CAR19 EngTregs offer broad capacity to modulate immune tolerance and improve safety in B and T cell mediated autoimmune disorders 3850

Abstract Description CD19 CAR T-effector (CAR19Teff) therapy is promising in autoimmunity but limited by the inability to modulate pathogenic T cells and safety concerns like cytokine release syndrome and neurotoxicity. To address these limitations, we developed CD19 CAR engineered regulatory T cells (CAR19 EngTregs), which offer B cell depletion with the crucial capacity to suppress pathogenic T cells via bystander suppression and lower inflammatory cytokine secretion. We engineered human CAR19 EngTregs with stable FOXP3 and CAR expression and enriched edited cells to high purity using a chemically induced IL-2 signaling complex (CISC). CAR19 EngTregs exhibited stable core Treg markers upon CAR or TCR stimulation and mediated robust T cell suppression. In a human plasma B cell generation assay, CAR19 EngTregs showed antigen-dependent activation, and prevented B cell proliferation, differentiation to plasmablasts and long-lived plasma cells, and immunoglobulin (Ig) production. In both in vitro killing assays and adoptive transfer studies in humanized mice, CAR19 EngTregs mediated B cell depletion with lower cytotoxic and inflammatory cytokine levels than CAR19Teff. In pristane-treated humanized mice, human CAR19 EngTregs depleted B cells in vivo, elicited lower serum inflammatory cytokines, lower Ig titers, and reduced pathology versus CAR19Teff. These data demonstrate CAR19 EngTreg therapy could treat B and T cell-mediated autoimmunity with superior efficacy and safety than CAR19Teff therapy. Topic Categories Therapeutic Approaches to Autoimmunity (THER)