title: Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses.
abstract: 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.
authors.affiliation: 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.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fulci
authors.forename: Laura
authors.initials: L
authors.lastname: Breymann
authors.forename: Davide
authors.initials: D
authors.lastname: Gianni
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kurozomi
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Rhee
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
mesh_terms: 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
chemical_list: D007371:Interferon-gamma; D003520:Cyclophosphamide