Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia
Hanren Dai, Zhiqiang Wu, Hejin Jia, Chuan Tong, Yelei Guo, Dongdong Ti, Xiao Han, Yang Liu, Wenying Zhang, Chunmeng Wang, Yajing Zhang, Meixia Chen, Qingming Yang, Yao Wang, Weidong Han, Hanren Dai, Zhiqiang Wu, Hejin Jia, Chuan Tong, Yelei Guo, Dongdong Ti, Xiao Han, Yang Liu, Wenying Zhang, Chunmeng Wang, Yajing Zhang, Meixia Chen, Qingming Yang, Yao Wang, Weidong Han
Abstract
Background: Despite the impressive complete remission (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: We here report the design of a bispecific CAR simultaneous targeting of CD19 and 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.
Results: We demonstrate bispecific CD19/CD22 CAR T cells could trigger robust cytolytic activity against target cells. 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.
Conclusion: In brief, autologous CD19/CD22 CAR T cell therapy is feasible and safe and mediates potent anti-leukemic 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: ClinicalTrials.gov identifier: NCT03185494.
Keywords: B-ALL; Bispecific; CAR; CD19; CD22; Immunotherapy; Tumor antigen escape.
Conflict of interest statement
The authors declare that they have no competing interests.
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Source: PubMed