1. ¹Cancer Research UK Clinical Centre, St James's University Hospital, University of Leeds, Leeds, UK
2. ²Targeted Therapy Laboratory, Chester Beatty Laboratories, Institute of Cancer Research, Cancer Research UK Centre for Cell and Molecular Biology, London, UK
3. ³Postgraduate Medical School, University of Surrey, Guildford, UK
4. ⁴Oncolytics Biotech Inc., Calgary, Canada
5. ⁵Mayo Clinic, Rochester, MN, USA
6. ⁶Head and Neck Unit, Royal Marsden Hospital, London, UK

Correspondence: Professor AA Melcher, Cancer Research UK Clinical Centre, St James's University Hospital, University of Leeds, Beckett Street, Leeds LS9 7TF, UK. E-mail: a.a.melcher@leeds.ac.uk

⁷Joint senior authors.

Received 20 September 2007; Revised 21 February 2008; Accepted 23 February 2008; Published online 10 April 2008.

Abstract

Reovirus is a promising unmodified double-stranded RNA (dsRNA) anti-cancer oncolytic virus, which is thought to specifically target cells with activated Ras. Although reovirus has been tested in a wide range of preclinical models and has entered early clinical trials, it has not previously been tested for the treatment of human melanoma. Here, we show that reovirus effectively kills and replicates in both human melanoma cell lines and freshly resected tumour; intratumoural injection also causes regression of melanoma in a xenograft in vivo model. Reovirus-induced melanoma death is blocked by caspase inhibition and is dependent on constituents of the Ras/RalGEF/p38 pathway. Reovirus melanoma killing is more potent than, and distinct from, chemotherapy or radiotherapy-induced cell death; a range of inflammatory cytokines and chemokines are released by infected tumour cells, while IL-10 secretion is abrogated. Furthermore, the inflammatory response generated by reovirus-infected tumour cells causes bystander toxicity against reovirus-resistant tumour cells and activates human myeloid dendritic cells (DC) in vitro. Hence, reovirus is suitable for clinical testing in melanoma, and may provide a useful danger signal to reverse the immunologically suppressive environment characteristic of this tumour.