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

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...

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Vydáno v:	Journal of hematology and oncology Ročník 13; číslo 1; s. 30 - 10
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 03.04.2020 BioMed Central Ltd Springer Nature B.V BMC
Témata:	Acute lymphoblastic leukemia Adolescent Adult Adults Antigens Antigens, CD19 - immunology Autografts B-ALL Bispecific Blast cells Blood Body weight Bone marrow Cancer Research 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 Medicine Medicine & Public Health 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
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Popis
Shrnutí:	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 × 10 6 to 3 × 10 6 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 .
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1756-8722 1756-8722
DOI:	10.1186/s13045-020-00856-8