Oncolytic vaccinia virus combined with radiotherapy induces apoptotic cell death in sarcoma cells by down-regulating the inhibitors of apoptosis

// Michelle J. Wilkinson 1, 2 , Henry G. Smith 1, 2 , Grainne McEntee 1 , Joan Kyula-Currie 1 , Tim D. Pencavel 1, 2, * , David C. Mansfield 1 , Aadil A. Khan 1 , Victoria Roulstone 1 , Andrew J. Hayes 2, 3, * , Kevin J. Harrington 1, 3, * 1 Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, London, UK 2 Sarcoma/Melanoma Unit, Department of Academic Surgery, Royal Marsden Hospital NHS Foundation Trust, London, UK 3 Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK * These authors have contributed equally to this work Correspondence to: Kevin J. Harrington, email: Kevin.Harrington@icr.ac.uk Keywords: oncolytic virotherapy, radiation, soft tissue sarcoma Received: May 20, 2016     Accepted: October 11, 2016     Published: October 22, 2016 ABSTRACT Advanced extremity melanoma and sarcoma present a significant therapeutic challenge, requiring multimodality therapy to treat or even palliate disease. These aggressive tumours are relatively chemo-resistant, therefore new treatment approaches are urgently required. We have previously reported on the efficacy of oncolytic virotherapy (OV) delivered by isolated limb perfusion. In this report, we have improved therapeutic outcomes by combining OV with radiotherapy. In vitro , the combination of oncolytic vaccinia virus (GLV-1h68) and radiotherapy demonstrated synergistic cytotoxicity. This effect was not due to increased viral replication, but mediated through induction of intrinsic apoptosis. GLV-1h68 therapy downregulated the anti-apoptotic BCL-2 proteins (MCL-1 and BCL-XL) and the downstream inhibitors of apoptosis, resulting in cleavage of effector caspases 3 and 7. In an in vivo ILP model, the combination of OV and radiotherapy significantly delayed tumour growth and prolonged survival compared to single agent therapy. These data suggest that the virally-mediated down-regulation of anti-apoptotic proteins may increase the sensitivity of tumour cells to the cytotoxic effects of ionizing radiation. Oncolytic virotherapy represents an exciting candidate for clinical development when delivered by ILP. Its ability to overcome anti-apoptotic signals within tumour cells points the way to further development in combination with conventional anti-cancer therapies.