Bispecific Chimeric Antigen Receptor Targeting Both CD19 and CD22 T Cell Therapy in Adults with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

Abstract

Background: Despite the impressive CR induced by CD19 CAR-T cell therapy in B-ALL, the high rate of complete responses is sometimes limited by the emergence of CD19-negative leukemia. Bispecific CAR-modified T cells targeting both CD19 and CD22 may overcome the limitation of CD19-negative relapse. Methods: Here, we report the design of a bispecific CAR that triggers robust cytolytic activity against target cells by targeting either CD19 or CD22. We performed a phase 1 trial of bispecific CAR T cell therapy in patients with relapsed/refractory precursor B-ALL at a dose that ranged from 1.7×106 to 3×106 CAR T cells per kilogram of body weight. Finding: MRD-negative CR was achieved in 6 out of 6 enrolled patients. Autologous CD19/CD22 CAR T cells proliferated in vivo and were detected in the blood, bone marrow, and cerebrospinal fluid. No neurotoxicity occurred in any of the 6 patients treated. Of note, one patient had a relapse with blast cells that no longer expressed CD19 and exhibited diminished CD22 site density approximately 5 months after treatment. Interpretation: In brief, autologous CD19/CD22 CAR T cell therapy is feasible and safe and mediates potent antileukemic activity in patients with relapsed/refractory B-ALL. Furthermore, the emergence of target antigen loss and expression downregulation highlights the critical need to anticipate antigen escape. Our study demonstrates the reliability of bispecific CD19/CD22 CAR T cell therapy in inducing remission in adult patients with relapsed/refractory B-ALL. Trial Registration: NCT03185494. Funding Statement: National Key Research and Development Program of China and National Natural Science Foundation of China. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study protocols were approved by the institutional review board at the Chinese PLA general hospital, and the patients provided written informed consent. This clinical investigation was conducted according to the principles of the Declaration of Helsinki.