Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus

Elizabeth Ilett, Timothy Kottke, Oliver Donnelly, Jill Thompson, Candice Willmon, Rosa Diaz, Shane Zaidi, Matt Coffey, Peter Selby, Kevin Harrington, Hardev Pandha, Alan Melcher, Richard Geoffrey Vile

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Optimum clinical protocols require systemic delivery of oncolytic viruses in the presence of an intact immune system. We show that preconditioning with immune modulators, or loading virus onto carrier cells ex vivo, enhances virus-mediated antitumor activity. Our early trials of systemic reovirus delivery showed that after infusion reovirus could be recovered from blood cells - but not from plasma - suggesting that rapid association with blood cells may protect virus from neutralizing antibody. We therefore postulated that stimulation of potential carrier cells directly in vivo before intravenous viral delivery would enhance delivery of cell-associated virus to tumor. We show that mobilization of the CD11b + cell compartment by granulocyte macrophage-colony stimulating factor immediately before intravenous reovirus, eliminated detectable tumor in mice with small B16 melanomas, and achieved highly significant therapy in mice bearing well-established tumors. Unexpectedly, cytokine conditioning therapy was most effective in the presence of preexisting neutralizing antibody. Consistent with this, reovirus bound by neutralizing antibody effectively accessed monocytes/macrophages and was handed off to tumor cells. Thus, preconditioning with cytokine stimulated recipient cells in vivo for enhanced viral delivery to tumors. Moreover, preexisting neutralizing antibody to an oncolytic virus may, therefore, even be exploited for systemic delivery to tumors in the clinic.

Original languageEnglish (US)
Pages (from-to)1851-1863
Number of pages13
JournalMolecular Therapy
Volume22
Issue number10
DOIs
StatePublished - Jan 1 2014

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Oncolytic Virotherapy
Cytokines
Neutralizing Antibodies
Oncolytic Viruses
Neoplasms
Viruses
Blood Cells
Satellite Viruses
Experimental Melanomas
Behavior Therapy
Granulocyte-Macrophage Colony-Stimulating Factor
Clinical Protocols
Conditioning (Psychology)
Monocytes
Immune System
Macrophages

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Ilett, E., Kottke, T., Donnelly, O., Thompson, J., Willmon, C., Diaz, R., ... Vile, R. G. (2014). Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus. Molecular Therapy, 22(10), 1851-1863. https://doi.org/10.1038/mt.2014.118

Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus. / Ilett, Elizabeth; Kottke, Timothy; Donnelly, Oliver; Thompson, Jill; Willmon, Candice; Diaz, Rosa; Zaidi, Shane; Coffey, Matt; Selby, Peter; Harrington, Kevin; Pandha, Hardev; Melcher, Alan; Vile, Richard Geoffrey.

In: Molecular Therapy, Vol. 22, No. 10, 01.01.2014, p. 1851-1863.

Research output: Contribution to journalArticle

Ilett, E, Kottke, T, Donnelly, O, Thompson, J, Willmon, C, Diaz, R, Zaidi, S, Coffey, M, Selby, P, Harrington, K, Pandha, H, Melcher, A & Vile, RG 2014, 'Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus', Molecular Therapy, vol. 22, no. 10, pp. 1851-1863. https://doi.org/10.1038/mt.2014.118
Ilett E, Kottke T, Donnelly O, Thompson J, Willmon C, Diaz R et al. Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus. Molecular Therapy. 2014 Jan 1;22(10):1851-1863. https://doi.org/10.1038/mt.2014.118
Ilett, Elizabeth ; Kottke, Timothy ; Donnelly, Oliver ; Thompson, Jill ; Willmon, Candice ; Diaz, Rosa ; Zaidi, Shane ; Coffey, Matt ; Selby, Peter ; Harrington, Kevin ; Pandha, Hardev ; Melcher, Alan ; Vile, Richard Geoffrey. / Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus. In: Molecular Therapy. 2014 ; Vol. 22, No. 10. pp. 1851-1863.
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