Use of multiply deleted adenovirus vectors to probe adenovirus vector performance and toxicities

Adenovirus (Ad)-based vectors have received considerable attention in recent years as the 'work-horse' of gene delivery, as evidenced by over 160 clinical trials utilizing this vector class. The Ad vectors utilized in these trials have been delivered into hundreds of humans via any number of intratumoral, intrabronchial, subcutaneous or intravenous routes. Most of these trials have utilized first-generation, E1-deleted [E1-] versions of these vectors. Multiple animal studies have demonstrated that [E1-]Ad vectors induce a variety of toxic responses, directed both to the Ad vector itself and the vector-transduced cells. Because of these limitations, the development of multiply attenuated (deleted) Ad vectors has been pursued by a number of research groups. These vectors retain many of the advantages of [E1-]Ad, while simultaneously improving the overall vector performance, primarily manifested as reduced sub-acute and chronic toxicities, combined with extended duration of persistence of the vectors within transduced cells. This review focuses upon the investigations that have been performed utilizing multiply deleted Ad vectors, and how these studies shed light upon the immune mechanisms directed against Ad vectors.