Farge Dominique, Biard Lucie, Weil Ben, Girault Virginie, Lansiaux Pauline, Munia Ingrid, Loisel Séverine, Charles Catney, Saout Judikael, Resche-Rigon Matthieu, Korganow Anne Sophie, Beuvon Clément, Pugnet Grégory, Cacciatore Carlotta, Abisror Noémie, Taupin Jean Luc, Cras Audrey, Lowdell Mark W, Tarte Karin
Unité de Médecine Interne (UF 04) CRMR MATHEC, Maladies Auto-Immunes et Thérapie Cellulaire, Centre de Référence des Maladies Auto-Immunes Systémiques Rares d'Ile-de-France MATHEC, AP-HP, Hôpital St-Louis, Paris, France; Université Paris Cité, IRSL, Recherche Clinique en Hématologie, Immunologie et Transplantation, URP3518, Paris, France; Department of Medicine, McGill University, Montreal, QC, Canada.
Université Paris Cité, AP-HP, Hôpital Saint Louis, Service de Biostatistique et Information Médicale (DMU PRISME), INSERM U1153 Team ECSTRRA, Paris, France.
Lancet Rheumatol. 2025 Apr;7(4):e261-e273. doi: 10.1016/S2665-9913(24)00298-4. Epub 2024 Dec 17.
Patients with systemic lupus erythematosus (SLE) with inadequate responses to standard therapies have unmet therapeutic needs. The immunomodulatory, proangiogenic, and antifibrotic properties of mesenchymal stromal cells support their use in treating patients with SLE. We aimed to assess the safety of a single intravenous infusion of allogeneic umbilical cord-derived mesenchymal stromal cells in patients with severe SLE.
This prospective, single-centre, open-label, dose-escalation, Bayesian phase 1 study was done at the Saint-Louis University Hospital (Paris, France). Eligible patients were aged 18-70 years, were diagnosed with SLE according to American College of Rheumatology criteria with positive antinuclear antibodies, had a baseline Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score of 6 or more, and had disease that was refractory to first and second line SLE therapies. Patients were to receive a single intravenous infusion of 1 × 10, 2 × 10, or 4 × 10 umbilical cord-derived mesenchymal stromal cells per kg (manufactured from a single umbilical cord) in cohorts of five patients per dose, starting at 2 × 10 cells per kg. The primary endpoint was the rate of treatment-related severe adverse events (grade ≥3) in the first 10 days after infusion of umbilical cord-derived mesenchymal stromal cells. People with lived experience were involved in study design, patient enrolment, and dissemination of the study findings. This study is registered with ClinicalTrials.gov, NCT03562065, and the EU Clinical Trials Register, EudraCT2017-001400-29.
From May 14, 2019, to March 6, 2023, 29 patients were screened for eligibility, eight of whom were enrolled in the study. Enrolment was terminated early after inclusion of eight patients and no patients received the 1 × 10 dose of umbilical cord-derived mesenchymal stromal cells. Seven (88%) of eight participants were cisgender women and one (13%) was a cisgender man. The median age was 35 years (range 26-57) and the median SLE disease duration was 12 years (5-19). All patients received at least 2 × 10 cells per kg (range 2 × 10 to 4 × 10). No severe adverse events and three infusion-related adverse events (two grade 1 and one grade 2) occurred in two patients in the first 10 days after infusion. After 12·4 months (range 12-13) of follow-up, no treatment-related severe adverse events and three non-treatment-related severe adverse events occurred in one patient after relapse.
Our results suggest that a single infusion of 2 × 10 cells per kg or 4 × 10 cells per kg of allogeneic umbilical cord-derived mesenchymal stromal cells was safe in patients with severe SLE. Placebo-controlled trials are needed to confirm clinical efficacy and the role of B-cell modifications in clinical benefit.
Fondation du Rein, Alliance Maladies Rares AFM-Téléthon, Direction de la Recherche Clinique et de l'Innovation AP-HP, and ANR eCellFrance.
对标准疗法反应不足的系统性红斑狼疮（SLE）患者存在未满足的治疗需求。间充质基质细胞的免疫调节、促血管生成和抗纤维化特性支持其用于治疗SLE患者。我们旨在评估单次静脉输注异体脐带间充质基质细胞对重症SLE患者的安全性。
这项前瞻性、单中心、开放标签、剂量递增的贝叶斯1期研究在圣路易大学医院（法国巴黎）进行。符合条件的患者年龄在18至70岁之间，根据美国风湿病学会标准诊断为SLE且抗核抗体呈阳性，基线狼疮性红斑中雌激素安全性全国评估-SLE疾病活动指数（SELENA-SLEDAI）评分≥6分，并且对一线和二线SLE疗法难治。患者将接受单次静脉输注每千克1×10、2×10或4×10个脐带间充质基质细胞（由单个脐带制备），每个剂量组5名患者，起始剂量为每千克2×10个细胞。主要终点是输注脐带间充质基质细胞后前10天内与治疗相关的严重不良事件（≥3级）发生率。有实际生活经验的人参与了研究设计、患者招募和研究结果传播。本研究已在ClinicalTrials.gov（NCT03562065）和欧盟临床试验注册库（EudraCT2017-001400-29）注册。
从2019年5月14日至2023年3月6日，29名患者接受资格筛查，其中8名患者入组。在纳入8名患者后提前终止入组，没有患者接受每千克1×10个脐带间充质基质细胞剂量。8名参与者中有7名（88%）为顺性别女性，1名（13%）为顺性别男性。中位年龄为35岁（范围26 - 57岁），SLE疾病中位病程为12年（5 - 19年）。所有患者至少接受了每千克2×10个细胞（范围为每千克2×10至4×10个细胞）。输注后前10天内，2名患者未发生严重不良事件，3名患者发生与输注相关的不良事件（2例1级和1例2级）。随访12.4个月（范围12 - 13个月）后，1例复发患者未发生与治疗相关的严重不良事件，发生3例与治疗无关的严重不良事件。
我们的结果表明，对重症SLE患者单次输注每千克2×10个细胞或每千克4×10个异体脐带间充质基质细胞是安全的。需要进行安慰剂对照试验以确认临床疗效以及B细胞修饰在临床获益中的作用。
肾脏基金会、罕见病联盟AFM - 电视募捐、巴黎公立医院集团临床研究与创新部以及法国国家科研署eCellFrance项目。
