Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease
Engineering T cells to treat autoimmunity Autoimmune diseases such as lupus and rheumatoid arthritis lack therapies that specifically target only the disease causing cells. Inspired by the clinical success of using chimeric antigen receptor T cells to treat certain types of cancers, Ellebrecht et al. asked whether a similar approach might also work against antibody driven autoimmune diseases. They engineered T cells to express chimeric receptors consisting of the disease causing autoantigen desmoglein 3 fused to signaling domains that activate T cells. When given to diseased mice, the engineered T cells targeted and killed B cells that express antibodies targeting desmoglein 3, hinting that such a strategy may be an effective way to treat antibody driven autoimmune diseases. Science, this issue p. 179 A proof of principle study indicates that engineered T cells may be an effective, targeted therapy for autoimmunity. Ideally, therapy for autoimmune diseases should eliminate pathogenic autoimmune cells while sparing protective immunity, but feasible strategies for such an approach have been elusive. Here, we show that in the antibody mediated autoimmune disease pemphigus vulgaris (PV) autoantigen based chimeric immunoreceptors can direct T cells to kill autoreactive B lymphocytes through the specificity of the B cell receptor (BCR) We engineered human T cells to express a chimeric autoantibody receptor (CAAR) consisting of the PV autoantigen, desmoglein (Dsg) 3, fused to CD137 CD3z signaling domains. Dsg3 CAAR T cells exhibit specific cytotoxicity against cells expressing anti Dsg3 BCRs in vitro and expand, persist, and specifically eliminate Dsg3 specific B cells in vivo. CAAR T cells may provide an effective and universal strategy for specific targeting of autoreactive B cells in antibody mediated autoimmune disease.
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