Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors  

作　　者：Zhenguang Wang Na Li Kaichao Feng Meixia Chen Yan Zhang Yang Liu Qingming Yang Jing Nie Na Tang Xingying Zhang Chen Cheng Lianjun Shen Jiaping He Xun Ye Wei Cao Haoyi Wang Weidong Han 

机构地区：[1]Medical School of Chinese PLA,Beijing,China [2]Department of Biotherapeutic,the First Medical Center,Chinese PLA General Hospital,Beijing,China [3]State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing,China [4]School of Life Sciences,University of Science and Technology of China,Hefei,China [5]Gracell Biotechnologies(Shanghai)Co.,Ltd,Shanghai,China [6]Institute for Stem Cell and Regeneration,Chinese Academy of Sciences,Beijing,China

出　　处：《Cellular & Molecular Immunology》2021年第9期2188-2198,共11页中国免疫学杂志（英文版）

基　　金：This research was supported by grants from the National Key Research and Development Program of China(No.2019YFC1316205 to J.N.);National Natural Science Foundation of China(Nos.31991171 and 81830002 to W.D.H.,81773269 and 31722036 to H.Y.W.);Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA16010503 to H.Y.W.).

摘　　要：Programmed cell death protein-1(PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors.We generated PD-1 and T cell receptor(TCR)deficient mesothelin-specific CAR-T(MPTK-CAR-T)cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study.A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion.No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients.The best overall response was stable disease(2/15 patients).Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month.TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion.We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models.Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.

关 键 词：CAR-T CRISPR-Cas9 PD-1 TCR MESOTHELIN 

分 类 号：R392[医药卫生—免疫学]