Journal of the National Cancer Institute Advance Access originally published online on November 27, 2007
JNCI Journal of the National Cancer Institute 2007 99(23):1768-1781; doi:10.1093/jnci/djm229
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Effect of Tumor Microenvironment Modulation on the Efficacy of Oncolytic Virus Therapy
Affiliations of authors: Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery (KK, JH, RT, EAC, BK), Integrated Biological Graduate Program of Studies (JH), and Departments of Radiology (MY, GC) and Surgery (WC), James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH; Center for Molecular Imaging Research (RW) and Department of Neurology (FHH), Massachusetts General Hospital, Charlestown, MA; Department of Neurosurgery, Brain Tumor Research Center, Massachusetts General Hospital, Boston, MA (GF)
Correspondence to: Balveen Kaur or E. Antonio Chiocca, Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University, 385-D OSUCCC, 410 West 12th Ave, Columbus, OH 43210 (e-mail: balveen.kaur{at}osumc.edu or ea.chiocca{at}osumc.edu)
Background: The tumor microenvironment is being increasingly recognized as an important determinant of tumor progression as well as of therapeutic response. We investigated oncolytic virus (OV) therapy–induced changes in tumor blood vessels and the impact of modulating tumor vasculature on the efficacy of oncolytic virus therapy.
Methods: Rat glioma cells (D74/HveC) were implanted intracranially in immune-competent rats. Seven days later, the rats (groups of 3–7 rats) were treated with oncolytic virus (hrR3), and, 3 days later, brains were harvested for evaluation. Some rats were treated with angiostatic cRGD peptide 4 days before oncolytic virus treatment. Some rats were treated with cyclophosphamide (CPA), an immunosuppressant, 2 days before oncolytic virus treatment. Changes in tumor vascular perfusion were evaluated by magnetic resonance imaging of live rats and by fluorescence microscopy of tumor sections from rats perfused with Texas red–conjugated lectin immediately before euthanasia. Leukocyte infiltration in tumors was evaluated by anti-CD45 immunohistochemistry, and the presence of oncolytic virus in tumors was evaluated by viral titration. Changes in cytokine gene expression in tumors were measured by quantitative real-time polymerase chain reaction–based microarrays. Survival was analyzed by the Kaplan–Meier method. All statistical tests were two-sided.
Results: Oncolytic virus treatment of experimental rat gliomas increased tumor vascular permeability, host leukocyte infiltration into tumors, and intratumoral expression of inflammatory cytokine genes, including interferon gamma (IFN-
). The increase in vascular permeability was suppressed in rats pretreated with cyclophosphamide. Compared with rats treated with hrR3 alone, rats pretreated with a single dose of cRGD peptide before hrR3 treatment had reduced tumor vascular permeability, leukocyte infiltration, and IFN- protein levels (mean IFN- level for hrR3 versus hrR3 + cRGD = 203 versus 65.6 µg/mg, difference = 137 µg/mg, 95% confidence interval = 72.7 to 202.9 µg/mg, P = .006); increased viral titers in tumor tissue; and longer median survival (21 days versus 17 days, P<.001).
Conclusions: A single dose of angiostatic cRGD peptide treatment before oncolytic virus treatment enhanced the antitumor efficacy of oncolytic virus.
| CONTEXT AND CAVEATS Prior knowledge Oncolytic viruses have tumor-killing properties in experimental models but have not shown convincing evidence of efficacy in patients. Innate host immune responses combined with changes in the tumor microenvironment in response to ongoing oncolysis may limit the therapeutic effectiveness of oncolytic viruses. Tumor vasculature is a major determinant of tumor microenvironment, and we hypothesized that changes in tumor vascular perfusion would affect therapeutic outcome. Study design In vivo study of oncolytic virus therapy–induced changes in tumor blood vessels and the impact of modulating tumor vasculature on the efficacy of oncolytic virus therapy in a rat glioma model. Contribution Oncolytic virus treatment of rat gliomas increased the permeability of the tumor vasculature, tumor inflammation, and leukocyte infiltration. Pretreatment of gliomas with an angiogenesis inhibitor reduced inflammation, vascular hyperpermeability, and leukocyte infiltration of tumor tissue upon treatment with oncolytic virus and enhanced the anticancer efficacy of oncolytic virus treatment by increasing oncolytic virus propagation in tumors. Implications The use of antiangiogenic agents may improve the efficacy of oncolytic virus in patients. Limitations The effect of antiangiogenic agents on the efficacy of oncolytic viral therapy in a human glioma model in athymic nude mice is not known. The increased viral replication supported by tumors pretreated with antiangiogenic agents could lead to toxic effects that are associated with increased viral burden.
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Manuscript received January 30, 2007; revised September 17, 2007; accepted October 18, 2007.
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J Natl Cancer Inst 2007 99: 1739-1741.
J Natl Cancer Inst 2007 99: 1737.
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