系统性红斑狼疮的细胞治疗：最新进展和未来方向

摘要(中文译文)

系统性红斑狼疮（SLE）是一种异质性自身免疫性疾病，以免疫应答失调、慢性炎症和进行性器官损害为特征。尽管在疾病发病机制的认识和靶向治疗的发展方面取得了实质性进展，仍有相当比例的患者对传统免疫抑制和生物制剂治疗无效，尤其是那些具有严重或复发性疾病表现（如狼疮性肾炎）的患者。持续存在的疾病活动性和累积的治疗毒性继续导致不可逆的器官损害和发病率增加。近年来细胞免疫治疗的进展使嵌合抗原受体（CAR）T细胞疗法成为SLE中一种有前景的新型治疗手段。通过靶向B细胞相关抗原，CAR T细胞疗法能够实现深度且持久的B细胞清除，有望克服基于单克隆抗体的B细胞靶向治疗的局限性。早期临床报告和新兴试验数据表明，靶向CD19的CAR T细胞疗法可在难治性SLE患者中诱导深刻的免疫学缓解和持续的、无药物的临床缓解。这些发现提示，CAR T细胞疗法不仅可能控制疾病活动性，还可能从根本上重置自身免疫应答。在本综述中，我们总结了CAR T细胞疗法用于SLE的免疫病理学依据，回顾了现有的临床前和临床证据，并讨论了开发更具选择性和更安全的、靶向与狼疮发病机制相关的B细胞亚群的CAR构建体的持续努力。我们还探讨了关键挑战，包括安全性考量、缓解的持久性、患者选择以及长期免疫学后果。总体而言，CAR T细胞疗法代表了一种变革性的、可能改变疾病进程的SLE治疗策略，值得在精心设计的临床试验中进一步研究。

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by dysregulated immune responses, chronic inflammation, and progressive organ damage. Despite substantial advances in understanding disease pathogenesis and the development of targeted therapies, a significant proportion of patients remain refractory to conventional immunosuppressive and biologic treatments, particularly those with severe or relapsing disease manifestations such as lupus nephritis. Persistent disease activity and cumulative treatment toxicity continue to contribute to irreversible organ damage and increased morbidity. Recent advances in cellular immunotherapy have positioned chimeric antigen receptor (CAR) T-cell therapy as a promising novel therapeutic approach in SLE. By targeting B-cell-associated antigens, CAR T-cell therapy enables deep and sustained B-cell depletion, potentially overcoming the limitations of monoclonal antibody-based B-cell-directed therapies. Early clinical reports and emerging trial data demonstrate that CD19-directed CAR T-cell therapy can induce profound immunologic remission and sustained, drug-free clinical remission in patients with refractory SLE. These findings suggest that CAR T-cell therapy may not only control disease activity but also fundamentally reset autoimmune immune responses. In this review, we summarize the immunopathogenic rationale for CAR T-cell therapy in SLE, review available preclinical and clinical evidence, and discuss ongoing efforts to develop more selective and safer CAR constructs targeting B-cell subsets relevant to lupus pathogenesis. We also address key challenges, including safety considerations, durability of response, patient selection, and long-term immunologic consequences. Collectively, CAR T-cell therapy represents a transformative and potentially disease-modifying strategy for SLE, warranting further investigation in well-designed clinical trials.

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