Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors following intravenous delivery of reovirus

Jian Qiao, Hongxun Wang, Timothy Kottke, Christine White, Katie Twigger, Rosa Maria Diaz, Jill Thompson, Peter Selby, Johann De Bono, Alan Melcher, Hardev Pandha, Matt Coffey, Richard Vile, Kevin Harrington

Research output: Contribution to journalArticle

120 Scopus citations

Abstract

Purpose: The purpose of the present study was to investigate whether it is possible to achieve truly systemic delivery of oncolytic reovirus, in immunocompetent hosts, using cyclophosphamide to overcome some of the barriers to effective intratumorald elivery and replication of i.v. injected virus. Experimental Design: I.v. delivery of reovirus was combined with different regimens of i.p. administered cyclophosphamide in C57Bl/6 mice bearing established s.c. B16 tumors. Intratumoralviral replication, tumor size, and survival were measured along with levels of neutralizing antibody (NAb) in the blood. Finally, differential toxicities of the virus/cyclophosphamide regimens were monitored through viral replication in systemic organs, survival, and cardiac damage. Results: Repeated i.v. injection of reovirus was poorly effective at seeding intratumoral viral replication/oncolysis. However, by combining i.v. virus with cyclophosphamide, viral titers of between 10 7 and 108 plaque-forming units per milligram were recovered from regressing tumors. Doses of cyclophosphamide that ablated NAb were associated with severe toxicities, characterized by viral replication in systemic organs - toxicities that are mirrored by repeated reovirus injections into B-cell knockout mice. Next, we restructured the dosing of cyclophosphamide and i.v. virus such that a dose of 3 mg cyclophosphamide was administered 24 h before reovirus injection, and this schedule was repeated every 6 days. Using this protocol, high levels of intratumoral viral access and replication (∼107 plaque-forming units per milligram tumor) were maintained along with systemically protective levels of NAb and only very mild, non - life-threatening toxicity. Conclusion: NAb to oncolytic viruses play a dual role in the context of systemic viral delivery; on one hand, they hinder repeated administration of virus but on the other, they provide an important safety mechanism by which virus released from vigorous intratumoral replication is neutralized before it can disseminate and cause toxicity. These data support the use of cyclophosphamide to modulate, but not ablate, patient NAb, in development of carefully controlled clinical trials of the systemic administration of oncolytic viruses.

Original languageEnglish (US)
Pages (from-to)259-269
Number of pages11
JournalClinical Cancer Research
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Qiao, J., Wang, H., Kottke, T., White, C., Twigger, K., Diaz, R. M., Thompson, J., Selby, P., De Bono, J., Melcher, A., Pandha, H., Coffey, M., Vile, R., & Harrington, K. (2008). Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors following intravenous delivery of reovirus. Clinical Cancer Research, 14(1), 259-269. https://doi.org/10.1158/1078-0432.CCR-07-1510