1. ¹Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
2. ²Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida, USA
3. ³Cancer Research UK Clinical Centre, Leeds Teaching Hospitals NHS Trust, University of Leeds, St. James's University Hospital, Leeds, UK
4. ⁴Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
5. ⁵The Institute of Cancer Research, London, UK
6. ⁶Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

Correspondence: Richard G. Vile, Mayo Clinic, Guggenheim 18, 200 First Street SW, Rochester, Minnesota 55905, USA. E-mail: vile.richard@mayo.edu

Received 5 February 2008; Accepted 28 March 2008; Published online 22 April 2008.

Abstract

There are several roadblocks that hinder systemic delivery of oncolytic viruses to the sites of metastatic disease. These include the tumor vasculature, which provides a physical barrier to tumor-specific virus extravasation. Although interleukin-2 (IL-2) has been used in antitumor therapy, it is associated with endothelial cell injury, leading to vascular leak syndrome (VLS). Here, we demonstrate that IL-2-mediated VLS, accentuated by depletion of regulatory T cells (Treg), facilitates localization of intravenously (IV) delivered oncolytic virus into established tumors in immune-competent mice. IL-2, in association with Treg depletion, generates "hyperactivated" natural killer (NK) cells, possessing antitumor activity and secreting factors that facilitate virus spread/replication throughout the tumor by disrupting the tumor architecture. As a result, the combination of Treg depletion/IL-2 and systemic oncolytic virotherapy was found to be significantly more therapeutic against established disease than either treatment alone. These data demonstrate that it is possible to combine biological therapy with oncolytic virotherapy to generate systemic therapy against established tumors.