1. ¹Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY, USA
2. ²Department of Microbiology, Mount Sinai School of Medicine, New York, NY, USA
3. ³Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA
4. ⁴Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY, USA

Correspondence: Professor SLC Woo, Department of Gene and Cell Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1496, New York, NY 10029-6574, USA. E-mail: savio.woo@mssm.edu

⁵These two authors contributed equally to this work.

⁶Current address: II. Medical Department, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

Received 13 April 2008; Revised 3 July 2008; Accepted 31 July 2008; Published online 10 October 2008.

Abstract

Recombinant oncolytic viruses represent a promising alternative option for the treatment of malignant cancers. We have reported earlier the safety and efficacy of recombinant vesicular stomatitis virus (VSV) vectors in a rat model of hepatocellular carcinoma (HCC). However, the full potential of VSV therapy is limited by a sudden decline in intratumoral virus replication observed early after viral administration, a phenomenon that coincides with an accumulation of inflammatory cells within infected lesions. To overcome the antiviral function of these cells, we present a recombinant virus, rVSV-UL141, which expresses a protein from human cytomegalovirus known to downregulate the natural killer (NK) cell-activating ligand CD155. The modified vector resulted in an inhibition of NK cell recruitment in vitro, as well as decreased intratumoral accumulations of NK and NKT cells in vivo. Administration of rVSV-UL141 through hepatic artery infusion in immune-competent Buffalo rats harboring orthotopic, multi-focal HCC lesions resulted in a one-log elevation of intratumoral virus replication over a control rVSV vector, which translated to enhance tumor necrosis and substantial prolongation of survival. Moreover, these results were achieved in the absence of apparent toxicities. The present study suggests the applicability of this strategy for the development of effective and safe oncolytic agents to treat multi-focal HCC, and potentially a multitude of other cancers, in the future.