Pre-existing Immunity and Passive Immunity to Adenovirus 5 Prevents Toxicity Caused by an Oncolytic Adenovirus Vector in the Syrian Hamster Model

• Published in: Molecular therapy 2009-10, Vol.17 (10), p.1724-1732
• Main Authors: Dhar, Debanjan, Spencer, Jacqueline F, Toth, Karoly, Wold, William SM
• Format: Article
• Language: English
• Subjects: Adenoviridae - immunology; Adenoviruses; Animals; Antibodies; Antibodies, Neutralizing - immunology; Cancer therapies; Chemotherapy; Clinical trials; Cricetinae; Cyclophosphamide - pharmacology; Drug dosages; Female; Genes; Genetic Vectors - immunology; Genetic Vectors - toxicity; Immunity - drug effects; Immunity - physiology; Immunocompetence; Immunology; Immunosuppressive Agents - pharmacology; Infections; Leukocytes; Liver; Liver - drug effects; Liver - metabolism; Mesocricetus; Oncolytic Virotherapy - adverse effects; Oncolytic Virotherapy - methods; Original; Toxicity; Tumors; Viruses
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2009.156

We have used Syrian hamsters to examine the role of pre-existing immunity to adenovirus (Ad) 5 in the toxicity of the oncolytic Ad vector INGN 007. Groups of hamsters were or were not immunized with Ad5. Half the hamsters were immunosuppressed using cyclophosphamide (CP), then injected intravenously (i.v.) with 3× the maximum tolerated dose (MTD) of INGN 007 (in immunocompetent hamsters), and toxicity and vector replication in the liver were quantitated. In nonimmunized immunocompetent hamsters, toxicity was observed early but the hamsters recovered by day 6 after vector injection. In nonimmunized immunosuppressed hamsters, the vector was lethal by 3 days. Pre-existing neutralizing antibody (NAb) prevented liver infection and hepatotoxicity in both immunocompetent and immunosuppressed hamsters. In another study, passive immunization of immunosuppressed hamsters 1 day before a lethal dose (1× MTD) of INGN 007 prevented liver infection and replication, but immunization 1 day after vector administration was barely effective. When immunosuppressed hamsters were passively immunized 1 day after injection of 1/3rd the MTD of INGN 007, then significant protection was observed against liver infection and toxicity. Therefore, serum NAb are sufficient to prevent oncolytic Ad vector liver infection and toxicity. We saw no evidence that pre-existing immunity was associated with increased vector toxicity.