肿瘤细胞治疗研究
英文原题：CAR T cell therapy beyond cancer: current status, challenges and future prospects.
嵌合抗原受体（CAR）T细胞疗法已经彻底改变了肿瘤学，其基础逻辑——精准的抗原识别与持久的效应活性相结合——自然延伸至由长寿命病理细胞维持的慢性非恶性疾病。
嵌合抗原受体（CAR）T 细胞疗法已革新肿瘤治疗，其核心原理——精准识别抗原并维持持久效应活性——也适用于由长寿命病理细胞持续驱动的慢性非恶性疾病。这些细胞包括病毒储存库、自身反应性 B 细胞和浆细胞、活化成纤维细胞、同种异体免疫克隆，以及能够重塑组织微环境并逃避常规治疗清除的衰老细胞。本综述介绍如何通过重新定向工程化免疫反应，靶向维持疾病的细胞群，将 CAR 策略应用于不同疾病。CD28、4-1BB 和 OX40 等共刺激结构域可增强细胞持续性及效应功能；程序性细胞死亡蛋白1（PD-1）-CD28 转换受体可逆转抑制性信号；含显性负性转化生长因子-β（TGF-β）受体的细胞因子耐受型 CAR，则可在免疫抑制微环境中维持活性。本文讨论这些方法在感染（包括人类免疫缺陷病毒 HIV 和 Epstein-Barr 病毒 EBV）、自身免疫（包括靶向 CD19 和 B 细胞成熟抗原 BCMA 的清除策略，以及 CAR 工程化调节性 T 细胞 CAR-Treg）、靶向成纤维细胞活化蛋白 FAP 的纤维化、使用 B 细胞抗体受体 BAR-CAR 靶向凝血因子 VIII 和 IX 抑制物的血友病、采用人白细胞抗原 HLA 特异性 CAR-Treg 的移植，以及靶向尿激酶型纤溶酶原激活物受体 uPAR 和NK 细胞2族成员D配体（NKG2DL）的衰老相关病理中的应用。系统性红斑狼疮、系统性硬化症、肌炎和多发性硬化症的早期临床经验，以及慢性感染和纤维化疾病的临床前成果，显示了该策略的可行性和持久疾病修饰潜力。CAR-T 疗法由肿瘤领域拓展至其他疾病后，可编程细胞免疫治疗有望成为广泛适用的平台，用于清除持续存在的病理细胞、重塑患病组织环境并恢复长期免疫稳态。
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized oncology, and its foundational logic-precise antigen recognition coupled with durable effector activity-extends naturally to chronic non-malignant diseases sustained by long-lived pathological cells. These include viral reservoirs, autoreactive B and plasma cells, activated fibroblasts, alloimmune clones, and senescent cells that remodel tissue niches and evade clearance by conventional therapies. This review highlights how CAR-based strategies can be adapted across diverse disease settings by redirecting engineered immune responses toward disease-sustaining cellular compartments. Co-stimulatory domains such as CD28, 4-1BB, and OX40 enhance persistence and effector function; programmed cell death protein 1 (PD-1)-CD28 switch receptors reverse inhibitory signaling; and cytokine-resistant CARs incorporating dominant-negative transforming growth factor- (TGF- ) receptors maintain activity within suppressive microenvironments. We discuss these approaches across infections, including human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV); autoimmunity involving CD19- and B-cell maturation antigen (BCMA)-directed depletion strategies and CAR-engineered regulatory T cells (CAR-Tregs); fibrosis targeting fibroblast activation protein (FAP); hemophilia using B-cell antibody receptor (BAR)-CARs against factor VIII and factor IX inhibitors; transplantation employing human leukocyte antigen (HLA)-specific CAR-Tregs; and senescence-associated pathologies targeting urokinase plasminogen activator receptor (uPAR) and natural killer group 2D ligands (NKG2DLs). Early clinical experiences in systemic lupus erythematosus, systemic sclerosis, myositis, and multiple sclerosis, together with preclinical successes in chronic infections and fibrotic disease, demonstrate both feasibility and durable disease modification. By extending CAR-T therapy beyond oncology, these applications position programmable cellular immunotherapy as a broadly adaptable platform for eliminating persistent pathological cells, remodeling diseased tissue environments, and restoring long-term immune homeostasis.
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