Gao Jie, Li Mengtao, Sun Ming, Yu Yiyi, Kong Ruina, Xu Xia, Liu Suxuan, Chen Qian, Li Xiaofang, Wu Yang, Xu Enshun, Yang Jianmin, Zhao Dongbao
Department of Rheumatology and Immunology, National Key Laboratory of Immunity and Inflammation, Changhai Hospital, Naval Medical University, Shanghai, China.
Department of Rheumatology, Peking Union Medical College Hospital (PUMCH), Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
Lancet. 2026 Dec 20;406(10522):2968-2979. doi: 10.1016/S0140-6736(25)01671-X. Epub 2025 Nov 12.
Lately, autologous CD19-targeting chimeric antigen receptor (CAR) T cells have shown excellent efficacy in treatment of autoimmune diseases, but with great safety concerns, such as infections. In this study, we aimed to evaluate the safety, tolerability, and efficacy of allogeneic CD19 CAR natural killer (NK)-cell therapy in patients with relapsed or refractory systemic lupus erythematosus (SLE).
In this open-label, single-arm, prospective, first-in-human case series, we evaluated allogeneic CD19 CAR NK-cell therapy in adult patients (aged 18-65 years) with relapsed or refractory SLE at one site in China. Patients who had received at least two previous standard systemic therapies and continued to exhibit moderate-to-severe disease activity were eligible for inclusion. This study consisted of schedule escalation and dose escalation, with schedule escalation from 7 days and dose escalation commencing at 0·75 × 10 CAR NK cells on day 0. All patients received a lymphodepleting conditioning regimen with fludarabine (25 mg/m per day) and cyclophosphamide (300 mg/m per day) administered daily from days -5 to -3, followed by three CAR NK-cell infusions within a single treatment cycle at identical dose levels and inter-infusion intervals. Dose-limiting adverse events were monitored in patients for 28 days. The primary endpoints of this study were safety and tolerability, including the incidence of dose-limiting toxicities and adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. This study was registered with ClinicalTrials.gov (NCT06010472) and follow-up is ongoing.
18 patients with relapsed or refractory SLE with moderate-to-severe disease activity were enrolled between Aug 21, 2023, and June 16, 2024. Of the 18 patients, 17 (94%) were female; the median age was 37·5 years (IQR 32·0-39·8), and the median disease duration was 10·5 years (IQR 4·5-14·8). Patients had received at least two standard systemic therapies, including biological agents (belimumab and telitacicept) in 14 (78%) of 18 patients, and plasmapheresis in one patient. Cytokine release syndrome was reported in one (6%) of 18 patients (grade 1). Neurotoxicity and other CAR NK-cell therapy-related severe adverse events were not observed, and there were no dose-limiting toxicities. Of the nine patients with more than 12 months' follow-up, six (67%) attained DORIS remission and lupus low disease activity state.
This study suggests that allogeneic CAR NK-cell therapy is a potent option for treatment of autoimmune diseases and indicates that such a therapy might address limitations of current autologous CAR T-cell therapy, including manufacturing scale and time, access, safety, and cost.
Shanghai Municipal Health Commission, Changhai Hospital Affiliated to Naval Medical University, and National Natural Science Foundation of China.
For the Chinese translation of the abstract see Supplementary Materials section.
最近，靶向自体CD19的嵌合抗原受体（CAR）T细胞在自身免疫性疾病的治疗中显示出优异的疗效，但存在诸如感染等重大安全问题。在本研究中，我们旨在评估异基因CD19 CAR自然杀伤（NK）细胞疗法在复发或难治性系统性红斑狼疮（SLE）患者中的安全性、耐受性和疗效。
在这项开放标签、单臂、前瞻性、首次人体病例系列研究中，我们在中国的一个地点评估了异基因CD19 CAR NK细胞疗法在成年（18 - 65岁）复发或难治性SLE患者中的应用。接受过至少两种先前标准全身治疗且仍表现为中度至重度疾病活动的患者符合纳入条件。本研究包括方案爬坡和剂量爬坡，方案爬坡从7天开始，剂量爬坡从第0天的0.75×10个CAR NK细胞开始。所有患者接受淋巴细胞清除预处理方案，从第 - 5天至第 - 3天每天给予氟达拉滨（25 mg/m²）和环磷酰胺（300 mg/m²），随后在单个治疗周期内分三次输注相同剂量水平且输注间隔相同的CAR NK细胞。对患者进行28天的剂量限制性不良事件监测。本研究的主要终点是安全性和耐受性，包括根据美国国立癌症研究所不良事件通用术语标准第5.0版的剂量限制性毒性和不良事件的发生率。本研究已在ClinicalTrials.gov注册（NCT06010472），随访正在进行中。
2023年8月21日至2024年6月16日期间，纳入了18例复发或难治性SLE且疾病活动为中度至重度的患者。在这18例患者中，17例（94%）为女性；中位年龄为37.5岁（IQR 32.0 - 39.8），中位病程为10.5年（IQR 4.5 - 14.8）。患者接受过至少两种标准全身治疗，18例患者中有14例（78%）接受过生物制剂（贝利尤单抗和替利珠单抗）治疗，1例患者接受过血浆置换。18例患者中有1例（6%）报告发生细胞因子释放综合征（1级）。未观察到神经毒性和其他与CAR NK细胞疗法相关的严重不良事件，也未出现剂量限制性毒性。在9例随访超过12个月的患者中，6例（67%）达到了DORIS缓解和狼疮低疾病活动状态。
本研究表明，异基因CAR NK细胞疗法是治疗自身免疫性疾病的一种有效选择，并表明这种疗法可能解决当前自体CAR T细胞疗法的局限性，包括生产规模和时间、可及性、安全性和成本。
上海市卫生健康委员会、海军军医大学附属长海医院和中国国家自然科学基金。
摘要的中文翻译见补充材料部分。
