A New Generation of Serotype Chimeric Infectivity-Enhanced Conditionally Replicative Adenovirals: The Safety Profile of Ad5/3-Δ24 in Advance of a Phase I Clinical Trial in Ovarian Cancer Patients
| Autor: | Brock M. Miniard, James O. Peggins, Raymond D. Harris, Ronald D. Alvarez, Thomas L. Rudge, Akseli Hemminki, Meredith A. Preuss, Minghui Wang, David T. Curiel, Rosemarie Aurigemma, Trevor Broadt, Michael J. Ryan, Gene P. Siegal, Kenneth H. Kim, James E. Estep |
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| Rok vydání: | 2011 |
| Předmět: |
Oncolytic adenovirus
Genetic Vectors Drug Evaluation Preclinical Virus Replication medicine.disease_cause Polymerase Chain Reaction Adenoviridae Cricetinae Genetics Animals Medicine Tissue Distribution Serotyping Virotherapy Molecular Biology Research Articles Oncolytic Virotherapy Ovarian Neoplasms Infectivity Mesocricetus business.industry Cancer Genetic Therapy medicine.disease Antibodies Neutralizing Virology Oncolytic virus Disease Models Animal Real-time polymerase chain reaction DNA Viral Molecular Medicine Female business Ovarian cancer Injections Intraperitoneal |
| Zdroj: | Human Gene Therapy. 22:821-828 |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/hum.2010.180 |
| Popis: | Conditionally replicative adenoviral (CRAd) virotherapy represents a promising therapeutic approach for cancer. We have demonstrated that a serotype chimeric adenoviral 5/3 fiber-knob modification achieves enhanced ovarian cancer infectivity, conditional replication, and oncolytic activity. This study evaluated the safety of intraperitoneal (IP) Ad5/3-Δ24 in advance of a phase I clinical trial in gynecologic cancers. Syrian hamster cohorts were treated with IP Ad5/3-Δ24 or control buffer for 3 consecutive days and euthanized on study days 8, 17, 57, and 89. Blood and tissue samples were harvested from each animal. For biodistribution studies, presence and quantitation of viral levels within samples were determined via quantitative polymerase chain reaction. For safety studies, animals were assessed for adverse vector-related tissue or laboratory effects. In the biodistribution study, low levels of Ad5/3-Δ24 DNA were noted outside of the abdominal cavity. Viral DNA levels in tissues obtained from the peritoneal cavity peaked at day 8 and declined thereafter. In the safety study, no specific histopathologic changes were attributable to virus administration. Hematologic findings noted in the 1 × 10(11) viral particles (vp)/dose group on Days 4 and/or 8 were indicative of an Ad5/3-Δ24-specific generalized inflammatory response; these findings resolved by day 56. The no observable adverse effect level was determined to be 1 × 10(10) vp/dose. This study elucidates the safety profile of IP administration of the serotype chimeric infectivity-enhanced CRAd, Ad5/3-Δ24, and provides guidance for a planned phase I trial for patients with recurrent gynecologic cancers. |
| Databáze: | OpenAIRE |
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