Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand.
Wellington Blood and Cancer Centre, Wellington Hospital, Newtown, Wellington, New Zealand.
BMJ Open. 2020 Feb 9;10(2):e034629. doi: 10.1136/bmjopen-2019-034629.
INTRODUCTION: Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL. METHODS AND ANALYSIS: Eligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×10 CAR T-cells/kg with a maximum dose of 1×10 CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy. ETHICS AND DISSEMINATION: Ethical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings. TRIAL REGISTRATION NUMBER: NCT04049513.
简介：表达靶向 CD19 的嵌合抗原受体（CAR）的自体 T 细胞在复发或难治性（r/r）B 细胞非霍奇金淋巴瘤（B-NHL）患者中产生了高缓解率。然而，第二代 CAR T 细胞治疗的患者中，只有不到一半的患者能够获得持久缓解。第三代（3G）CAR 采用了两个共刺激结构域，从而提高了 CAR T 细胞在体外和体内动物模型中的疗效。这项由研究者发起的、I 期剂量递增试验称为 ENABLE，将研究自体 T 细胞表达包含 CD28 和 Toll 样受体 2（TLR2）细胞内信号结构域的 3G 抗 CD19 CAR 的 WZTL-002 的安全性和初步疗效，用于治疗 r/r B-NHL。 方法和分析：合格的参与者将是患有 r/r B-NHL 的成年人，包括弥漫性大 B 细胞淋巴瘤及其变体、滤泡性淋巴瘤、滤泡性淋巴瘤转化和套细胞淋巴瘤。参与者必须具有满意的器官功能，并且没有其他治愈方法。自体 T 细胞将通过白细胞分离术获得。在 WZTL-002 制造和产品放行后，参与者将接受包含静脉注射氟达拉滨和环磷酰胺的淋巴清除化疗。2 天后静脉给予单次剂量的 WZTL-002。根据美国移植和细胞治疗协会的标准，对细胞因子释放综合征和免疫细胞效应器相关神经毒性综合征进行靶向评估，并进行分级。计划采用改良的 3+3 剂量递增方案，起始剂量为 5×10^6 CAR T 细胞/kg，最大剂量为 1×10^6 CAR T 细胞/kg。该试验的主要终点是 WZTL-002 的安全性。次要终点包括 WZTL-002 制造的可行性和初步疗效措施。 伦理和传播：该研究于 2019 年 6 月 23 日获得新西兰健康和残疾伦理委员会（参考号 19/STH/69）的批准，用于协议 V.1.2。试验结果将在同行评议的期刊上报告，并在科学会议或会议上报告结果。 试验注册号：NCT04049513。
Biomedicines. 2025-5-12
Front Immunol. 2025-3-13
Int J Mol Sci. 2025-2-5
J Transl Autoimmun. 2024-12-16
J Natl Cancer Cent. 2021-7-10
Clin Transl Immunology. 2019-5-11
Int J Mol Sci. 2019-3-14
Biol Blood Marrow Transplant. 2018-12-25
Blood Rev. 2018-11-14
N Engl J Med. 2018-12-1
Clin Cancer Res. 2018-8-10
Zotero 插件