Genetically modified CD7-targeting allogeneic CAR-T cell therapy with enhanced efficacy for relapsed/refractory CD7-positive hematological malignancies: a phase I clinical study

被引:95
|
作者
Hu, Yongxian [1 ,2 ,3 ,4 ]
Zhou, Yali [5 ,6 ]
Zhang, Mingming [1 ,2 ,3 ,4 ]
Zhao, Houli [1 ,2 ,3 ,4 ]
Wei, Guoqing [1 ,2 ,3 ,4 ]
Ge, Wengang [5 ]
Cui, Qu [7 ]
Mu, Qitian [8 ]
Chen, Gong [5 ]
Han, Lu [5 ]
Guo, Tingting [5 ]
Cui, Jiazhen [1 ,2 ,3 ,4 ]
Jiang, Xiaoyan [5 ]
Zheng, Xiujun [5 ]
Yu, Shuhui [5 ]
Li, Xiaolong [5 ]
Zhang, Xingwang [5 ]
Chen, Mingxi [5 ]
Li, Xiuju [5 ]
Gao, Ming [5 ]
Wang, Kang [5 ]
Zu, Cheng [1 ,2 ,3 ,4 ]
Zhang, Hao [6 ]
He, Xiaohong [5 ]
Wang, Yanbin [5 ]
Wang, Dongrui [1 ,2 ,3 ,4 ]
Ren, Jiangtao [5 ]
Huang, He [1 ,2 ,3 ,4 ]
机构
[1] Zhejiang Univ, Affiliated Hosp 1, Sch Med, Bone Marrow Transplantat Ctr, Hangzhou, Zhejiang, Peoples R China
[2] Zhejiang Univ, Liangzhu Lab, Med Ctr, Hangzhou, Zhejiang, Peoples R China
[3] Zhejiang Univ, Inst Hematol, Hangzhou, Zhejiang, Peoples R China
[4] Zhejiang Prov Engn Lab Stem Cell & Immun Therapy, Hangzhou, Zhejiang, Peoples R China
[5] Nanjing Bioheng Biotech Co Ltd, Nanjing, Jiangsu, Peoples R China
[6] Ruian Peoples Hosp, Dept Hematol, Wenzhou, Zhejiang, Peoples R China
[7] Capital Med Univ, Beijing Tiantan Hosp, Dept Hematol, Beijing, Peoples R China
[8] Ningbo First Hosp, Lab Stem Cell Transplantat, Ningbo, Zhejiang, Peoples R China
基金
中国国家自然科学基金;
关键词
CHIMERIC ANTIGEN RECEPTOR; EXPRESSION; LEUKEMIA; 1ST-IN-HUMAN; MANAGEMENT; ADULTS;
D O I
10.1038/s41422-022-00721-y
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:995 / 1007
页数:13
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