Volume 32, No 11, Nov 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 11, November 2022: 995-1007

ORIGINAL ARTICLES

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

Yongxian Hu^{1,2,3,4,†,*} , Yali Zhou^5,6,† , Mingming Zhang^1,2,3,4,† , Houli Zhao^1,2,3,4,† , Guoqing Wei^1,2,3,4 , Wengang Ge⁵ , Qu Cui⁷ , Qitian Mu⁸ , Gong Chen⁵ , Lu Han⁵ , Tingting Guo⁵ , Jiazhen Cui^1,2,3,4 , Xiaoyan Jiang⁵ , Xiujun Zheng⁵ , Shuhui Yu⁵ , Xiaolong Li⁵ , Xingwang Zhang⁵ , Mingxi Chen⁵ , Xiuju Li⁵ , Ming Gao⁵ , Kang Wang⁵ , Cheng Zu^1,2,3,4 , Hao Zhang⁶ , Xiaohong He⁵ , Yanbin Wang⁵ , Dongrui Wang^1,2,3,4,* , Jiangtao Ren^5,* , He Huang^1,2,3,4,*

¹Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
²Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
³Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China
⁴Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang, China
⁵Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China
⁶Department of Hematology, Ruian people’s Hospital, Wenzhou, Zhejiang, China
⁷Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
⁸Laboratory of Stem Cell Transplantation, Ningbo First Hospital, Ningbo, Zhejiang, China
^†These authors contributed equally: Yongxian Hu, Yali Zhou, Mingming Zhang, Houli Zhao
Correspondence: Yongxian Hu(1313016@zju.edu.cn)Dongrui Wang(dongrui-wang@zju.edu.cn)Jiangtao Ren(jiangtao.ren@bioheng.com)He Huang(huanghe@zju.edu.cn)

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.

https://doi.org/10.1038/s41422-022-00721-y

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