德国埃尔兰根大学Georg Schett团队研究了CD19 CAR - t细胞治疗一系列自身免疫性疾病的疗效与安全性。该项研究成果发表在2024年2月21日出版的《新英格兰医学杂志》上。

系统性红斑狼疮（SLE）、特发性炎性肌炎和系统性硬化症等自身免疫性疾病的治疗通常涉及长期免疫抑制。通过B细胞的深度耗竭来重置这些疾病中的异常自身免疫是实现持续无药物缓解的潜在策略。

研究组评估了15名患有严重SLE（8名患者）、特发性炎性肌炎（3名患者）或系统性硬化症（4名患者）的患者，他们在用氟达拉滨和环磷酰胺预处理后接受了单次CD19嵌合抗原受体（CAR）T细胞输注。CAR T细胞输注后2年内的疗效通过SLE缓解定义（DORIS）缓解标准、美国风湿病学会-欧洲风湿病联盟（ACR–EULAR）主要临床缓解和欧洲硬皮病试验和研究小组（EUSTAR）活动指数评分（评分越高表示疾病活动越大）进行评估。记录安全性变量，包括细胞因子释放综合征和感染。

中位随访时间为15个月（4至29个月）。B细胞再生障碍的平均（±SD）持续时间为112±47天。所有SLE患者的DORIS缓解，所有特发性炎性肌炎患者的ACR–EULAR主要临床缓解，所有系统性硬化症患者的EUSTAR活性指数得分下降。所有患者完全停止免疫抑制治疗。10例患者出现1级细胞因子释放综合征。各有一名患者患有2级细胞因子释放综合征、1级免疫效应细胞相关神经毒性综合征和导致住院的肺炎。

研究结果表明，在这一系列病例中，CD19 CAR T细胞输注在三种不同的自身免疫性疾病中似乎是可行、安全和有效的，为进一步的对照临床试验提供了依据。

附：英文原文

Title: CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-up

Author: Fabian Müller, Jule Taubmann, Laura Bucci, Artur Wilhelm, Christina Bergmann, Simon Vlkl, Michael Aigner, Tobias Rothe, Ioanna Minopoulou, Carlo Tur, Johannes Knitza, Soraya Kharboutli, Sascha Kretschmann, Ingrid Vasova, Silvia Spoerl, Hannah Reimann, Luis Munoz, Roman G. Gerlach, Simon Schfer, Ricardo Grieshaber-Bouyer, Anne-Sophie Korganow, Dominique Farge-Bancel, Dimitrios Mougiakakos, Aline Bozec, Thomas Winkler, Gerhard Krnke, Andreas Mackensen, Georg Schett

Issue&Volume: 2024-02-21

Abstract:

Background

Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission.

Methods

We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology–European League against Rheumatism (ACR–EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded.

Results

The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR–EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell–associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization.

Conclusions

In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials.

DOI: 10.1056/NEJMoa2308917

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2308917