Author:
Dai Hanren,Wu Zhiqiang,Jia Hejin,Tong Chuan,Guo Yelei,Ti Dongdong,Han Xiao,Liu Yang,Zhang Wenying,Wang Chunmeng,Zhang Yajing,Chen Meixia,Yang Qingming,Wang Yao,Han Weidong
Abstract
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.
Funder
National Key Research and Development Program of China
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Biology,Hematology
Cited by
219 articles.
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