Ilett, E orcid.org/0000-0002-9875-0322, Kottke, T, Donnelly, O et al. (10 more authors) (2014) Cytokine Conditioning Enhances Systemic Delivery and Therapy of an Oncolytic Virus. Molecular Therapy, 22 (10). pp. 1851-1863. ISSN 1525-0016
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2014, The American Society of Gene & Cell Therapy. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (CC-BY-NC-ND 4.0). |
Keywords: | Animals; Antibodies, Neutralizing; Antibodies, Viral; Antigens, CD11b; Cytokines; Cytotoxicity, Immunologic; Female; Gene Expression Regulation; Gene Transfer Techniques; Genetic Vectors; Granulocyte-Macrophage Colony-Stimulating Factor; Immunity; Killer Cells, Natural; Macrophages; Mammalian orthoreovirus 3; Melanoma, Experimental; Mice; Monocytes; Oncolytic Virotherapy; Oncolytic Viruses; Receptors, Fc; Transduction, Genetic; Tumor Burden |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Biomarkers and Therapy (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Oncology and Cancer Research - Labs (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Oncology and Clinical Research (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 30 Jul 2015 15:18 |
Last Modified: | 19 Mar 2021 15:22 |
Published Version: | http://dx.doi.org/10.1038/mt.2014.118 |
Status: | Published |
Publisher: | Nature Publishing Group |
Identification Number: | 10.1038/mt.2014.118 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:87579 |