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

Nature Medicine volume 5, pages 881–887 (1999)Cite this article

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.

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Figure 1: CPA inhibits the generation of neutralizing antibodies in immunocompetent or athymic rats.
Figure 2: Presence of an innate antiviral activity in rat plasma that is CPA-labile.
Figure 3: The innate antiviral activity is also present in human plasma.
Figure 4: The innate antiviral activity interacts with complement in a calcium-dependent manner.
Figure 5: Pretreatment of rat plasma with rabbit antibody against rat IgM abrogates the innate antiviral activity in a dose-dependent manner.
Figure 6: Intravascular administration of oncolytic virus to a single human U87dEGFR glioma xenograft in rat brain.
Figure 7: Intravascular administration of oncolytic virus to human glioma xenografts established in brains of nude rats.

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Acknowledgements

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).

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Authors and Affiliations

  1. Molecular Neuro-Oncology Laboratories, Neurosurgery Service, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Keiro Ikeda, Tomotsugu Ichikawa, Hiroaki Wakimoto, Thomas S. Deisboeck, Griffith R. Harsh IV, David N. Louis & E. Antonio Chiocca

  2. Molecular Neuro-Oncology Laboratories, Neuropathology, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Jonathan S. Silver & David N. Louis

  3. MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Dianne Finkelstein

  4. Alkermes, Cambridge, 02111, Massachusetts, USA

    Raymond T. Bartus

  5. Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Fred H. Hochberg

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Correspondence to E. Antonio Chiocca.

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Ikeda, K., Ichikawa, T., Wakimoto, H. et al. Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses. Nat Med 5, 881–887 (1999). https://doi.org/10.1038/11320

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