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Blood. 2017 Jan 12;129(2):238-245. doi: 10.1182/blood-2016-07-727834. Epub 2016 Nov 15.

FVIII-specific human chimeric antigen receptor T-regulatory cells suppress T- and B-cell responses to FVIII.

Author information

1
Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD; and.
2
Department of Pediatrics, Molecular Hemostasis and Immunodeficiency, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.

Abstract

Replacement therapy with factor VIII (FVIII) is used in patients with hemophilia A for treatment of bleeding episodes or for prophylaxis. A common and serious problem with this therapy is the patient's immune response to FVIII, because of a lack of tolerance, leading to the formation of inhibitory antibodies. Development of tolerogenic therapies, other than standard immune tolerance induction (ITI), is an unmet goal. We previously generated engineered antigen-specific regulatory T cells (Tregs), created by transduction of a recombinant T-cell receptor (TCR) isolated from a hemophilia A subject's T-cell clone. The resulting engineered T cells suppressed both T- and B-cell effector responses to FVIII. In this study, we have engineered an FVIII-specific chimeric antigen receptor (ANS8 CAR) using a FVIII-specific scFv derived from a synthetic phage display library. Transduced ANS8 CAR T cells specific for the A2 domain proliferated in response to FVIII and ANS8 CAR Tregs were able to suppress the proliferation of FVIII-specific T-effector cells with specificity for a different FVIII domain in vitro. These data suggest that engineered cells are able to promote bystander suppression. Importantly, ANS8 CAR-transduced Tregs also were able to suppress the recall antibody response of murine splenocytes from FVIII knockout mice to FVIII in vitro and in vivo. In conclusion, CAR-transduced Tregs are a promising approach for future tolerogenic treatment of hemophilia A patients with inhibitors.

PMID:
28064157
PMCID:
PMC5234219
DOI:
10.1182/blood-2016-07-727834
[Indexed for MEDLINE]
Free PMC Article

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