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

Jeongheon Yoon, Anja Schmidt, Ai-Hong Zhang, Christoph Königs, Yong Chan Kim and David W. Scott

Key points

  • Generation and functional analysis of FVIII-specific human CAR Tregs.

  • Specific regulation of FVIII responses by engineered human CAR Tregs.

Abstract

Replacement therapy with factor VIII (FVIII) is used in hemophilia A patients for treatment of bleeding episodes or for prophylaxis. A common and serious problem with this therapy is the patient's immune response to FVIII, due to a lack of tolerance, leading to the formation of inhibitory antibodies. Development of tolerogenic therapies, other than standard 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.

  • Submitted July 13, 2016.
  • Accepted November 8, 2016.