T cells expressing CD5/CD7 bispecific chimeric antigen receptors with fully human heavy-chain-only domains mitigate tumor antigen escape

作     者：Zhenyu Dai Wei Mu Ya Zhao Jiali Cheng Haolong Lin Kedong Ouyang Xiangyin Jia Jianwei Liu Qiaoe Wei Meng Wang Chaohong Liu Taochao Tan Jianfeng Zhou 

作者机构：Department of HematologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430030China Nanjing IASO BiotherapeuticsNanjingJiangsu 210000China Department of Pathogen BiologyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430030China 

出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)

年 卷 期：2022年第7卷第4期

页      面：1322-1333页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100102[医学-免疫学] 100214[医学-肿瘤学] 10[医学] 

基　　金：Nanjing IASO Biotherapeutics 

主　　题：CD7 CRISPR/Cas9 expressing 

摘      要：Bispecific chimeric antigen receptor T-cell(CAR-T)therapies have shown promising results in clinical trials for advanced B-cell ***,it is challenging to broaden the success of bispecific CAR-T therapies to treat refractory/relapse(r/r)T-cell leukemia/lymphoma because targeting multiple T-cell-expressing antigens leads to exacerbated CAR-T cell fratricide and potential safety *** human heavy chain variable(FHVH)antibodies that specifically target CD5 or CD7 were screened and constructed to CD5/CD7 bispecific CARs.A truncated Epidermal growth factor receptor were integrated into CAR constructs to address safety *** tackle the fratricidal issue of CAR-T cells targeting T-cell-pan marker(s),CRISPR/Cas9-based CD5 and CD7 genes knockout were performed before lentiviral transduction of bispecific *** comparison between different bispecific CAR structures:tandem CARs and dual CAR were performed in vitro and in vivo to determine the optimal construct suitable for addressing T-cell malignancy antigen escape in clinical *** of CD5 and CD7 prevents fratricide of CD5/CD7 bispecific CAR-T cells,and FHVH-derived CD5/CD7 bispecific CAR-T cells demonstrate potent antitumor activity in vitro and in *** fratricide-resistant FHVH-derived CD5/CD7 bispecific CAR-T cells have potent antitumor activity against T-cell malignancies,and tandem CARs are more effective than dual CAR in preventing tumor escape in heterogeneous leukemic *** meaningful clinical efficacy and safety of tandem CD5/CD7 CAR-T cells deserve to be explored urgently.