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

F. Errington, C. L. White, K. R. Twigger, A. Rose, K. Scott, L. Steele, L. J. Ilett, R. Prestwich, H. S. Pandha, M. Coffey, P. Selby, Richard Geoffrey Vile, K. J. Harrington, A. A. Melcher

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1257-1270
Number of pages14
JournalGene Therapy
Volume15
Issue number18
DOIs
StatePublished - 2008

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Melanoma
Neoplasms
Therapeutics
Oncolytic Viruses
Double-Stranded RNA
Myeloid Cells
Caspases
Chemokines
Heterografts
Interleukin-10
Dendritic Cells
Cell Death
Radiotherapy
Clinical Trials
Cytokines
Drug Therapy
Cell Line
Injections

ASJC Scopus subject areas

  • Genetics

Cite this

Errington, F., White, C. L., Twigger, K. R., Rose, A., Scott, K., Steele, L., ... Melcher, A. A. (2008). Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma. Gene Therapy, 15(18), 1257-1270. https://doi.org/10.1038/gt.2008.58

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma. / 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, Richard Geoffrey; Harrington, K. J.; Melcher, A. A.

In: Gene Therapy, Vol. 15, No. 18, 2008, p. 1257-1270.

Research output: Contribution to journalArticle

Errington, F, White, CL, Twigger, KR, Rose, A, Scott, K, Steele, L, Ilett, LJ, Prestwich, R, Pandha, HS, Coffey, M, Selby, P, Vile, RG, Harrington, KJ & Melcher, AA 2008, 'Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma', Gene Therapy, vol. 15, no. 18, pp. 1257-1270. https://doi.org/10.1038/gt.2008.58
Errington F, White CL, Twigger KR, Rose A, Scott K, Steele L et al. Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma. Gene Therapy. 2008;15(18):1257-1270. https://doi.org/10.1038/gt.2008.58
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, Richard Geoffrey ; Harrington, K. J. ; Melcher, A. A. / Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma. In: Gene Therapy. 2008 ; Vol. 15, No. 18. pp. 1257-1270.
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