Helper-Dependent Adenovirus Vectors Elicit Intact Innate but Attenuated Adaptive Host Immune Responses In Vivo

Abstract

Helper-dependent adenovirus (HD-Ad

PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile

“…Recent studies have found that animals treated with HD-Ad exhibit similar cytokine secretion patterns and toxicity as those treated with comparable doses of FG-Ad during the very early acute phase of the immune response. 24,25 We also found this to be the case in animals treated with either unmodified vector ( Figure 5). The fact that cytokine levels in animals treated with PEGylated FG-Ad were not statistically significant from those treated with PEGylated HD-Ad further supports the hypothesis that virus capsid proteins play a key role in triggering early innate immunity.…”

“…23 This interaction precipitates the acute phase of the innate immune response as animals treated with HD-Ad exhibit similar cytokine secretion patterns and toxicity profiles including coagulopathy and multiorgan failure as those described in animals treated with comparable doses of FG-Ad. 24,25 In addition, neutralizing antibodies against the viral capsid are produced, preventing successful readministration of HD-Ad vectors of the same serotype. 26 Thus, interaction of vector capsid proteins with the innate immune system is, at the moment, the final obstacle that must be overcome in the host with respect to the development of nonimmunogenic adenoviral vectors.…”

Factors influencing retention of adenovirus within tumours following direct intratumoural injection

“…Adenovirus particles trigger a capsid-dependent innate inflammatory response independent of virus gene expression or replication, 14,27 well documented using intravascular delivery routes in mouse and non-human primate studies and also in clinical trials. 15,23,[28][29][30][31] Although IT injection of adenovirus vectors should reduce the overall likelihood of inflammatory responses, our data suggest that the use of larger volumes of injectate may give substantial dissemination of virus into the systemic circulation.…”

Gutless adenovirus: last-generation adenovirus for gene therapy

“…Initially, gutless vectors are capable of transducing dendritic cells and stimulating Ad-specific T-cell responses, independent of viral gene transcription. 69 However, the expression of viral genes is required for T cells to exert their effector functions in the liver, 70 which possibly explains the vector persistence and improved transgene expression following transduction with gutless vectors compared to results with firstgeneration Ad vectors.…”

“…70 Vectors that mediate transgene expression in APCs trigger antibody formation because they increase the probability of neoantigen presentation by APCs, 71 and, hence, careful selection of tissue-specific promoters may significantly improve adenovirus-associated toxicity profiles and diminish or abolish APC transduction and transgene expression. 72 In addition, systemic administration of gutless vectors in a clinical setting might be inefficient because of the presence of circulating neutralizing antibodies against the same or crossreactive serotype as a consequence of a natural infection or as a result of previous vector administration.…”