Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Envt cells in vivo  

作　　者：Hanyu Pan Xinyi Yang Jing Wang Huitong Liang Zhengtao Jiang Lin Zhao Yanan Wang Zhiming Liang Xiaoting Shen Qinru Lin Yue Liang Jinglong Yang Panpan Lu Yuqi Zhu Min Li Pengfei Wang Jianqing Xu Hongzhou Lu Huanzhang Zhu 

机构地区：[1]State Key Laboratory of Genetic Engineering,And Key Laboratory of Medical Molecular Virology of Ministry of Education/Health,School of Life Sciences,Fudan University,Shanghai,200438,China [2]Shanghai Institute of Infectious Disease and Biosecurity,School of Life Sciences,Fudan University,Shanghai,200438,China [3]Department of Infectious Disease,Key Laboratory of Medical Molecular Virology of Ministry of Education/Health,School of Basic Medical Sciences and Shanghai Public Health Clinical Center,Fudan University,Shanghai,201508,China [4]Scientific Research Center,Shanghai Public Health Clinical Center,Fudan University,Shanghai,201508,China [5]Department of Infectious Diseases and Immunology,Shanghai Public Health Clinical Center,Fudan University,Shanghai,201508,China [6]Department of Infectious Diseases and Nursing Research Institution,National Clinical Research Center for Infectious Diseases,The Third People's Hospital of Shenzhen,Shenzhen,518112,China

出　　处：《Virologica Sinica》2023年第2期285-295,共11页中国病毒学（英文版）

基　　金：funded by the National Natural Science Foundation of China(81761128020 and 82041001);the National Grand Program on Key Infectious Diseases(2017ZX10202102-002).

摘　　要：HIV-specific chimeric antigen receptor(CAR)T-cells have been developed to target HIV-1 infected CD4t T-cells that express HIV Env proteins.However,T cell exhaustion and the patient-specific autologous paradigm of CAR-T cell hurdled clinical applications.Here,we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27(3BE)CAR construct that enabled the expression of programmed cell death protein(PD-1)-blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV Env.Compared with T cells expressing 3BNC117-CAR alone,3BE CAR-T cells showed greater cytotoxic activity against HIV Envt cells with stronger proliferation capability,higher killing efficiency,and enhanced cytokine secretion in the presence of HIV Env-expressing cells.Furthermore,we manufactured TCR-deficient 3BE CAR-T cells through gene editing and demonstrated that these CAR-T cells could effectively kill HIV Env^(+) cells in vivo without the occurrence of severe graft-versus-host disease(GvHD)in NSG mice.These data suggest that we have provided a feasible approach to the generation of“off-theshelf”anti-HIV CAR-T cells in combination with PD-1 checkpoint blockade immunotherapy,which can be a powerful therapeutic candidate for the functional cure of HIV.

关 键 词：Anti-HIV CAR-T PD-1 blocking TCR disruption Cellular immunotherapy 

分 类 号：R285[医药卫生—中药学]