Current Strategies and Future Directions for Eluding Adenoviral Vector Immunity

Abstract

Adenoviral (Ad) vectors can efficiently transduce a broad range of cell types and have been used extensively in preclinical and clinical studies for gene delivery applications. The presence of preexisting Ad immunity in the majority of human population and a rapid development of immune response against the Ad vector backbone following the first inoculation with the vector have impeded clinical use of these vectors. In addition, a number of animal inoculation studies have demonstrated that high systemic doses of Ad vectors invariably lead to initiation of acute inflammatory responses. This is mainly due to activation of innate immunity by vector particles. In general, vector and innate immune responses drastically limit the vector transduction efficiency and the duration of transgene expression. In order to have a predictable response with Ad vectors for gene therapy applications, the above limitations must be overcome. Strategies that are being examined to circumvent these drawbacks of Ad vectors include immunosuppression, immunomodulation, serotype switching, use of targeted Ad vectors, microencapsulation of Ad vectors, use of helper-dependent (HD) Ad vectors, and development of nonhuman Ad vectors. Here we review the current understanding of immune responses to Ad vectors, and recent advances in the strategies for immune evasion to improve the vector transduction efficiency and the duration of transgene expression. Development of novel strategies for targeting specific cell types would further boost the utility of Ad vectors by enhancing the safety, efficacy and duration of transgene expression.

Ultrasound-assisted non-viral gene transfer to the salivary glands

“…6 Viral vectors have clearly proven the principle that gene transfer to the salivary glands has the potential to transform many facets of oral medicine, but viral vector technology has drawbacks. 7 Despite significant progress, viral vectors elicit host immune responses, [8][9][10] can pose onocogenic risks 11,12 and cannot achieve life-long expression in vivo.…”

Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells

“…20,21 This is thought to hamper clinical applications of Ad5-based vaccines and oncolytic Ad5 viruses. 22,23 Therefore, we evaluated the recombinant GFP-expressing, fiber-modified Ad5 vectors in a newly developed human blood loop system. 24 Viruses were mixed with whole blood or medium and incubated in heparin-coated polyvinyl chloride tubing at 37 1C while rotating.…”

Wild-type adenoviruses from groups A–F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent

“…[15][16][17] Multiple Ad serotypes are currently under investigation for their potential ability to uniquely target various tissues and/or evade HAd5-specific innate and adaptive immune responses. 18,19 To date, various members of groups A-F have been vectorized and evaluated in vitro and/or in vivo. These alternative serotype vectors have been demonstrated to show altered cell-type tropisms, retain their ability to avoid neutralizing antibodies to other Ad serotypes and can also stimulate antigen-specific CD8+ T-cell responses to transgenes they encode.…”