Chimeric antigen receptor(CAR)-T cell therapy against T cell malignancies faces major challenges including fratricide between CAR-T cells and product contamination from the blasts.Allogeneic CAR-T cells,generated from healthy donor T cells,can provide ready-to-use,blast-free therapeutic products,but their application could be complicated by graft-versus-host disease(GvHD)and host rejection.Here we developed healthy donor-derived,CD7-targeting CAR-T cells(RD13-01)with genetic modifications to resist fratricide,GvHD and allogeneic rejection,as well as to potentiate antitumor function.A phase I clinical trial(NCT04538599)was conducted with twelve patients recruited(eleven with T cell leukemia/lymphoma,and one with CD7-expressing acute myeloid leukemia).All patients achieved pre-set end points and eleven proceeded to efficacy evaluation.No dose-limiting toxicity,GvHD,immune effector cell-associated neurotoxicity or severe cytokine release syndrome(grade≥3)were observed.28 days post infusion,81.8％of patients(9/11)showed objective responses and the complete response rate was 63.6％(7/11,including the patient with AML).3 of the responding patients were bridged to allogeneic hematopoietic stem cell transplantation.With a median follow-up of 10.5 months,4 patients remained in complete remission.Cytomegalovirus(CMV)and/or Epstein-Barr virus(EBV)reactivation was observed in several patients,and one died from EBV-associated diffuse large B-cell lymphoma(DLBCL).Expansion of CD7-negative normal T cells was detected post infusion.In summary,we present the first report of a Phase I clinical trial using healthy donor-derived CD7-targeting allogeneic CAR-T cells to treat CD7+hematological malignancies.Our results demonstrated the encouraging safety and efficacy profiles of the RD13-01 allogeneic CAR-T cells for CD7+tumors.

Yongxian Hu;Yali Zhou;Mingming Zhang;Houli Zhao;Guoqing Wei;Wengang Ge;Qu Cui;Qitian Mu;Gong Chen;Lu Han;Tingting Guo;Jiazhen Cui;Xiaoyan Jiang;Xiujun Zheng;Shuhui Yu;Xiaolong Li;Xingwang Zhang;Mingxi Chen;Xiuju Li;Ming Gao;Kang Wang;Cheng Zu;Hao Zhang;Xiaohong He;Yanbin Wang;Dongrui Wang;Jiangtao Ren;He Huang

Bone Marrow Transplantation Center,The First Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou,Zhejiang,China;Liangzhu Laboratory,Zhejiang University Medical Center,Hangzhou,Zhejiang,China;Institute of Hematology,Zhejiang University,Hangzhou,Zhejiang,China;Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy,Hangzhou,Zhejiang,China;Nanjing Bioheng Biotech Co.,Ltd,Nanjing,Jiangsu,China;Department of Hematology,Ruian people's Hospital,Wenzhou,Zhejiang,China;Department of Hematology,Beijing Tiantan Hospital,Capital Medical University Beijing China;Laboratory of Stem Cell Transplantation Ningbo First Hospital Ningbo,Zhejiang,China

细胞研究（英文版）

[1]Yongxian Hu;Yali Zhou;Mingming Zhang;Houli Zhao;Guoqing Wei;Wengang Ge;Qu Cui;Qitian Mu;Gong Chen;Lu Han;Tingting Guo;Jiazhen Cui;Xiaoyan Jiang;Xiujun Zheng;Shuhui Yu;Xiaolong Li;Xingwang Zhang;Mingxi Chen;Xiuju Li;Ming Gao;Kang Wang;Cheng Zu;Hao Zhang;Xiaohong He;Yanbin Wang;Dongrui Wang;Jiangtao Ren;He Huang-.Genetically modified CD7-targeting allogeneic CAR-T cell therapy with enhanced efficacy for relapsed/refractory CD7-positive hematological malignancies:a phase I clinical study)[J].细胞研究（英文版）,2022(11):995-1007

fratricide,RD13,NCT04538599,CD7+hematological,CD7+tumors

Genetically,modified,targeting,allogeneic,CAR,therapy,enhanced,efficacy,relapsed,refractory,positive,malignancies,phase,clinical,study,Chimeric,antigen,receptor,against,faces,major,challenges,including,between,cells,contamination,from,blasts,Allogeneic,generated,healthy,donor,can,provide,ready,free,therapeutic,products,but,their,application,could,complicated,by,graft,versus,host,disease,GvHD,rejection,Here,developed,derived,genetic,modifications,resist,well,potentiate,antitumor,function,trial,was,conducted,twelve,patients,recruited,eleven,leukemia,lymphoma,one,expressing,acute,myeloid,achieved,set,end,points,proceeded,evaluation,No,dose,limiting,immune,effector,associated,neurotoxicity,severe,cytokine,release,syndrome,grade,were,observed,days,post,infusion,showed,objective,responses,complete,AML,responding,bridged,hematopoietic,stem,transplantation,With,median,follow,up,months,remained,remission,Cytomegalovirus,CMV,Epstein,Barr,EBV,reactivation,several,died,diffuse,large,DLBCL,Expansion,negative,normal,detected,In,summary,present,first,report,Phase,using,treat,Our,results,demonstrated,encouraging,safety,profiles

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