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

• Published in: Blood Vol. 129; no. 2; pp. 238 - 245
• Main Authors: Yoon, Jeongheon, Schmidt, Anja, Zhang, Ai-Hong, Königs, Christoph, Kim, Yong Chan, Scott, David W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.01.2017; American Society of Hematology
• Subjects: Animals; B-Lymphocytes; Cell Engineering - methods; Factor VIII - immunology; Flow Cytometry; Humans; Immunosuppression - methods; Lymphocyte Activation - immunology; Mice; Mice, Knockout; Receptors, Antigen, T-Cell - immunology; T-Lymphocytes, Regulatory - immunology; Thrombosis and Hemostasis; Transduction, Genetic
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2016-07-727834

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. •Generation and functional analysis of FVIII-specific human CAR Tregs.•Specific regulation of FVIII responses by engineered human CAR Tregs.