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：96

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

来源：

CELL RESEARCH | 2022年 / 32卷 / 11期

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

页码：995 / 1007

页数：13