From the Departments of Internal Medicine 5-Hematology and Oncology (F.M., S.V., M.A., S. Kharboutli, S. Kretschmann, I.V., S. Spoerl, H.R., A.M.) and Internal Medicine 3-Rheumatology and Immunology (J.T., L.B., A.W., C.B., T.R., I.M., C.T., J.K., L.M., R.G.-B., A.B., G.K., G.S.), Deutsches Zentrum Immuntherapie (F.M., J.T., L.B., A.W., C.B., S.V., M.A., T.R., I.M., C.T., J.K., S. Kharboutli, S. Kretschmann, I.V., S. Spoerl, H.R., L.M., R.G.-B., A.B., G.K., A.M., G.S.), and the Institute of Clinical Microbiology, Immunology, and Hygiene (R.G.G.), Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, and the Department of Biology, Division of Genetics, Nikolaus-Fiebiger Center for Molecular Medicine, FAU Erlangen-Nürnberg (S. Schäfer, T.W.), Erlangen, the Department of Hematology and Oncology and Health Campus Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University, Magdeburg (D.M.), and the Department of Rheumatology, Charité-Universitätsmedizin Berlin, Berlin (G.K.) - all in Germany; the Department of Rheumatology, Catholic University of the Sacred Heart, Rome (C.T., G.S.); the Department of Clinical Immunology, Nouvel Hôpital Civil, Strasbourg University, Strasbourg (A.-S.K.), and Centre de Référence des Maladies Auto-immunes Systémiques Rares d'Ile-de-France, Hôpital Saint-Louis and Université Paris Cité, Paris (D.F.-B.) - both in France; and Karolinska Institutet, Stockholm (G.S.).
N Engl J Med. 2024 Feb 22;390(8):687-700. doi: 10.1056/NEJMoa2308917.
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. (Funded by Deutsche Forschungsgemeinschaft and others.).
背景：治疗系统性红斑狼疮（SLE）、特发性炎性肌病和系统性硬化症等自身免疫性疾病通常需要长期免疫抑制。通过深度耗尽 B 细胞来重置这些疾病中的异常自身免疫反应是实现持续无药物缓解的潜在策略。
方法：我们评估了 15 例接受过氟达拉滨和环磷酰胺预处理后单次输注 CD19 嵌合抗原受体（CAR）T 细胞的重症 SLE（8 例）、特发性炎性肌病（3 例）或系统性硬化症（4 例）患者。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-欧洲抗风湿病联盟（ACR-EULAR）主要临床反应和欧洲硬皮病试验和研究组（EUSTAR）活动指数评分（评分越高表示疾病活动度越高）等来评估。记录安全性变量，包括细胞因子释放综合征和感染。
结果：中位随访时间为 15 个月（范围 4 至 29 个月）。B 细胞缺失的平均（±SD）持续时间为 112±47 天。所有 SLE 患者均达到 DORIS 缓解，所有特发性炎性肌病患者均达到 ACR-EULAR 主要临床反应，所有系统性硬化症患者的 EUSTAR 活动指数评分均降低。所有患者均完全停止了免疫抑制治疗。10 例患者出现 1 级细胞因子释放综合征。各有 1 例患者出现 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。
结论：在这项病例系列研究中，CD19 CAR-T 细胞转移似乎在三种不同的自身免疫性疾病中是可行、安全和有效的，为进一步的对照临床试验提供了依据。（由德国研究基金会等资助）。
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