Journal of Blood Disorders & Transfusion

Novel approaches to treat hemophilia inhibitor formation: Engineered specific human regulatory and cytotoxic T-cells

5^th World Hematologists Congress

August 18-19, 2016 London, UK

David W Scott, Jeong Heon Yoon, Kalpana Parvathaneni, Ai-Hong Zhang, Anja Schmidt, Christoph Konigs and Yong Chan Kim

Uniformed Services University of Health Sciences, USA
University Hospital Frankfurt, Germany

Posters & Accepted Abstracts: J Blood Disord Transfus

Abstract:

Anti-FVIII antibody (inhibitor) formation is a major complication in the treatment of Hemophilia A. Thus, it is necessary to develop effective tolerogenic therapies to prevent as well as reverse inhibitor formation. Our lab has focused on developing novel approaches to modulate inhibitor formation at multiple levels for example by modulating the function of FVIII-specific T effector cells as well as by directly targeting anti-FVIII B cells. We have 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 are specific for the C2 domain of FVIII. These Tregs bind MHC tetramers, proliferate in response to a specific FVIII epitope and suppress effector responses to FVIII. Moreover, these Tregs can inhibit the secondary antibody response to multiple epitopes in FVIII in-vitro. We have now generated additional human Tregs by transduction of a single chain Fv (scFv) directed against the A2 domain of FVIII. These scFv Tregs (ANS8) can effect bystander suppression of the response to C2 when FVIII is present. Finally, we have developed a novel chimeric antigen-like receptor called B-cell antibody recognizing receptor (BAR) to target and directly kill the FVIII-specific B-cells and antibody-producing cells. CD8 T-cells transduced to express C2-BAR caused suppression of antibody secretion of C2-specific hybridoma cells suggesting that BAR CD8 T-cells expressing FVIII domains can be used to target specific B-cells to suppress inhibitor formation and may also provide an additional platform to treat other undesirable antibody responses.

Biography :

Email: scottd43@gmail.com