A New Generation of Serotype Chimeric Infectivity-Enhanced Conditionally Replicative Adenovirals: The Safety Profile of Ad5/3-Delta 24 in Advance of a Phase I Clinical Trial in Ovarian Cancer Patients

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-Delta 24 in advance of a phase I clinical trial in gynecologic cancers. Syrian hamster cohorts were treated with IP Ad5/3-Delta 24 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-Delta 24 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 x 10(11) viral particles (vp)/dose group on Days 4 and/or 8 were indicative of an Ad5/3-Delta 24-specific generalized inflammatory response; these findings resolved by day 56. The no observable adverse effect level was determined to be 1 x 10(10) vp/dose. This study elucidates the safety profile of IP administration of the serotype chimeric infectivity-enhanced CRAd, Ad5/3-Delta 24, and provides guidance for a planned phase I trial for patients with recurrent gynecologic cancers.

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