The influence of innate and pre‐existing immunity on adenovirus therapy

Abstract

Recombinant adenovirus serotype 5 (Ad5) vectors have been studied extensively in preclinical gene therapy models and in a range of clinical trials. However, innate immune responses to adenovirus vectors limit effectiveness of Ad5 based therapies. Moreover, extensive pre-existing Ad5 immunity in human populations will likely limit the clinical utility of adenovirus vectors, unless methods to circumvent neutralizing antibodies that bind virus and block target cell transduction can be developed; Furthermore, memory T cell and humoral responses to Ad5 are associated with increased toxicity, raising safety concerns for therapeutic adenovirus vectors in immunized hosts. Most preclinical studies have been performed in naïve animals; although pre-existing immunity is among the greatest hurdles for adenovirus therapies, it is also one of the most neglected experimentally. Here we summarize findings using adenovirus vectors in naïve animals, in Ad-immunized animals and in clinical trials, and review strategies proposed to overcome innate immune responses and preexisting immunity. Keywords ADENOVIRUS; INNATE IMMUNITY; NEUTRALIZING ANTIBODY; GENE THERAPY; VACCINATIONAdenovirus vectors have many promising traits for gene therapy; they efficiently transduce many proliferating and quiescent cell types, can "package" large amounts of foreign DNA, can be grown to high titers and are not germ line transmitted. However, adenovirus-mediated transgene expression is generally transient; ranging from weeks to a few months. Temporal limitation of transgene expression results mainly from immune responses that develop against both vector and transgene products.

Chemotactic antiviral cytokines promote infectious apical entry of human adenovirus into polarized epithelial cells

“…Alveolar macrophages are sensors for infection and detect adenoviruses in the airway lumen 28 . On contact with viruses, they undergo rapid activation and secrete pro-inflammatory cytokines, such as IL-6, CXCL8 and TNF-α 29,30 .…”

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.…”

Progress and prospects: Immunobiology of gene therapy for neurodegenerative disease: prospects and risks

“…84 Capsid modification with polyethylene glycol (PEGylation) reduced the innate immune response of fully deleted vectors in the periphery and therefore such modification also has potential for reducing the immune response in the CNS. 85 To evade an immune response to AAV vectors, capsid modification also holds promise. In addition, there are now several different serotypes of AAV in use for the CNS, which have greater and more widespread transduction efficiencies than earlier serotypes.…”

“…Where patients have preexisting antibodies or cytotoxic T cells to a vector from a previous wild-type exposure, these levels should be carefully monitored in view of data from peripheral gene therapy trials, as both innate immune responses to adenovirus challenge and preexisting adenovirus immunity represent fundamental problems, with great implications for both safety and efficacy of adenovirus vector gene therapy applications. 85,95 In a recent clinical trial involving an adenoviral-based vaccination against HIV individuals with preexisting immunity to adenovirus showed preferential expansion of activated CD4 cells, increasing the number of virus targets and leading to higher susceptibility to HIV infection. 95 Thus, for the purposes of virus delivery to people with a previous exposure to the vector, the problem may be overcome by using vectors from rarer serotypes.…”