title: Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus.
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.
authors: 1] Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK [2] Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Elizabeth
authors: E
authors: Ilett
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Timothy
authors: T
authors: Kottke
authors: Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK.
authors: Oliver
authors: O
authors: Donnelly
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Jill
authors: J
authors: Thompson
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Candice
authors: C
authors: Willmon
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Rosa
authors: R
authors: Diaz
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Shane
authors: S
authors: Zaidi
authors: Oncolytics Biotech Incorporated, Calgary, Alberta, Canada.
authors: Matt
authors: M
authors: Coffey
authors: Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK.
authors: Peter
authors: P
authors: Selby
authors: The Institute of Cancer Research, London, UK.
authors: Kevin
authors: K
authors: Harrington
authors: Department of Microbial and Cellular Sciences, University of Surrey, Guildford, UK.
authors: Hardev
authors: H
authors: Pandha
authors: Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK.
authors: Alan
authors: A
authors: Melcher
authors: 1] Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK [2] Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA [3] Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Richard
authors: R
authors: Vile
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000378:metabolism; D000914:Antibodies, Viral; D039481:CD11b Antigen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D007109:Immunity / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012089:Mammalian orthoreovirus 3 / Q000235:genetics / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics* / Q000276:immunology; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D047368:Tumor Burden
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D039481:CD11b Antigen; D016207:Cytokines; D011961:Receptors, Fc; D016178:Granulocyte-Macrophage Colony-Stimulating Factor