JX-594, a targeted oncolytic poxvirus for the treatment of cancer.
JX-594 is a replication-competent Wyeth strain vaccinia virus that was genetically modified to inactive the endogenous thymidine kinase gene and to express human GM-CSF and LacZ genes. In development by Jennerex Inc and licensee Green Cross Corp, the modified virus is a novel therapy for treatment-refractive metastatic malignancies from various sites of origin. Targeted oncolytic virotherapy has demonstrated promise in preclinical studies, and more than ten viral species have subsequently entered clinical trials. JX-594 has been modified to augment the intrinsic targeting and oncolytic potential of the vaccinia virus and to enhance antitumor immunity by the expression of the GM-CSF transgene in situ. In vitro and in vivo animal studies have demonstrated the replication specificity of JX-594 for cancer cell lines and tumors, and the restriction of serum human GM-CSF expression to tumor-bearing animals, resulting in significantly reduced tumor burden and an increase in median survival. In phase I trials, JX-594 was well tolerated, with mild systemic toxicity reported. In a phase I trial in seven patients with melanoma, one partial response and one complete response after surgery were observed. In another phase I trial in patients with hepatic carcinoma, three out of ten evaluable patients had a partial response and six had stable disease; the MTD was also established. A phase II trial in patients (expected n = 30) with unresectable primary hepatocellular carcinoma was recruiting at the time of publication, with completion expected in March 2010, and a phase III trial in patients with hepatocellular carcinoma was planned for the second half of 2010. Further clinical investigations are needed to explore the potential of this agent as a single therapy and as part of multimodal treatment regimens.
Merrick
Alison E
AE
St James's University Hospital, Leeds Institute of Molecular Medicine, Targeted and Biological Therapies, Beckett Street, Leeds, LS9 7TF, UK. a.merrick@leeds.ac.uk
Ilett
Elizabeth J
EJ
Melcher
Alan A
AA
D000818:Animals; D002986:Clinical Trials as Topic; D006801:Humans; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D016896:Treatment Outcome; D014616:Vaccinia virus / Q000235:genetics; D014779:Virus Replication
D013937:Thymidine Kinase