TY - JOUR
T1 - Effect of tumor microenvironment modulation on the efficacy of oncolytic virus therapy
AU - Kurozumi, Kazuhiko
AU - Hardcastle, Jayson
AU - Thakur, Roopa
AU - Yang, Ming
AU - Christoforidis, Gregory
AU - Fulci, Giulia
AU - Hochberg, Fred H.
AU - Weissleder, Ralph
AU - Carson, William
AU - Chiocca, E. Antonio
AU - Kaur, Balveen
N1 - Funding Information:
The National Brain Tumor Foundation, Glioblastoma Multiforme Grant (to B. K.); National Institutes of Health Grant (P01 CA069246 to F. H. H, E. A. C, and R. W.); American Association for Neurological Surgeons/Congress of Neurological Surgeons, Section on Tumors/BrainLab International Research Fellowship (to K. K.).
PY - 2007/12
Y1 - 2007/12
N2 - 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-γ). 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-γ protein levels (mean IFN-γ 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.
AB - 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-γ). 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-γ protein levels (mean IFN-γ 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.
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U2 - 10.1093/jnci/djm229
DO - 10.1093/jnci/djm229
M3 - Article
C2 - 18042934
AN - SCOPUS:38449114010
SN - 0027-8874
VL - 99
SP - 1768
EP - 1781
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 23
ER -
