Using chimeric antigen receptor (CAR) T cells to specifically eliminate autoreactive B cells in Graves’ Disease 2556

Description Chimeric antigen receptor (CAR) T cells have been successful in treating hematological cancers, and have recently been used to treat B cell mediated autoimmune diseases by targeting CD19 or BCMA for deep B cell depletion to reset the immune system. Early results have been promising; however, B cell depletion can cause immunosuppression and some patients have not seen a return of normal B cell populations. Graves’ Disease (GD) is an autoantibody mediated autoimmune disease of the thyroid, where autoreactive B cells produce antibodies which bind to thyroid stimulating hormone receptor (TSHR). These autoreactive B cells are the primary cause of disease, but there are no treatments that specifically target them. We have generated a novel CAR with TSHR as the binding domain and have found that in vitro they can eliminate autoreactive Graves’ Disease B cells, while leaving healthy B cells untouched. Soluble autoantibodies and TSH have the potential to over-activate or block these TSHR CAR T cells, so we evaluated their effect on activation, cytotoxicity, and cytokine production. The TSHR CAR T cells were able to eliminate GD autoreactive B cells under these conditions; however, certain constructs with different epitopes of TSHR were more effective. To better understand how they function, the TSHR CAR T cells cytotoxic function was evaluated when incubated with GD patient plasma, and there was some inhibition, but the GD autoreactive B cells were still eliminated. Funding Sources Simmons Center for Cancer Research Topic Categories Therapeutic Approaches to Autoimmunity (THER)