Hemophilia A inhibitor treatment: the promise of engineered T-cell therapy

Hemophilia A is a bleeding disorder caused by mutations in the gene encoding factor VIII (FVIII), a cofactor protein that is essential for normal blood clotting. Approximately, 1 in 3 patients with severe hemophilia A produce neutralizing antibodies (inhibitors) that block its biologic function in the clotting cascade. Current efforts to eliminate inhibitors consist of repeated FVIII injections under what is termed an "ITI" protocol (Immune Tolerance Induction). However, this method is extremely costly and approximately 30% of patients undergoing ITI do not achieve peripheral tolerance. Human T regulatory cells (Tregs) have been proposed as a new strategy to treat this antidrug antibody response, as well as other diseases. Polyclonal Tregs are nonspecific and could potentially cause general immunosuppression. Novel approaches to induce tolerance to FVIII include the use of engineered human and mouse antigen-specific Tregs, or alternatively antigen-specific cytotoxic cells, to delete, anergize, or kill FVIII-specific lymphocytes. In this review, we discuss the current state of engineered T-cell therapies, and we describe the recent progress in applying these therapies to induce FVIII-specific tolerance.