BCMA-CD19 compound CAR T cells for systemic lupus erythematosus: a phase 1 open-label clinical trial.

IF 20.3 1区 医学 Q1 RHEUMATOLOGY
Weijia Wang, Shanzhi He, Wenli Zhang, Hongyu Zhang, Vincent M DeStefano, Masayuki Wada, Kevin Pinz, Greg Deener, Darshi Shah, Nabil Hagag, Min Wang, Ming Hong, Ronghao Zeng, Ting Lan, Yu Ma, Fugui Li, Yingwen Liang, Zhencong Guo, Chanjuan Zou, Mingxia Wang, Ling Ding, Yupo Ma, Yong Yuan
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Abstract

Objectives: This study aims to evaluate the safety and efficacy of BCMA-CD19 compound chimeric antigen receptor T cells (cCAR) to dual reset the humoral and B cell immune system in patients with systemic lupus erythematosus (SLE) with lupus nephritis (LN).

Methods: This is a single-arm open-label multicentre phase 1 study of BCMA and CD19-directed cCAR in patients suffering from SLE/LN with autoantibodies produced by B cells and plasma/long-lived plasma cells. In this clinical trial, we sequentially assigned biopsy-confirmed (classes III-V) LN patients to receive 3×106 cCAR cells/kg postcessation of all SLE medications and conditioning. The primary endpoint of safety and toxicity was assessed. Complete immune reset was indicated by B cell receptor (BCR) deep sequencing and flow cytometry analysis. Patient 11 (P11) had insufficient lymphocyte counts and was underdosed as compassionate use.

Results: P1 and P2 achieved symptom and medication-free remission (MFR) from SLE and complete remission from lymphoma. P3-P13 (excluding P11) received an initial dose of 3×106 cCAR cells /kg and were negative for all autoantibodies, including those derived from long-lived plasma cells, 3 months post-cCAR and the complement returned to normal levels. These patients achieved symptom and MFR with post-cCAR follow-up to 46 months. Complete recovery of B cells was seen in 2-6 months post-cCAR. Mean SLE Disease Activity Index 2000 reduced from 10.6 (baseline) to 2.7 (3 months), and renal function significantly improved in 10 LN patients ≤90 days post-cCAR. cCAR T therapy was well tolerant with mild cytokine-release syndrome.

Conclusions: Data suggest that cCAR therapy was safe and effective in inducing MFR and depleting disease-causing autoantibodies in patients with SLE.

BCMA-CD19 复合 CAR T 细胞治疗系统性红斑狼疮:一期开放标签临床试验。
研究目的本研究旨在评估BCMA-CD19复合嵌合抗原受体T细胞(cCAR)对系统性红斑狼疮(SLE)合并狼疮性肾炎(LN)患者体液免疫和B细胞免疫系统双重重置的安全性和有效性:这是一项单臂开放标签多中心1期研究,研究对象是由B细胞和血浆/长寿命血浆细胞产生自身抗体的系统性红斑狼疮/狼疮肾炎患者。在这项临床试验中,我们按顺序将活检确诊的(III-V 级)LN 患者分配到接受 3×106 个 cCAR 细胞/公斤的治疗,这些患者在接受所有系统性红斑狼疮药物治疗和调理后接受治疗。评估的主要终点是安全性和毒性。B细胞受体(BCR)深度测序和流式细胞术分析表明免疫完全重置。患者11(P11)的淋巴细胞计数不足,作为同情使用剂量不足:结果:P1和P2实现了系统性红斑狼疮的无症状和无药物缓解(MFR)以及淋巴瘤的完全缓解。P3-P13(不包括P11)接受了初始剂量为3×106 cCAR细胞/公斤的治疗,在接受cCAR治疗3个月后,所有自身抗体(包括来自长寿命浆细胞的自身抗体)均为阴性,补体也恢复到正常水平。这些患者在 cCAR 后随访 46 个月,症状和 MFR 均得到改善。B细胞在cCAR后2-6个月完全恢复。系统性红斑狼疮疾病活动指数2000的平均值从10.6(基线)降至2.7(3个月),10名LN患者在cCAR治疗后90天内肾功能明显改善:数据表明,cCAR疗法在诱导系统性红斑狼疮患者的MFR和清除致病自身抗体方面安全有效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Annals of the Rheumatic Diseases
Annals of the Rheumatic Diseases 医学-风湿病学
CiteScore
35.00
自引率
9.90%
发文量
3728
审稿时长
1.4 months
期刊介绍: Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal covering all aspects of rheumatology, which includes the full spectrum of musculoskeletal conditions, arthritic disease, and connective tissue disorders. ARD publishes basic, clinical, and translational scientific research, including the most important recommendations for the management of various conditions.
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