Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses.
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.
Fulci
Giulia
G
Dardinger Center for Neuro-Oncology and Neurosciences, Department of Neurological Surgery, James Cancer Hospital and Solove Research Institute, Ohio State University Medical Center, Columbus, OH 43210, USA.
Breymann
Laura
L
Gianni
Davide
D
Kurozomi
Kazuhiko
K
Rhee
Sarah S
SS
Yu
Jianhua
J
Kaur
Balveen
B
Louis
David N
DN
Weissleder
Ralph
R
Caligiuri
Michael A
MA
Chiocca
E Antonio
EA
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005910:Glioma / Q000276:immunology* / Q000473:pathology / Q000628:therapy* / Q000821:virology; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D010586:Phagocytes; D051381:Rats; D018139:Simplexvirus / Q000187:drug effects / Q000276:immunology*; D014771:Virion / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D007371:Interferon-gamma; D003520:Cyclophosphamide