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Supplementary Data from Autologous Nanobody-Derived Fratricide-Resistant CD7-CAR T-cell Therapy for Patients with Relapsed and Refractory T-cell Acute Lymphoblastic Leukemia/Lymphoma

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posted on 2023-03-31, 23:50 authored by Mingzhi Zhang, Dan Chen, Xiaorui Fu, Huimin Meng, Feifei Nan, Zhenchang Sun, Hui Yu, Lei Zhang, Ling Li, Xin Li, Xinhua Wang, Min Wang, Fengtao You, Zhaoming Li, Yu Chang, Zhiyuan Zhou, Jiaqin Yan, Jiwei Li, Xiaolong Wu, Yu Wang, Yinyan Wang, Shufen Xiang, YuSheng Chen, Guifang Pan, Hanying Xu, Bozhen Zhang, Lin Yang
Supplementary Data from Autologous Nanobody-Derived Fratricide-Resistant CD7-CAR T-cell Therapy for Patients with Relapsed and Refractory T-cell Acute Lymphoblastic Leukemia/Lymphoma

Funding

National Key Research and Development Project

Natural Science Foundation of China

National Key R&D Program of China

Priority Academic Program Development of Jiangsu Higher Education Institutions

Collaborative Innovation Major Project

Six Talent Peaks Project in Jiangsu Province

Natural Science Foundation of the Jiangsu Higher Education Institutions of China

Project of State Key Laboratory of Radiation Medicine and Protection, Soochow University

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ARTICLE ABSTRACT

Since CD7 may represent a potent target for T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) immunotherapy, this study aimed to investigate safety and efficacy of autologous CD7–chimeric antigen receptor (CAR) T cells in patients with relapsed and refractory (R/R) T-ALL/LBL, as well as its manufacturing feasibility. Preclinical phase was conducted in NPG mice injected with Luc+ GFP+CCRF-CEM cells. Open-label phase I clinical trial (NCT04004637) enrolled patients with R/R CD7-positive T-ALL/LBL who received autologous CD7-CAR T-cell infusion. Primary endpoint was safety; secondary endpoints included efficacy and pharmacokinetic and pharmacodynamic parameters. CD7 blockade strategy was developed using tandem CD7 nanobody VHH6 coupled with an endoplasmic reticulum/Golgi-retention motif peptide to intracellularly fasten CD7 molecules. In preclinical phase CD7 blockade CAR T cells prevented fratricide and exerted potent cytolytic activity, significantly relieving leukemia progression and prolonged the median survival of mice. In clinical phase, the complete remission (CR) rate was 87.5% (7/8) 3 months after CAR T-cell infusion; 1 patient with leukemia achieved minimal residual disease–negative CR and 1 patient with lymphoma achieved CR for more than 12 months. Majority of patients (87.5%) only had grade 1 or 2 cytokine release syndrome with no T-cell hypoplasia or any neurologic toxicities observed. The median maximum concentration of CAR T cells was 857.2 cells/μL at approximately 12 days and remained detectable up to 270 days. Autologous nanobody-derived fratricide-resistant CD7-CAR T cells demonstrated a promising and durable antitumor response in R/R T-ALL/LBL with tolerable toxicity, warranting further studies in highly aggressive CD7-positive malignancies.

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