original reports Donor-Derived CD7 Chimeric Antigen Receptor T Cells for T-Cell Acute Lymphoblastic Leukemia: First-in-Human, Phase I Trial Jing Pan, MD 1 ; Yue Tan, BS 2 ; Guoling Wang, BS 2 ; Biping Deng, MS 3 ; Zhuojun Ling, MD 4 ; Weiliang Song, MD 4 ; Samuel Seery, PhD 5,6 ; Yanlei Zhang, MS 7 ; Shuixiu Peng, MS 7 ; Jinlong Xu, MD 4 ; Jiajia Duan, MD 4 ; Zelin Wang, MD 4 ; Xinjian Yu, MD 8 ; Qinlong Zheng, MD 8 ; Xiuwen Xu, MD 8 ; Ying Yuan, PhD 9 ; Fangrong Yan, PhD 10 ; Zhenglong Tian, PhD 11 ; Kaiting Tang, BS 4 ; Jiecheng Zhang, BS 12 ; Alex H. Chang, PhD 7,13 ; and Xiaoming Feng, PhD 2,14 abstract PURPOSE Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) have few options and poor prognosis. The aim was to assess donor-derived anti-CD7 chimeric antigen receptor (CAR) T-cell safety and efficacy in patients with r/r T-ALL. METHODS In this single-center, phase I trial, we administered anti-CD7 CAR T cells, manufactured from either previous stem-cell transplantation donors or new donors, to patients with r/r T-ALL, in single infusions at doses of 5 3 10 5 or 1 3 10 6 (630%) cells per kilogram of body weight. The primary end point was safety with efficacy secondary. RESULTS Twenty participants received infusions. Adverse events including cytokine release syndrome grade 1-2 occurred in 90% (n 5 18) and grade 3-4 in 10% (n 5 2), cytopenia grade 3-4 in 100% (n 5 20), neurotoxicity grade 1-2 in 15% (n 5 3), graft-versus-host disease grade 1-2 in 60% (n 5 12), and viral activation grade 1-2 in 20% (n 5 4). All adverse events were reversible, except in one patient who died through pulmonary hemorrhage related to fungal pneumonia, which occurred at 5.5 months, postinfusion. Ninety percent (n 5 18) achieved complete remission with seven patients proceeding to stem-cell transplantation. At a median follow-up of 6.3 months (range 4.0-9.2), 15 remained in remission. CAR T cells were still detectable in five of five patients assessed in month 6, postinfusion. Although patients’ CD7-positive normal T cells were depleted, CD7-negative T cells expanded and likely alleviated treatment-related T-cell immunodeficiency. CONCLUSION Among 20 patients with r/r T-ALL enrolled in this trial, donor-derived CD7 CAR T cells exhibited efficient expansion and achieved a high complete remission rate with manageable safety profile. A multicenter, phase II trial of donor-derived CD7 CAR T cells is in progress (NCT04689659). J Clin Oncol 00. © 2021 by American Society of Clinical Oncology INTRODUCTION T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, accounting for 10%-15% of pediatric acute lymphoblastic leukemia (ALL) cases and 20% of adult ALL cases. 1-3 The 5-year event-free survival can be as high as 70%-85% and 15%-30% of those who are diagnosed with refractory disease or experience relapse after receiving thera- pies. Allogeneic stem-cell transplantation (SCT) is only recommended for those who encounter first relapse but may be reinduced to achieve complete remission (CR) status. 4 Patients with multiple relapsed or re- fractory (r/r) T-ALL are difficult to treat and have dismal outcomes. 1,5 Poor prognoses are compounded by a shortage of targeted and immunotherapeutic salvage options. 6-9 Chimeric antigen receptor (CAR) T-cell therapies can improve outcomes in patients with relapsed or refrac- tory B-cell ALL. 10-13 However, CAR immunotherapies remain untested for patients with T-ALL, despite pre- clinical studies demonstrating that CAR T cells target some T-ALL antigens. 14-16 This maybe because there are no cell surface markers that distinguish malignant cells from normal T lymphocytes. Therefore, most CARs counteract general T-cell lineage markers such as CD7, which is a transmembrane glycoprotein expressed in 90%-96% of all normal T cells, 90%-98% of all natural killer (NK) cells in healthy individuals, 17,18 and 95% in all lymphoblastic T-cell leukemias and a subset of peripheral T-cell lymphomas. 19,20 However, CD7 does not appear to make a contribution to T-cell develop- ment or functions, 21,22 which may cause CAR T-cell fratricide during manufacture and deplete normal T lymphocytes raising the risk of immunodeficiency. Additionally, it may be difficult to separate healthy from malignant T cells for CAR T-cell manufacture. Pre- clinical researchers have recently proposed that uni- versal CAR T cells targeting CD7 may be useful for treating T-ALL, 23 and this off-the-shelf strategy may ASSOCIATED CONTENT Data Supplement Protocol Author affiliations and support information (if applicable) appear at the end of this article. Accepted on June 30, 2021 and published at ascopubs.org/journal/ jco on July 29, 2021: DOI https://doi.org/10. 1200/JCO.21.00389 1 Downloaded from ascopubs.org by Michigan State University--East Lansing on July 29, 2021 from 035.008.011.002 Copyright © 2021 American Society of Clinical Oncology. All rights reserved.