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Enhancing Poxvirus Oncolytic Effects through Increased Spread and Immune Evasion

¹ Jennerex Biotherapeutics, Ltd., San Francisco, California; ² Cancer Research UK Molecular Oncology Center, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, United Kingdom; ³ Department of Pediatrics, Microbiology and Immunology and Radiology and Bio-X Program, Stanford University, Stanford, California; and ⁴ Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for reprints: Stephen Thorne, University of Pittsburgh Cancer Institute, Hillman Cancer Center, G12g, 5115 Center Avenue, Pittsburgh, PA 15232. Phone: 412-623-4896; Fax: 412-623-2525; E-mail: ThorneSH{at}UPMC.edu.

Key Words: Oncolytic virus • Therapy • Vaccinia

The antitumoral effects of oncolytic viruses have generally been limited by inefficient spread of the viruses within infected tumors and by inefficient systemic delivery, particularly in preimmunized hosts. Tumor-selective poxviruses have biological characteristics that may overcome these limitations. Nevertheless, physical barriers within the tumor microenvironment, including the extracellular matrix, can still limit intratumoral spread, and neutralizing antibodies can impede systemic delivery. To counter these limitations, we sought to take advantage of a naturally occurring poxvirus form known as extracellular enveloped virus (EEV). The EEV is shrouded by a host cell–derived lipid bilayer containing anticomplement proteins and is typically released from infected cells early during the infection cycle. Therefore, the EEV form evolved for rapid systemic spread within the host and for evasion of immune-mediated clearance. We compared the oncolytic potential of low versus high EEV-producing strains of vaccinia. EEV-enhanced vaccinia strains displayed improved spread within tumors after systemic delivery, resulting in significantly improved antitumor effects. The EEV-enhanced strains also displayed a greater ability to spread between injected and noninjected distant tumors through the blood and, importantly, displayed reduced clearance by neutralizing antibody. Safety was unaffected. The incorporation of EEV-enhancing mutations into next generation oncolytic vaccinia strains may improve the potency of these viruses without sacrificing safety. [Cancer Res 2008;68(7):2071–5]