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J Autoimmun. 2018 Jun;90:116-131. doi: 10.1016/j.jaut.2018.02.006. Epub 2018 Mar 2.

Engrafting human regulatory T cells with a flexible modular chimeric antigen receptor technology.

Author information

1
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraße 400, 01328 Dresden, Germany.
2
Tumor Immunology, UniversityCancerCenter (UCC), 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
3
Cellex Patient Treatment GmbH, Tatzberg 47, 01307 Dresden, Germany.
4
GEMoaB Monoclonals GmbH, Tatzberg 47, 01307 Dresden, Germany.
5
Medical Clinic and Policlinic I, University Hospital, 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, Fetscherstr. 74, 01307 Dresden, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; National Center for Tumor Diseases (NCT), 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany; Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
6
Medical Clinic and Policlinic I, University Hospital, 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
7
German Cancer Consortium (DKTK), Partner Site Dresden, Fetscherstr. 74, 01307 Dresden, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; National Center for Tumor Diseases (NCT), 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany; Institute of Immunology, Medical Faculty, 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
8
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraße 400, 01328 Dresden, Germany; Department of Chemistry and Food Chemistry, Technische Universität Dresden, Mommsenstr. 4, 01069 Dresden, Germany.
9
Center of Clinical Neuroscience, Department of Neurology, University Hospital, 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
10
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraße 400, 01328 Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, Fetscherstr. 74, 01307 Dresden, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; National Center for Tumor Diseases (NCT), 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany; Department of Chemistry and Food Chemistry, Technische Universität Dresden, Mommsenstr. 4, 01069 Dresden, Germany.
11
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraße 400, 01328 Dresden, Germany; Tumor Immunology, UniversityCancerCenter (UCC), 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, Fetscherstr. 74, 01307 Dresden, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; National Center for Tumor Diseases (NCT), 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany; Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany. Electronic address: Michael.Bachmann@uniklinikum-dresden.de.

Abstract

As regulatory T cells (Tregs) play a fundamental role in immune homeostasis their adoptive transfer emerged as a promising treatment strategy for inflammation-related diseases. Preclinical animal models underline the superiority of antigen-specific Tregs compared to polyclonal cells. Here, we applied a modular chimeric antigen receptor (CAR) technology called UniCAR for generation of antigen-specific human Tregs. In contrast to conventional CARs, UniCAR-endowed Tregs are indirectly linked to their target cells via a separate targeting module (TM). Thus, transduced Tregs can be applied universally as their antigen-specificity is easily adjusted by TM exchange. Activation of UniCAR-engrafted Tregs occurred in strict dependence on the TM, facilitating a precise control over Treg activity. In order to augment efficacy and safety, different intracellular signaling domains were tested. Both 4-1BB (CD137) and CD28 costimulation induced strong suppressive function of genetically modified Tregs. However, in light of safety issues, UniCARs comprising a CD137-CD3ζ signaling domain emerged as constructs of choice for a clinical application of redirected Tregs. In that regard, Tregs isolated from patients suffering from autoimmune or inflammatory diseases were, for the first time, successfully engineered with UniCAR 137/ζ and efficiently suppressed patient-derived effector cells. Overall, the UniCAR platform represents a promising approach to improve Treg-based immunotherapies for tolerance induction.

KEYWORDS:

CD137 (4-1BB); CD28; Chimeric antigen receptor; Immunotherapy; Regulatory T cells

PMID:
29503042
DOI:
10.1016/j.jaut.2018.02.006
[Indexed for MEDLINE]

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