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Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms

Cancer Gene Therapy volume 14, pages 590–597 (2007)Cite this article

Abstract

In this model of hepatic micrometastases, the antitumor efficacy and role of the T-cell and natural killer (NK) cell populations were studied for oncolytic herpes simplex virus type-1 (HSV-1) viral mutants containing the granulocyte-monocyte colony stimulating factor (GM-CSF (NV1034)) or interluken-12 (IL-12 (NV1042)) cytokine genes. These were compared to saline and control virus (NV1023) in vitro and in vivo. HSV-1 mutants were assessed for cytotoxicity, replication and cytokine expression in CT-26 cells. A syngeneic micrometastatic liver model was then established in naive and immune cell-depleted animals to assess the antitumor efficacy of these viruses. In vitro cytotoxicity and viral replication were similar for each virus, resulting in greater than 80 and 98% cytotoxicity at multiplicity of infection of 1 and 10, respectively. Peak viral titers were 25- to 50-fold higher than initial titer and were not significantly different between viruses. In vivo, all three viruses reduced metastases relative to control, but cytokine-secreting viruses did so with greater efficacy compared to NV1023. This effect was abrogated by T-cell depletion, but not NK-cell depletion. Single-agent therapy with oncolytic viral agents containing GM-CSF or IL-12 is effective in a murine model of liver metastases and likely involves direct viral oncolysis and actions of specific immune effector cells.

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Acknowledgements

Supported in part by Grants RO1 CA75416 (YF), RO1 CA72632 (YF) and RO1 CA615524 (YF) from the National Institutes of Health grant, MBC-99366 (YF) from the American Cancer Society and the Byrne Fund.

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  1. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    B G DeRubertis, B M Stiles, A Bhargava, N J Gusani, M Hezel, M D'Angelica & Y Fong

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  1. B G DeRubertis
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Correspondence to Y Fong.

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DeRubertis, B., Stiles, B., Bhargava, A. et al. Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms. Cancer Gene Ther 14, 590–597 (2007). https://doi.org/10.1038/sj.cgt.7701053

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