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Open Access Green as soon as Postprint is submitted to ZB.
Chimeric Antigen Receptor (CAR)-engineered T cells redirected against Hepatitis C Virus (HCV) E2 glycoprotein.
Gut 65, 512-523 (2016)
OBJECTIVE: The recent availability of novel antiviral drugs has raised new hope for a more effective treatment of hepatitis C virus (HCV) infection and its severe sequelae. However, in the case of non-responding or relapsing patients, alternative strategies are needed. To this end we have used chimeric antigen receptors (CARs), a very promising approach recently used in several clinical trials to redirect primary human T cells against different tumours. In particular, we designed the first CARs against HCV targeting the HCV/E2 glycoprotein (HCV/E2). DESIGN: Anti-HCV/E2 CARs were composed of single-chain variable fragments (scFvs) obtained from a broadly cross-reactive and cross-neutralising human monoclonal antibody (mAb), e137, fused to the intracellular signalling motif of the costimulatory CD28 molecule and the CD3ζ domain. Activity of CAR-grafted T cells was evaluated in vitro against HCV/E2-transfected cells as well as hepatocytes infected with cell culture-derived HCV (HCVcc). RESULTS: In this proof-of-concept study, retrovirus-transduced human T cells expressing anti-HCV/E2 CARs were endowed with specific antigen recognition accompanied by degranulation and secretion of proinflammatory and antiviral cytokines, such as interferon γ, interleukin 2 and tumour necrosis factor α. Moreover, CAR-grafted T cells were capable of lysing target cells of both hepatic and non-hepatic origin expressing on their surface the HCV/E2 glycoproteins of the most clinically relevant genotypes, including 1a, 1b, 2a, 3a, 4 and 5. Finally, and more importantly, they were capable of lysing HCVcc-infected hepatocytes. CONCLUSIONS: Clearance of HCV-infected cells is a major therapeutic goal in chronic HCV infection, and adoptive transfer of anti-HCV/E2 CARs-grafted T cells represents a promising new therapeutic tool.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Hepatitis C ; Immune Response ; Immunology In Hepatology ; Immunotherapy ; Infectious Disease; Human Monoclonal-antibodies; Recombinant Fab Fragments; Humoral Immune-response; Neutralizing Antibodies; Mixed Cryoglobulinemia; Repertoire Cloning; Animal-models; Infection; Proteins; Binding
ISSN (print) / ISBN
0017-5749
e-ISSN
1468-3288
Journal
Gut (eGut)
Quellenangaben
Volume: 65,
Issue: 3,
Pages: 512-523
Publisher
BMJ Publishing Group
Publishing Place
London
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Virology (VIRO)