Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia

• Published in: Journal of hematology and oncology Vol. 13; no. 1; pp. 30 - 10
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.04.2020; BioMed Central; BMC
• Subjects: Acute lymphoblastic leukemia; Adolescent; Adult; Adults; Antigens; Antigens, CD19 - immunology; Autografts; B-ALL; Bispecific; Blast cells; Blood; Body weight; Bone marrow; CAR; CD19; CD19 antigen; CD22; CD22 antigen; Cell therapy; Cerebrospinal fluid; Chemotherapy; Clinical trials; Cytokines; Cytolytic activity; FDA approval; Female; Flow cytometry; Hematology; Humans; Immunotherapy; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Leukemia; Lymphatic leukemia; Lymphocytes; Lymphocytes T; Male; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - therapy; Neurotoxicity; Oncology; Patients; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - therapy; Rapid Communication; Remission; Sialic Acid Binding Ig-like Lectin 2 - immunology; T cells; Tisagenlecleucel; Treatment Outcome; Young Adult; B-ALL; CAR; Bispecific; CD19; Immunotherapy; Tumor antigen escape; CD22
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-020-00856-8

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. 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 × 10 to 3 × 10 CAR T cells per kilogram of body weight. 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. 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. ClinicalTrials.gov identifier: NCT03185494.