaneously, would be that sorafenib could block JX-594 replication through its raf inhibition.

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