Chen Xiaomei, Liu Kaifan, Liu Bowen, Li Shiyin, Wang Yulian, Du Xin, Weng Jianyu, Song Bing, Wu Kongming, Lai Peilong
Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, Guangdong, P.R. China.
Cancer Center, Tongji Shanxi Hospital, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
J Hematol Oncol. 2025 Nov 28;19(1):1. doi: 10.1186/s13045-025-01769-0.
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated substantial efficacy against various hematological malignancies. The remarkable success of CAR-T cell therapy in targeting B-cell malignancies has generated significant interest in its potential application for treating autoimmune diseases (ADs). By engineering T cells to express CARs that specifically recognize B-cell antigens, researchers aim to selectively eliminate or modulate the dysregulated autoimmune responses underlying disease pathology. Early clinical trials targeting the B-cell marker CD19 have shown promising results, including clinical remission in patients with B-cell-mediated ADs. To broaden therapeutic potential and improve the safety profile of CAR-T cell therapy in autoimmunity, innovative strategies are under investigation. These include the development of chimeric autoantibody receptors (CAARs) for the precise depletion of autoantigen-specific B cells, and the engineering of regulatory T cells (Tregs) expressing antigen-specific CARs to achieve targeted immune modulation. Critical considerations for the safe and effective translation of CAR-T therapy to ADs include optimal target cell identification, CAR construct design, toxicity management, and the capacity to induce durable immune tolerance. This review explores strategies to optimize CAR-T cell therapies for ADs, focusing on enhancing efficacy and addressing current limitations. We summarize recent advances in alternative cell sources, CAR structural modifications, genetic and metabolic interventions, clinical translation, and the integration of novel technologies, presenting approaches poised to improve the efficacy and applicability of CAR-T cell therapy in ADs.
嵌合抗原受体（CAR）T细胞疗法已在多种血液系统恶性肿瘤中显示出显著疗效。CAR-T细胞疗法在靶向B细胞恶性肿瘤方面取得的显著成功，引发了人们对其治疗自身免疫性疾病（AD）潜在应用的浓厚兴趣。通过对T细胞进行工程改造，使其表达能够特异性识别B细胞抗原的CAR，研究人员旨在选择性消除或调节疾病病理基础中失调的自身免疫反应。针对B细胞标志物CD19的早期临床试验已显示出有前景的结果，包括B细胞介导的AD患者的临床缓解。为了拓宽治疗潜力并改善CAR-T细胞疗法在自身免疫性疾病中的安全性，正在研究创新策略。这些策略包括开发嵌合自身抗体受体（CAAR）以精确清除自身抗原特异性B细胞，以及对表达抗原特异性CAR的调节性T细胞（Treg）进行工程改造以实现靶向免疫调节。将CAR-T疗法安全有效地转化用于AD的关键考虑因素包括最佳靶细胞识别、CAR构建体设计、毒性管理以及诱导持久免疫耐受的能力。本综述探讨了优化用于AD的CAR-T细胞疗法的策略，重点是提高疗效和解决当前的局限性。我们总结了替代细胞来源、CAR结构修饰、基因和代谢干预、临床转化以及新技术整合方面的最新进展，介绍了有望提高CAR-T细胞疗法在AD中的疗效和适用性的方法。
