Chimeric antigen receptor (CAR) T cell immunotherapies that target B cells have shown efficacy in B cell- and autoantibody-mediated autoimmune diseases. However, patients with refractory autoimmunity are often immunocompromised and have T cell defects. Moreover, the preparation of autologous CAR T cell products is costly and time-consuming and lacks scalability. Off-the-shelf CAR T cells might help overcome those limitations. A Cell study now presents initial data on the safety and efficacy of allogeneic CAR T cell therapy targeting the B cell marker CD19 in three patients with refractory autoimmunity.

T cells isolated from the peripheral blood of a single healthy donor were transduced with a lentiviral CD19-targeting CAR construct and the extracellular domain of PDL1, an inhibitory receptor with the potential to suppress alloreactivity after binding to PD1. In addition, genes encoding the HLA class I molecules HLA-A and HLA-B and all HLA class II molecules were disrupted via the CRISPR–Cas9 gene-editing system, to shield allogeneic cells from immediate recognition and depletion by the host immune system. Other HLA class I molecules were maintained, to avoid natural killer cell-mediated rejection of the grafted cells. Gene editing also targeted the T cell receptor gene TRAC, with the aim of avoiding graft-versus-host disease (GVHD), and the inhibitory receptor PD1, to ensure prolonged reactivity of the CAR T cells in vivo.