异体脐带间充质基质细胞 MSC(UC)作为系统性红斑狼疮(SLE)的治疗方法:I-II 期概念验证临床研究的安全性和早期临床/生物学结果

IF 3.7 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
D. Farge , L. Biard , B. Weil , S. Loisel , P. LANSIAUX , I. Munia , V. Girault , C. Charles , A. Korganow , C. Beuvon , G. Pugnet , C. Cacciatore , N. Abisror , J. Taupin , A. Cras , M. Lowdell , K. Tarte
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引用次数: 0

摘要

背景& 目的:背景临床研究显示间充质干细胞(MSC)具有独特的免疫调节、促血管生成和抗纤维化作用。目的测试单次静脉注射异体脐带间充质干细胞(UC)治疗严重系统性红斑狼疮的安全性和初步疗效:方法一项前瞻性、单中心、贝叶斯I/II期研究(NCT03562065)招募了年龄在18-70岁(年)、基线时疾病处于活动期(SELENA-SLEDAI-2K≥6)、对>2种免疫抑制疗法(包括泼尼松≥6毫克/天,持续≥28天)至少3个月难治的系统性红斑狼疮患者,接受单次输注2或4.106 MSC(UC)/kg。主要终点是输注间充质干细胞(UC)后前 10 天内治疗相关 (TR) 严重不良事件(SAE,≥ 3 级)的发生率。次要终点是间充质干细胞(UC)生产的充分性、输注后M1和1年后每季度的所有AE、临床、HrQol和免疫反应。结果从2019年9月到2023年2月,共纳入8名(7名女性)患者,中位年龄35 [IQR27-60]岁,系统性红斑狼疮病程12 [6-21]年,PGA 2 [1.5-2], SELENA-SLEDAI-2K 11.5 [8-14.2], BILAG A (50%), B (38%) or C (12%) and SLICC-ACR 1.5 [0-2.8] prior MSC(UC) infusion (median dose 2 [IQR 2-4]x106/kg)。所有患者均接受了≥2.106/kg的间充质干细胞(UC)(5例分配到2.106/kg,3例分配到4.106/kg),其中1批的释放剂量低于预期目标剂量。前 10 天无 SAE,2 名患者出现 3 例输注相关 AE(2 例 1 级,1 例 2 级)。随访 12.4 个月(最短 9.6 个月,最长 13 个月)后,1 例患者复发后未发生 SAE,3 例患者未发生 SAE。7/8 例患者在 M3 期临床状况改善(见表),并持续 1 年,M12 期有 2 例主要临床反应和 2 例部分临床反应。1 名患者在 M3 期从新产生了捐献者特异性抗 HLA 抗体。虽然循环中的T细胞、B细胞、NK细胞和单核细胞未被间充质干细胞(UC)修饰,但CD24hiCD38hi过渡性B细胞和CD27posCD38neg/loCD24hi记忆性B细胞(即调节性B细胞亚群)的频率在M1时显著增加,而且是一过性的。这项概念验证研究显示临床症状有所改善。还需要进行安慰剂对照试验,以确认临床疗效并探索 B 细胞修饰在临床获益中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ALLOGENEIC UMBILICAL-CORD DERIVED MESENCHYMAL STROMAL CELLS MSC(UC) AS TREATMENT FOR SYSTEMIC LUPUS ERYTHEMATOSUS (SLE): SAFETY AND EARLY CLINICAL/BIOLOGICAL RESULTS FROM A PHASE I-II PROOF-OF-CONCEPT CLINICAL STUDY

Background & Aim: Background

Preclinical studies show Mesenchymal Stromal Cells (MSC) unique immunomodulatory, proangiogenic, and antifibrotic effects. Few clinical data report MSC use to treat Systemic Lupus (SLE) patients (pts) resistant to standard immunosuppressors and biologics, who suffer from high morbidity and increased mortality.

Aims

To test the safety and preliminary efficacy of a single intravenous injection of allogeneic umbilical cord-derived (UC) MSC in severe SLE.

Methods, Results & Conclusion: Methods

A prospective, single-center, Bayesian phase I/II study (NCT03562065) enrolled SLE pts (ACR criteria + antinuclear antibodies), aged 18–70 years (yr) with active disease (SELENA-SLEDAI-2K ≥6) at baseline and refractory to >2 immunosuppressive therapies for at least 3 months (M), including Prednisone ≥ 6 mg daily for ≥ 28 days, to receive a single infusion of 2 or 4.106 MSC(UC)/kg obtained from a single UC. Primary endpoint was the rate of treatment-related (TR) severe adverse events (SAE, grade ≥ 3) in the first 10 days post-MSC(UC) infusion. Secondary endpoints were adequacy of MSC(UC) production, all AE, clinical, HrQol and immune responses at M1 and quarterly for 1 yr post-infusion.

Results

From Sept 2019 to Feb 2023, 8 (7 female) pts, median age 35 [IQR 27-60] yrs after 12 [6-21] yrs SLE duration, were included with PGA 2 [1.5-2], SELENA-SLEDAI-2K 11.5 [8-14.2], BILAG A (50%), B (38%) or C (12%) and SLICC-ACR 1.5 [0-2.8] prior MSC(UC) infusion (median dose 2 [IQR 2-4]x106/kg). All pts received ≥2.106/kg MSC(UC) (5 assigned to 2.106/kg, 3 to 4.106/kg) with 1 batch released at lower than expected target dose. No SAE and 3 infusion-related AE (2 grade 1, 1 grade 2) in 2 pts occurred in the first 10 days. After 12.4 (min 9.6-max 13) months of follow-up, there were no TR SAE and 3 non-TR SAE after relapse in 1 pt. Improved clinical status (Table) in 7/8 pts at M3 persisted over 1 yr with 2 major and 2 partial clinical responses at M12. Donor-specific anti-HLA antibodies developed de novo in 1 pt at M3. While circulating T, B, NK and monocytes were unmodified by MSC(UC), CD24hiCD38hi transitional and CD27posCD38neg/loCD24hi memory B-cells frequencies, i.e. regulatory B-cell subsets, increased significantly and transiently at M1.

Conclusion

A single infusion of MSC(UC) was safe in 8 severe SLE pts. This proof of concept study showed clinical improvement. Placebo-controlled trials are needed to confirm clinical efficacy and explore the role of B-cell modifications in clinical benefit.

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来源期刊
Cytotherapy
Cytotherapy 医学-生物工程与应用微生物
CiteScore
6.30
自引率
4.40%
发文量
683
审稿时长
49 days
期刊介绍: The journal brings readers the latest developments in the fast moving field of cellular therapy in man. This includes cell therapy for cancer, immune disorders, inherited diseases, tissue repair and regenerative medicine. The journal covers the science, translational development and treatment with variety of cell types including hematopoietic stem cells, immune cells (dendritic cells, NK, cells, T cells, antigen presenting cells) mesenchymal stromal cells, adipose cells, nerve, muscle, vascular and endothelial cells, and induced pluripotential stem cells. We also welcome manuscripts on subcellular derivatives such as exosomes. A specific focus is on translational research that brings cell therapy to the clinic. Cytotherapy publishes original papers, reviews, position papers editorials, commentaries and letters to the editor. We welcome "Protocols in Cytotherapy" bringing standard operating procedure for production specific cell types for clinical use within the reach of the readership.
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