Effect of a costimulatory endodomain on the performance of T cells expressing CD19-directed chimeric antigen receptors (CARs) in subjects with relapsed/refractory B-cell malignancies.

2541 Background: CARs usually combine the antigen binding domain of a monoclonal antibody with the ζ signaling domain of the T cell receptor complex. CAR expression in T cells produces potent MHC-unrestricted effector function against tumor cells in vitro but limited T-cell persistence in vivo, likely due to their incomplete activation, as tumors do not express costimulatory molecules. Incorporation of costimulatory endodomains in the CAR (e.g. CD28) may enhance their benefit in vivo. Methods: We report a phase I trial of T cells redirected to CD19 given to patients with refractory/relapsed B-cell malignancies. Subjects simultaneously received 2 autologous T-cell products, both expressing CARs with identical CD19-specific exodomains. In one product, the endodomain contained only the ζ sequence (CAR.19ζ) while the second incorporated a costimulatory CD28 domain (CAR.19-28ζ). We generated the T-cell products by activating autologous peripheral blood mononuclear cells with OKT3 followed by transduction with ...