16 - Methods to Mitigate Immune Responses to Adenoviral Vectors

Abstract

Recombinant adenovirus (Ad) vectors are widely utilized vehicles for gene therapy applications in preclinical settings, as well as in clinical human gene therapy trials. Importantly, the clinical use of Ad-based vectors continues to surpass all other gene transfer platforms relative to numbers of patients treated and number of clinical trials overall. Despite their numerous advantages, including efficient transduction of therapeutic transgenes into a variety of cells in vivo and ease for scaled production, the elicitation of innate and adaptive immune responses, both to the Ad vector itself and to the transgenes expressed by the vectors, is a major limitation for their utilization in clinical applications in general, and in gene therapy trials in particular. These issues, however, are not unique to Ad-based gene transfer vectors. Thus, lessons learned with regard to overcoming these problems with Ad-based vectors are also highly relevant to all gene transfer vectors. Recent advances in adenovirus biology and immunology fields have shed light on how this virus vector interacts with both the innate and the adaptive immune systems. These facts, coupled with utilization of several strategies that allow for modulation of these immune responses, have improved the outcome of Ad-based gene transfer in several human clinical trials. In this chapter, we review the current understanding of innate and adaptive immune responses to Ad vectors, as well as some recent novel strategies that attempt to harness Ad vector- and/or host-induced immune responses to further broaden the safe and efficient use of Ad-based gene transfer therapies.