Allogeneic CD19 CAR T cells armed with an anti-rejection CD70 CAR overcome antigen escape and evade alloimmune responses

Allogeneic chimeric antigen receptor (CAR) T cells can achieve sustained clinical benefit in B cell malignancies and autoimmune diseases. Despite the many potential advantages over autologous products, allogeneic CAR T cells carry a higher risk of rejection, which may limit persistence and therapeutic efficacy. We report the design and evaluation of an optimized CD70 CAR that prevents rejection of allogeneic CAR T cells by targeting activated alloreactive lymphocytes. Co-expression of this CD70 CAR with a CD19 CAR resulted in sustained CAR T cell persistence in the presence of alloreactive lymphocytes and prolonged antitumor activity in a CD19 antigen escape model. In vivo, CD19/CD70 dual CAR T cells resisted rejection and eliminated B cells and CD70 ⁺ T cells from patients with systemic lupus erythematosus, lowering immunoglobulin production. An allogeneic CD19/CD70 dual CAR T cell therapy may therefore reduce the need for lymphodepleting conditioning regimens required prior to CAR T cell infusion.