1. ¹Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, MN, USA
2. ²Ottawa Health Research Institute, Ottawa, Ontario, Canada
3. ³Cancer Research UK Clinical Centre, Leeds, UK
4. ⁴Leeds Teaching Hospitals NHS Trust, Leeds, UK
5. ⁵Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
6. ⁶The Institute of Cancer Research, London, UK
7. ⁷Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA

Correspondence: Dr RG Vile, Molecular Medicine Program, Mayo Clinic, Guggenheim 1836, 200 First Street SW, Rochester, MN 55902, USA. E-mail: vile.richard@mayo.edu

Received 20 August 2007; Revised 6 November 2007; Accepted 6 November 2007; Published online 28 February 2008.

Abstract

Although adoptive T-cell therapy has shown clinical success, efficacy is limited by low levels of T-cell trafficking to, and survival in, the immunosuppressive environment of an established tumor. Oncolytic virotherapy has recently emerged as a promising approach to induce both direct tumor cell killing and local proinflammatory environments within tumors. However, inefficient systemic delivery of oncolytic viruses remains a barrier to use of these agents against metastatic disease that is not directly accessible to the end of a needle. Here we show that the ability of antigen-specific T cells to circulate freely, and to localize to tumors, can be exploited to achieve the systemic delivery of replication-competent, oncolytic vesicular stomatitis virus (VSV). Thus, VSV loaded onto OT-I T cells, specific for the SIINFEKL epitope of the ovalbumin antigen, was efficiently delivered to established B16ova tumors in the lungs of fully immune-competent C57Bl/6 mice leading to significant increases in therapy compared to the use of virus, or T cells, alone. Although OT-I T-cell-mediated delivery of VSV led to viral replication within tumors and direct viral oncolysis, therapy was also dependent upon an intact host immune system. Moreover, VSV loading onto the T cells increased both T-cell activation in vitro and T-cell trafficking in vivo. The combination of adoptive T-cell transfer of antigen-specific T cells, along with oncolytic virotherapy, can, therefore, increase the therapeutic utility of both approaches through multiple mechanisms and should be of direct translational value.