Immune-mediated antitumor activity of reovirus is required for therapy and is independent of direct viral oncolysis and replication

Robin J. Prestwich, Elizabeth J. Ilett, Fiona Errington, Rosa M. Diaz, Lynette P. Steele, Tim Kottke, Jill Thompson, Feorillo Galivo, Kevin J. Harrington, Hardev S. Pandha, Peter J. Selby, Richard Geoffrey Vile, Alan A. Melcher

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Abstract

Purpose: Reovirus is a naturally occurring oncolytic virus in clinical trials. Although tumor infection by reovirus can generate adaptive antitumor immunity, its therapeutic importance versus direct viral oncolysis is undefined. This study addresses the requirement for viral oncolysis and replication, and the relative importance of antitumor immunity and direct oncolysis in therapy. Experimental Design: Nonantigen specificTcells loaded with reovirus were delivered i.v. to C57BL/6 and severe combined immunodeficient mice bearing lymph node and splenic metastases fromthemurine melanoma, B16ova,with assessment of viral replication, metastatic clearance by tumor colony outgrowth, and immune priming. Human cytotoxic lymphocyte priming assays were done with dendritic cells loaded withMel888 cells before the addition of reovirus. Results: B16ova was resistant to direct oncolysis in vitro, and failed to support reovirus replication in vitro or in vivo. Nevertheless, reovirus purged lymph node and splenic metastases in C57BL/6 mice and generated antitumor immunity. In contrast, reovirus failed to reduce tumor burden in severe combined immunodeficient mice bearing either B16ova or reovirus-sensitive B16tk metastases. In the human system, reovirus acted solely as an adjuvant when added to dendritic cells already loaded with Mel888, supporting priming of specific antitumor cytotoxic lymphocyte, in the absence of significant direct tumor oncolysis; UV-treated nonreplicating reovirus was similarly immunogenic. Conclusion:The immune response is critical in mediating the efficacy of reovirus, and does not depend upon direct viral oncolysis or replication. The findings are of direct relevance to fulfilling the potential of this novel anticancer agent.

Original languageEnglish (US)
Pages (from-to)4374-4381
Number of pages8
JournalClinical Cancer Research
Volume15
Issue number13
DOIs
StatePublished - Jul 1 2009

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SCID Mice
Neoplasm Metastasis
Dendritic Cells
Immunity
Reoviridae Infections
Lymph Nodes
Oncolytic Viruses
Lymphocytes
Neoplasms
Adaptive Immunity
Tumor Burden
Inbred C57BL Mouse
Antineoplastic Agents
Melanoma
Research Design
Therapeutics
Clinical Trials
In Vitro Techniques

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Prestwich, R. J., Ilett, E. J., Errington, F., Diaz, R. M., Steele, L. P., Kottke, T., ... Melcher, A. A. (2009). Immune-mediated antitumor activity of reovirus is required for therapy and is independent of direct viral oncolysis and replication. Clinical Cancer Research, 15(13), 4374-4381. https://doi.org/10.1158/1078-0432.CCR-09-0334

Immune-mediated antitumor activity of reovirus is required for therapy and is independent of direct viral oncolysis and replication. / Prestwich, Robin J.; Ilett, Elizabeth J.; Errington, Fiona; Diaz, Rosa M.; Steele, Lynette P.; Kottke, Tim; Thompson, Jill; Galivo, Feorillo; Harrington, Kevin J.; Pandha, Hardev S.; Selby, Peter J.; Vile, Richard Geoffrey; Melcher, Alan A.

In: Clinical Cancer Research, Vol. 15, No. 13, 01.07.2009, p. 4374-4381.

