近日，海军医科大学长海医院赵东宝团队研究了异基因CD19-CAR NK细胞治疗系统性红斑狼疮的疗效和安全性。相关论文于2025年11月12日发表在《柳叶刀》杂志上。

近年来，自体靶向CD19嵌合抗原受体（CAR） T细胞在治疗自身免疫性疾病方面显示出优异的疗效，但存在很大的安全性问题，如感染。在这项研究中，研究组旨在评估同种异体CD19 CAR自然杀伤（NK）细胞治疗复发或难治性系统性红斑狼疮（SLE）患者的安全性、耐受性和有效性。

在这个开放标签、单臂、前瞻性、首次人体病例系列研究中，研究组评估了异基因CD19 CAR - NK细胞治疗在中国一个机构复发或难治性SLE的成年患者（18-65岁）的疗效。既往接受过至少两种标准全身治疗并持续表现出中度至重度疾病活动性的患者符合纳入条件。该研究包含给药方案递增与剂量递增两个阶段：给药方案从7天起始，剂量自治疗首日（第0天）的0.75×10⁹个CAR-NK细胞开始递增。所有患者均接受淋巴细胞清除预处理，即在第-5至-3天每日静脉注射氟达拉滨（25 mg/m²/天）与环磷酰胺（300 mg/m²/天），随后在同一治疗周期内以相同剂量水平与输注间隔接受三次CAR-NK细胞输注。研究人员对患者进行了为期28天的剂量限制性不良事件监测。该研究主要终点是安全性与耐受性，包括依据《美国国家癌症研究所不良事件通用术语标准5.0版》判定的剂量限制性毒性及不良事件发生率。研究已在ClinicalTrials.gov注册（注册号NCT06010472），目前正在进行随访工作。

发现:在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患者，伴有中度至重度疾病活动。18例患者中，17例（94%）为女性；中位年龄为37.5岁（IQR为32.0 ~ 39.8），中位病程为10.5年（IQR为4.5 ~ 14.8）。患者接受了至少两种标准的全身治疗，包括18例患者中14例（78%）的生物制剂（贝利单抗和telitacicept）和1例患者的血浆置换。18例患者（1级）中有1例（6%）出现细胞因子释放综合征。未观察到神经毒性和其他CAR - NK细胞治疗相关的严重不良事件，也没有剂量限制性毒性。在随访超过12个月的9例患者中，6例（67%）达到DORIS缓解和狼疮低疾病活动性状态。

研究结果表明，同种异体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，包括制造规模和时间、可及性、安全性和成本。

附：英文原文

Title: Efficacy and safety of allogeneic CD19 CAR NK-cell therapy in systemic lupus erythematosus: a case series in China

Author: Jie Gao, Mengtao Li, Ming Sun, Yiyi Yu, Ruina Kong, Xia Xu, Suxuan Liu, Qian Chen, Xiaofang Li, Yang Wu, Enshun Xu, Jianmin Yang, Dongbao Zhao

Issue&Volume: 2025-11-12

Abstract:

Background

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).

Methods

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 0·75×109 CAR NK cells on day 0. All patients received a lymphodepleting conditioning regimen with fludarabine (25 mg/m2 per day) and cyclophosphamide (300 mg/m2 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.

Findings

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.

Interpretation

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.

DOI: 10.1016/S0140-6736(25)01671-X

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01671-X/abstract