Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

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 test...

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Bibliographic Details
Published in:	Gene therapy Vol. 15; no. 18; pp. 1257 - 1270
Main Authors:	Errington, F, White, C L, Twigger, K R, Rose, A, Scott, K, Steele, L, Ilett, L J, Prestwich, R, Pandha, H S, Coffey, M, Selby, P, Vile, R, Harrington, K J, Melcher, A A
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-09-2008 Nature Publishing Group
Subjects:	Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals Apoptosis Applied cell therapy and gene therapy Biological and medical sciences Biomedical and Life Sciences Biomedical research Biomedicine Biotechnology Cancer cells Care and treatment Caspase Cell Biology Cell death Cell Line, Tumor Cell Survival Cellular biology Chemokines Chemotherapy Chromones - pharmacology Clinical trials Cytokines - immunology Cytotoxicity Tests, Immunologic Dendritic cells Dendritic Cells - immunology Double-stranded RNA Flow Cytometry Fundamental and applied biological sciences. Psychology Gene Expression Gene Therapy Genetic aspects Health aspects Health. Pharmaceutical industry Human Genetics Humans Imidazoles - pharmacology Industrial applications and implications. Economical aspects Inflammation Interleukin 10 Medical sciences Melanoma Melanoma - immunology Melanoma - therapy Molecular and cellular biology Morpholines - pharmacology Nanotechnology Oncolysis Oncolytic Virotherapy - methods original-article p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors Phosphoinositide-3 Kinase Inhibitors Pyridines - pharmacology Radiation therapy ras Proteins - metabolism Reoviridae - physiology Reovirus Reoviruses Ribonucleic acid RNA RNA viruses Signal Transduction - physiology Skin cancer Skin Neoplasms - immunology Skin Neoplasms - therapy Toxicity Transfusions. Complications. Transfusion reactions. Cell and gene therapy Tumor cell lines Tumor Cells, Cultured Tumors Virus Replication Viruses Xenografts United Kingdom melanoma inflammatory cytokines reovirus oncolytic virus Virus Treatment Cytokine Malignant melanoma Inflammation Malignant tumor Gene therapy Cancer
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Joint senior authors.
ISSN:	0969-7128 1476-5462
DOI:	10.1038/gt.2008.58