In vivo profiling of a first-in-human study of chimeric autoantibody receptor T cells for MuSK myasthenia gravis

About This Grant

Project summary: Our laboratory invented a novel precision medicine approach for autoimmune disease treatment known as chimeric autoantibody receptor T cell (CAART) therapy, which aims to eliminate only the disease-causing autoimmune B cells while sparing healthy B cells, thus avoiding the risks of general immune suppression. We established initial efficacy of the approach in experimental autoimmune disease models and subsequently initiated a first-in-human clinical trial of DSG3-CAART in mucosal-dominant pemphigus vulgaris, a potentially fatal blistering disease caused by autoantibodies to the epithelial adhesion protein desmoglein 3 (DSG3), and more recently, MuSK-CAART in muscle-specific tyrosine kinase (MuSK) myasthenia gravis, in which autoantibodies to MuSK cause muscle weakness and potentially life-threatening respiratory crisis. DSG3- CAART was generally well-tolerated, although no consistent pattern of clinical or serologic improvement was observed. In contrast, 4 of the first 6 MuSK-CAART-treated patients experienced improvement in clinical disease activity scores, associated with MuSK-CAART expansion and persistence, and 2 of 4 subjects in the higher dose cohort experienced serious adverse events related to therapy. DSG3-CAART and MuSK-CAART are the first precision cellular immunotherapies for autoimmunity to enter clinical trials, which presents a unique opportunity to define the effects of these living drugs in human patients. In a separate line of studies we are investigating DSG3-CAART immune profiles; in this proposal, we will define immune profiles before and after infusion to evaluate pathways activated in MuSK-CAART and host immune cells that may identify biomarkers of safety and efficacy. Our studies will elucidate the cellular mechanisms of MuSK-CAART in vivo and may lead to new strategies for engineering the next generation of precision immunotherapies to achieve safe and durable autoimmune disease remission.