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Research Article

Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy

Robert A. Berkeley, Lynette P. Steele, Aat A. Mulder, Diana J.M. van den Wollenberg, Timothy J. Kottke, Jill Thompson, Matthew Coffey, Rob C. Hoeben, Richard G. Vile, Alan Melcher and Elizabeth J. Ilett
Robert A. Berkeley
Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
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Lynette P. Steele
Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
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Aat A. Mulder
Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands.
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  • ORCID record for Aat A. Mulder
Diana J.M. van den Wollenberg
Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands.
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Timothy J. Kottke
Department of Immunology, Mayo Clinic, Rochester, Minnesota.
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Jill Thompson
Department of Immunology, Mayo Clinic, Rochester, Minnesota.
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Matthew Coffey
Oncolytics Biotech Incorporated, Calgary, Alberta, Canada.
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Rob C. Hoeben
Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands.
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Richard G. Vile
Department of Immunology, Mayo Clinic, Rochester, Minnesota.
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Alan Melcher
Institute of Cancer Research, London, United Kingdom.
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Elizabeth J. Ilett
Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
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  • For correspondence: e.ilett@leeds.ac.uk
DOI: 10.1158/2326-6066.CIR-18-0309
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Abstract

Immunotherapy is showing promise for otherwise incurable cancers. Oncolytic viruses (OVs), developed as direct cytotoxic agents, mediate their antitumor effects via activation of the immune system. However, OVs also stimulate antiviral immune responses, including the induction of OV-neutralizing antibodies. Current dogma suggests that the presence of preexisting antiviral neutralizing antibodies in patients, or their development during viral therapy, is a barrier to systemic OV delivery, rendering repeat systemic treatments ineffective. However, we have found that human monocytes loaded with preformed reovirus–antibody complexes, in which the reovirus is fully neutralized, deliver functional replicative reovirus to tumor cells, resulting in tumor cell infection and lysis. This delivery mechanism is mediated, at least in part, by antibody receptors (in particular FcγRIII) that mediate uptake and internalization of the reovirus/antibody complexes by the monocytes. This finding has implications for oncolytic virotherapy and for the design of clinical OV treatment strategies. Cancer Immunol Res; 1–13. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • A. Melcher and E.J. Ilett share senior authorship of this article.

  • Received May 9, 2018.
  • Revision received August 14, 2018.
  • Accepted August 16, 2018.
  • Published first September 12, 2018.
  • ©2018 American Association for Cancer Research.

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Published OnlineFirst September 12, 2018
doi: 10.1158/2326-6066.CIR-18-0309

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Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy
Robert A. Berkeley, Lynette P. Steele, Aat A. Mulder, Diana J.M. van den Wollenberg, Timothy J. Kottke, Jill Thompson, Matthew Coffey, Rob C. Hoeben, Richard G. Vile, Alan Melcher and Elizabeth J. Ilett
Cancer Immunol Res September 12 2018 DOI: 10.1158/2326-6066.CIR-18-0309

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Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy
Robert A. Berkeley, Lynette P. Steele, Aat A. Mulder, Diana J.M. van den Wollenberg, Timothy J. Kottke, Jill Thompson, Matthew Coffey, Rob C. Hoeben, Richard G. Vile, Alan Melcher and Elizabeth J. Ilett
Cancer Immunol Res September 12 2018 DOI: 10.1158/2326-6066.CIR-18-0309
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