Transient Pretreatment With Glucocorticoid Ablates Innate Toxicity of Systemically Delivered Adenoviral Vectors Without Reducing Efficacy

Abstract

More than 300 human clinical trials utilize recombinant adenoviruses (rAds) as a gene transfer vector, confirming that rAds continue to be of high clinical interest. A primary weakness of rAds is their known propensity to trigger an innate, proinflammatory immune response rapidly after high-dose, systemic administration. In this study, we investigated what affects that pre-emptive treatment with anti-inflammatory glucocorticoids might have upon Ad vector-triggered inflammatory immune responses. We found that a simple pretreatment regimen with Dexamethasone (DEX) can significantly reduce most Ad-induced innate immune responses. DEX prevented rAd induction of systemic cytokine/chemokine releases in a dose-dependent fashion, with higher dosages preventing rAd induction of acute thrombocytopenia, endothelial cell activation, proinflammatory gene induction, and leukocyte infiltration into transduced organs. Transient glucocorticoid pretreatment also significantly reduced rAd-induced adaptive immune responses, including a decreased induction of Ad-neutralizing antibodies (NAbs). Importantly, use of DEX did not reduce the efficacy of rAd-mediated gene transduction nor rAd-derived transgene expression. Our results demonstrate that a simple, pre-emptive and transient glucocorticoid pretreatment is a viable approach to reduce rAd-associated acute toxicities that currently limit the use of Ad vectors in systemic clinical applications.

In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors

“…Levels of the pro-inflammatory chemokine membrane cofactor protein-1 were elevated compared with untreated animals but still markedly lower than in other studies with Ad vectors, 29 most likely due to dexamethasone administration before virus injection. 30 The genotoxic potential of SB1003-mediated transgene integration after in vivo transduction was assessed in genomic DNA isolated from GFP 1 progenitor colonies through genome-wide integration analysis using linear amplification method-PCR and next-generation sequencing. A total of 155 distinct SB1003-mediated integration sites were identified ( Figures 6A-B).…”

Expression of the SLAM Family of Receptors Adapter EAT-2 as a Novel Strategy for Enhancing Beneficial Immune Responses to Vaccine Antigens

“…These EAT-2-expressing Ad vectors were fully viable, grew to high titers, and were purified and quantified exactly as done for conventional [E12]Ad vaccines (25). To analyze the maximal impact that Ad-EAT2 expression might have upon innate immune responses, we administered Ad-EAT2 into C57BL/6 mice and measured the levels of cytokines and chemokines in the plasma 6 h postinjection (hpi), a time point we have previously demonstrated to be when maximal induction of proinflammatory cytokines and chemokines occurs after Ad vector administration (9,27,28). Administration of the Ad-EAT2 vector into C57BL/6 mice resulted in induction of significantly higher plasma levels of RANTES and MCP-1 at 6 hpi as directly compared with those of mice injected identically and treated with an Ad-GFP control vector (Fig.…”

Readministration of helper-dependent adenoviral vectors to mouse airway mediated via transient immunosuppression

“…Systemic and local administration of Ad vector results in the immediate production of cytokines/ chemokines. 17,30 The antigen-nonspecific, cytokine-dependent acute inflammatory response leads to rapid clearance of transfected cells and have an important role for initiating the adaptive immune response. Muruve et al 31 reported that HD-Ad vectors induced significant levels of inflammatory cytokines in liver following systemic administration.…”

“…Glucocorticoids have been shown to be very effective in blocking the host innate immune response to Ad vectors. 17,30 However, cyclophosphamide is a preferred immunosuppressant over glucocorticoids for reducing host adaptive immune responses because glucocorticoids inhibit the cellular immune response but not the humoral immune response because they block Th1 but enhance Th2 cytokine secretion. 30,41 Future studies should explore the possibility of combining the two types of drugs in transient immunosuppression to achieve the maximal benefits in reducing the host immune responses to viral vectors.…”

“…[13][14][15][16] Although Ad vectors do not have the E1 region that is required for expressing Ad genes, leaky expression of the viral genes provides enough viral antigens to cause host adaptive immune responses. 17,18 Thus, continuous immune suppression will be required to maintain the transgene expression if these vectors are used for gene delivery. However, compromising the host immune system is not desirable for treatments of human diseases associated with chronic infection, such as cystic fibrosis.…”