Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses

被引:278
作者
Fulci, Giulia
Breymann, Laura
Gianni, Davide
Kurozomi, Kazuhiko
Rhee, Sarah S.
Yu, Jianhua
Kaur, Balveen
Louis, David N.
Weissleder, Ralph
Caligiuri, Michael A.
Chiocca, E. Antonio
机构
[1] Ohio State Univ, Med Ctr, James Canc Hosp, Dardinger Ctr Neurooncol & Neurosci,Dept Neurol S, Columbus, OH 43210 USA
[2] Ohio State Univ, Med Ctr, Solove Res Inst, Columbus, OH 43210 USA
[3] Massachusetts Gen Hosp, Mol Neurooncol Labs, Neurosurg Serv, Charlestown, MA 02129 USA
[4] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA
[5] Massachusetts Gen Hosp, Pathol Serv, Charlestown, MA 02129 USA
[6] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA
关键词
gene therapy; innate immunity; oncolytic virus; brain tumor; herpes simplex virus;
D O I
10.1073/pnas.0605496103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Clinical trials are testing oncolytic viruses (OVs) as therapies for cancer. We have shown that animals that have brain tumors and are treated with a herpes simplex virus (HSV)-derived OV live significantly longer when cyclophosphamide (CPA) is preadministered. Here, we explore the mechanisms behind this finding. In a syngeneic rat glioma model, intratumoral HSV administration is associated with rapid increase of natural killer cells, microglia/ macrophages (CD68(+) and CD163(+)), and IFN-gamma. Pretreatment with CPA enhances HSV replication and oncolysis and reduces an HSV-mediated increase in CD68(+) and CD163+ cells and intratumoral IFN-gamma. Molecular imaging shows CPA pretreatment to inhibit HSV-induced infiltration of tumor-associated phagocytic cells. Our results reveal molecular and cellular mechanisms that inhibit intratumoral spread of HSV and suggest a therapeutic path for improving the efficacy of virotherapy as a treatment for cancer.
引用
收藏
页码:12873 / 12878
页数:6
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