Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses

Keiro Ikeda; Tomotsugu Ichikawa; Hiroaki Wakimoto; Jonathan S. Silver; Thomas S. Deisboeck; Dianne Finkelstein; Griffith R. Harsh IV; David N. Louis; Raymond T. Bartus; Fred H. Hochberg; E. Antonio Chiocca

doi:10.1038/11320

Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses

Keiro Ikeda, Tomotsugu Ichikawa, Hiroaki Wakimoto, Jonathan S. Silver, Thomas S. Deisboeck, Dianne Finkelstein, Griffith R. Harsh IV, David N. Louis, Raymond T. Bartus, Fred H. Hochberg, E. Antonio Chiocca

Research output: Contribution to journal › Article › peer-review

273 Citations (Scopus)

Abstract

The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was shown to interact with complement in a calcium-dependent fashion, and antibody neutralization studies indicated preimmune IgM has a contributing role. Short-term exposure to cyclophosphamide (CPA) partially suppressed this activity in rodents and humans. At longer time points, cyclophosphamide also abrogated neutralizing antibody responses. Cyclophosphamide treatment of rats with large single or multiple intracerebral tumors substantially increased viral survival and propagation, leading to neoplastic regression.

Original language	English
Pages (from-to)	881-887
Number of pages	7
Journal	Nature Medicine
Volume	5
Issue number	8
DOIs	https://doi.org/10.1038/11320
Publication status	Published - Aug 1999
Externally published	Yes

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1038/11320

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@article{2fec6f1d10ad4429831b1c1f580f32a0,

title = "Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses",

abstract = "The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was shown to interact with complement in a calcium-dependent fashion, and antibody neutralization studies indicated preimmune IgM has a contributing role. Short-term exposure to cyclophosphamide (CPA) partially suppressed this activity in rodents and humans. At longer time points, cyclophosphamide also abrogated neutralizing antibody responses. Cyclophosphamide treatment of rats with large single or multiple intracerebral tumors substantially increased viral survival and propagation, leading to neoplastic regression.",

author = "Keiro Ikeda and Tomotsugu Ichikawa and Hiroaki Wakimoto and Silver, {Jonathan S.} and Deisboeck, {Thomas S.} and Dianne Finkelstein and {Harsh IV}, {Griffith R.} and Louis, {David N.} and Bartus, {Raymond T.} and Hochberg, {Fred H.} and {Antonio Chiocca}, E.",

note = "Funding Information: Acknowledgments The authors acknowledge members of the EAC laboratory for their input in described experiments. We thank N. Rainov (Halle University, Germany) for initial technical aid, K. Suling and S. Jhung (Massachusetts General Hospital) for assistance with analyses by computer, P. Stark (Massachusetts General Hospital) for assistance with statistical analyses, W.P. Petros, S. Ludeman and M. Colvin (Duke University) for human plasma samples, and M. Pasternack (Massachusetts General Hospital) for discussions. This work was supported by an NIH research grant (P01CA 69246).",

year = "1999",

month = aug,

doi = "10.1038/11320",

language = "English",

volume = "5",

pages = "881--887",

journal = "Nature Medicine",

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T1 - Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses

AU - Ikeda, Keiro

AU - Ichikawa, Tomotsugu

AU - Wakimoto, Hiroaki

AU - Silver, Jonathan S.

AU - Deisboeck, Thomas S.

AU - Finkelstein, Dianne

AU - Harsh IV, Griffith R.

AU - Louis, David N.

AU - Bartus, Raymond T.

AU - Hochberg, Fred H.

AU - Antonio Chiocca, E.

N1 - Funding Information: Acknowledgments The authors acknowledge members of the EAC laboratory for their input in described experiments. We thank N. Rainov (Halle University, Germany) for initial technical aid, K. Suling and S. Jhung (Massachusetts General Hospital) for assistance with analyses by computer, P. Stark (Massachusetts General Hospital) for assistance with statistical analyses, W.P. Petros, S. Ludeman and M. Colvin (Duke University) for human plasma samples, and M. Pasternack (Massachusetts General Hospital) for discussions. This work was supported by an NIH research grant (P01CA 69246).

PY - 1999/8

Y1 - 1999/8

N2 - The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was shown to interact with complement in a calcium-dependent fashion, and antibody neutralization studies indicated preimmune IgM has a contributing role. Short-term exposure to cyclophosphamide (CPA) partially suppressed this activity in rodents and humans. At longer time points, cyclophosphamide also abrogated neutralizing antibody responses. Cyclophosphamide treatment of rats with large single or multiple intracerebral tumors substantially increased viral survival and propagation, leading to neoplastic regression.

AB - The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was shown to interact with complement in a calcium-dependent fashion, and antibody neutralization studies indicated preimmune IgM has a contributing role. Short-term exposure to cyclophosphamide (CPA) partially suppressed this activity in rodents and humans. At longer time points, cyclophosphamide also abrogated neutralizing antibody responses. Cyclophosphamide treatment of rats with large single or multiple intracerebral tumors substantially increased viral survival and propagation, leading to neoplastic regression.

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Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses

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