title: Cyclophosphamide allows for in vivo dose reduction of a potent oncolytic virus.
abstract: The success of cancer virotherapy depends on its efficacy versus toxicity profile in human clinical trials. Progress towards clinical trials can be hampered by the relatively elevated doses of oncolytic viruses administered in animal models to achieve an anticancer effect and by the even higher doses required in humans to approximate an animal bioequivalent dose. Such elevated doses of injected viral proteins may also lead to undesirable toxicities and are also very difficult to produce in a biotechnological setting. We report that a relatively potent herpes simplex virus type 1 oncolytic virus (rQNestin34.5) produces 45% survivors at a dose of 3 x 10(4) plaque-forming units (pfu) in a 9-day-old mouse model of human glioma. Unlike our previous findings with less potent oncolytic viruses, though, the preadministration of cyclophosphamide did not enhance this survival or affect oncolytic virus tumor distribution and tumor volume. However, when oncolytic virus doses were reduced (3 x 10(3) and 3 x 10(2) pfu), cyclophosphamide significantly enhanced both animal survival and oncolytic virus tumor distribution and also reduced tumor volumes. These findings thus show that cyclophosphamide allows for dose reduction of doses of a relatively potent oncolytic virus, a finding with implications for the development of clinical trials.
authors.affiliation: Dardinger Center for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, 43210, USA.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kambara
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Saeki
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005910:Glioma / Q000473:pathology / Q000628:therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D051379:Mice; D050504:Oncolytic Viruses / Q000235:genetics*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014779:Virus Replication
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide