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
相关论文
共 39 条
[1]   Stability of lentiviral vector-mediated transgene expression in the brain in the presence of systemic antivector immune responses [J].
Abordo-Adesida, E ;
Follenzi, A ;
Barcia, C ;
Sciascia, S ;
Castro, MG ;
Naldini, L ;
Lowenstein, PR .
HUMAN GENE THERAPY, 2005, 16 (06) :741-751
[2]   Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins [J].
Andreansky, S ;
He, B ;
van Cott, J ;
McGhee, J ;
Markert, JM ;
Gillespie, GY ;
Roizman, B ;
Whitley, RJ .
GENE THERAPY, 1998, 5 (01) :121-130
[3]   A FADD-dependent innate immune mechanism in mammalian cells [J].
Balachandran, S ;
Thomas, E ;
Barber, GN .
NATURE, 2004, 432 (7015) :401-405
[4]   Defective translational control facilitates vesicular stomatitis virus oncolysis [J].
Balachandran, S ;
Barber, GN .
CANCER CELL, 2004, 5 (01) :51-65
[5]   Interleukin 12 secretion enhances antitumor efficacy of oncolytic herpes simplex viral therapy for colorectal cancer [J].
Bennett, JJ ;
Malhotra, S ;
Wong, RJ ;
Delman, K ;
Zager, J ;
St-Louis, M ;
Johnson, P ;
Fong, Y .
ANNALS OF SURGERY, 2001, 233 (06) :819-826
[6]   An adenovirus mutant that replicates selectively in p53-deficient human tumor cells [J].
Bischoff, JR ;
Kim, DH ;
Williams, A ;
Heise, C ;
Horn, S ;
Muna, M ;
Ng, L ;
Nye, JA ;
SampsonJohannes, A ;
Fattaey, A ;
McCormick, F .
SCIENCE, 1996, 274 (5286) :373-376
[7]   SPECIFICITY OF HUMAN NATURAL-KILLER-CELLS IN LIMITING DILUTION CULTURE FOR DETERMINANTS OF HERPES-SIMPLEX VIRUS TYPE-1 GLYCOPROTEINS [J].
BISHOP, GA ;
KUMEL, G ;
SCHWARTZ, SA ;
GLORIOSO, JC .
JOURNAL OF VIROLOGY, 1986, 57 (01) :294-300
[8]  
BISHOP GA, 1984, J IMMUNOL, V133, P2207
[9]   Human natural killer cells produce abundant macrophage inflammatory protein-1 in response to monocyte-derived cytokines [J].
Bluman, EM ;
Bartynski, KJ ;
Avalos, BR ;
Caligiuri, MA .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 97 (12) :2722-2727
[10]   Oncolytic viruses [J].
Chiocca, EA .
NATURE REVIEWS CANCER, 2002, 2 (12) :938-950