Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses

• Published in: Nature medicine Vol. 5; no. 8; pp. 881 - 887
• Main Authors: Chiocca, E. Antonio, Ikeda, Keiro, Ichikawa, Tomotsugu, Wakimoto, Hiroaki, Silver, Jonathan S, Deisboeck, Thomas S, Finkelstein, Dianne, Harsh, Griffith R, Louis, David N, Bartus, Raymond T, Hochberg, Fred H
• Format: Journal Article
• Language: English
• Published: United States 01.08.1999
• Subjects: Animals; Antibodies, Viral - blood; Antibody Formation - drug effects; Brain Neoplasms - immunology; Brain Neoplasms - mortality; Brain Neoplasms - therapy; Brain Neoplasms - virology; Complement System Proteins - immunology; cyclophosphamide; Cyclophosphamide - pharmacology; Female; Glioma - immunology; Glioma - mortality; Glioma - therapy; Glioma - virology; Humans; Immunity, Innate - drug effects; Immunoglobulin M - blood; Immunosuppression; Male; Neoplasm Transplantation; oncolytic viruses; Rats; Rats, Inbred F344; Rats, Nude; Survival Rate; Time Factors; Tumor Cells, Cultured; Viruses - immunology; Viruses - isolation & purification
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/11320

The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was shown to interact with complement in a calcium-dependent fashion, and antibody neutralization studies indicated preimmune IgM has a contributing role. Short-term exposure to cyclophosphamide (CPA) partially suppressed this activity in rodents and humans. At longer time points, cyclophosphamide also abrogated neutralizing antibody responses. Cyclophosphamide treatment of rats with large single or multiple intracerebral tumors substantially increased viral survival and propagation, leading to neoplastic regression.