Enhanced efficacy of CD19/CD22 bispecific CAR‐T cells with EAAAK linker on B‐cell malignancies

Objectives Despite the great success of CD19 CAR‐T cell therapy, its clinical efficacy has been greatly hampered by the high relapse rate. In this study, we designed and compared four structures of CD19/CD22 bispecific CAR‐T cells with different linkers and different orders of the antibody sequences...

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Published in:European journal of haematology 2024-01, Vol.112 (1), p.64-74
Main Authors: Ma, Renyuxue, You, Fengtao, Tian, Shuaiyu, Zhang, Tingting, Tian, Xiaopeng, Xiang, Shufen, Wu, Hai, Yang, Nan, An, Gangli, Yang, Lin
Format: Article
Language:English
Subjects:
bispecific antibody
CAR‐T cells
CD19 antigen
CD22 antigen
Cell therapy
Cytokines
Cytotoxicity
immunotherapy
Lymphocytes
Lymphocytes T
Malignancy
Memory cells
Phenotypes
Tumor cells
Tumors
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Summary:Objectives Despite the great success of CD19 CAR‐T cell therapy, its clinical efficacy has been greatly hampered by the high relapse rate. In this study, we designed and compared four structures of CD19/CD22 bispecific CAR‐T cells with different linkers and different orders of the antibody sequences. Methods We detected the cytotoxicity, cytokine secretion levels, sustainable killing ability, differentiation, exhaustion of these four CAR‐T cells in vitro. The optimal Bis‐C CAR‐T cells were evaluated the efficacy using NSG mice. Results The two structures of CD19/CD22 bispecific CAR‐T cells using (EAAAK)3 as linker had more significant cytotoxicity and cytokine secretion levels. In the process of continuous killing, Bis‐C CAR‐T cells showed better sustained killing ability, memory phenotype differentiation, and exhaustion. In the in vivo experiment mimicking CD19‐negative relapse, Bis‐C CAR‐T was more able to control the tumor progression of mice in the CD19 low expression or no expression groups than CD19 CAR‐T. Conclusions This study has generated a novel bispecific CAR‐T cell that can simultaneously target CD19 or CD22 positive tumor cells, providing a new strategy to address the limitations of single‐targeted CAR‐T therapy in B‐cell tumors (limited response or relapse).
ISSN:0902-4441
1600-0609
DOI:10.1111/ejh.14090