Research output: Contribution to journalArticle

Prestwich, RJ, Ilett, EJ, Errington, F, Diaz, RM, Steele, LP, Kottke, T, Thompson, J, Galivo, F, Harrington, KJ, Pandha, HS, Selby, PJ, Vile, RG & Melcher, AA 2009, 'Immune-mediated antitumor activity of reovirus is required for therapy and is independent of direct viral oncolysis and replication', Clinical Cancer Research, vol. 15, no. 13, pp. 4374-4381. https://doi.org/10.1158/1078-0432.CCR-09-0334
Prestwich, Robin J. ; Ilett, Elizabeth J. ; Errington, Fiona ; Diaz, Rosa M. ; Steele, Lynette P. ; Kottke, Tim ; Thompson, Jill ; Galivo, Feorillo ; Harrington, Kevin J. ; Pandha, Hardev S. ; Selby, Peter J. ; Vile, Richard Geoffrey ; Melcher, Alan A. / Immune-mediated antitumor activity of reovirus is required for therapy and is independent of direct viral oncolysis and replication. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 13. pp. 4374-4381.
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abstract = "Purpose: Reovirus is a naturally occurring oncolytic virus in clinical trials. Although tumor infection by reovirus can generate adaptive antitumor immunity, its therapeutic importance versus direct viral oncolysis is undefined. This study addresses the requirement for viral oncolysis and replication, and the relative importance of antitumor immunity and direct oncolysis in therapy. Experimental Design: Nonantigen specificTcells loaded with reovirus were delivered i.v. to C57BL/6 and severe combined immunodeficient mice bearing lymph node and splenic metastases fromthemurine melanoma, B16ova,with assessment of viral replication, metastatic clearance by tumor colony outgrowth, and immune priming. Human cytotoxic lymphocyte priming assays were done with dendritic cells loaded withMel888 cells before the addition of reovirus. Results: B16ova was resistant to direct oncolysis in vitro, and failed to support reovirus replication in vitro or in vivo. Nevertheless, reovirus purged lymph node and splenic metastases in C57BL/6 mice and generated antitumor immunity. In contrast, reovirus failed to reduce tumor burden in severe combined immunodeficient mice bearing either B16ova or reovirus-sensitive B16tk metastases. In the human system, reovirus acted solely as an adjuvant when added to dendritic cells already loaded with Mel888, supporting priming of specific antitumor cytotoxic lymphocyte, in the absence of significant direct tumor oncolysis; UV-treated nonreplicating reovirus was similarly immunogenic. Conclusion:The immune response is critical in mediating the efficacy of reovirus, and does not depend upon direct viral oncolysis or replication. The findings are of direct relevance to fulfilling the potential of this novel anticancer agent.",
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AU - Prestwich, Robin J.

AU - Ilett, Elizabeth J.

AU - Errington, Fiona

AU - Diaz, Rosa M.

AU - Steele, Lynette P.

AU - Kottke, Tim

AU - Thompson, Jill

AU - Galivo, Feorillo

AU - Harrington, Kevin J.

AU - Pandha, Hardev S.

AU - Selby, Peter J.

AU - Vile, Richard Geoffrey

AU - Melcher, Alan A.

PY - 2009/7/1

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N2 - Purpose: Reovirus is a naturally occurring oncolytic virus in clinical trials. Although tumor infection by reovirus can generate adaptive antitumor immunity, its therapeutic importance versus direct viral oncolysis is undefined. This study addresses the requirement for viral oncolysis and replication, and the relative importance of antitumor immunity and direct oncolysis in therapy. Experimental Design: Nonantigen specificTcells loaded with reovirus were delivered i.v. to C57BL/6 and severe combined immunodeficient mice bearing lymph node and splenic metastases fromthemurine melanoma, B16ova,with assessment of viral replication, metastatic clearance by tumor colony outgrowth, and immune priming. Human cytotoxic lymphocyte priming assays were done with dendritic cells loaded withMel888 cells before the addition of reovirus. Results: B16ova was resistant to direct oncolysis in vitro, and failed to support reovirus replication in vitro or in vivo. Nevertheless, reovirus purged lymph node and splenic metastases in C57BL/6 mice and generated antitumor immunity. In contrast, reovirus failed to reduce tumor burden in severe combined immunodeficient mice bearing either B16ova or reovirus-sensitive B16tk metastases. In the human system, reovirus acted solely as an adjuvant when added to dendritic cells already loaded with Mel888, supporting priming of specific antitumor cytotoxic lymphocyte, in the absence of significant direct tumor oncolysis; UV-treated nonreplicating reovirus was similarly immunogenic. Conclusion:The immune response is critical in mediating the efficacy of reovirus, and does not depend upon direct viral oncolysis or replication. The findings are of direct relevance to fulfilling the potential of this novel anticancer agent.

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