首个人体 regulatory T 细胞来源外泌体联合雷珠单抗治疗难治性新生血管性年龄相关性黄斑变性。
完整摘要 · 中文译文
尽管接受了玻璃体内抗血管内皮生长因子（VEGF）治疗，新生血管性年龄相关性黄斑变性（nAMD）患者中持续性积液仍很常见。调节性T细胞来源的外泌体（TregExo）具有临床前免疫调节活性。评估玻璃体内注射自体TregExo联合雷珠单抗治疗难治性nAMD的安全性和最大耐受剂量（MTD）。设计、设置和参与者：在河北省人民医院开展的单中心、前瞻性、开放标签1a期试验，采用3+3剂量递增设计。四名尽管连续至少3次每月玻璃体内抗VEGF注射后仍存在持续性视网膜内或视网膜下积液的患者接受了治疗。一次玻璃体内注射自体TregExo（计划剂量0.05、0.5或1.5 mg）与雷珠单抗0.5 mg联合配制。主要结局为安全性和MTD确定。剂量限制性毒性（DLT）预先设定为严重无菌性眼内炎症、持续眼内压大于30 mm Hg、ETDRS视力丧失超过15个字母，或30天内其他严重眼部不良事件。探索性视觉和解剖学结局评估至第90天。四名参与者接受治疗：3名接受0.05 mg，1名接受0.5 mg。0.05 mg队列中未发生DLT或眼内炎症，眼内压保持稳定。两名低剂量参与者从基线ETDRS评分3和9改善至第90天的35；患者1的黄斑厚度从318.2降至253.9 µm。接受0.5 mg的参与者出现了无菌性眼内炎症，伴有视力丧失和大的 视网膜内囊肿，经局部皮质类固醇治疗后消退。停止剂量递增，0.05 mg 为方案规定的最大耐受剂量（MTD）。玻璃体内注射自体 TregExo 联合雷珠单抗具有可识别的剂量上限：0.05 mg 可耐受，而 0.5 mg 与剂量限制性毒性（DLT）相关。有必要对低剂量 TregExo 辅助治疗难治性新生血管性年龄相关性黄斑变性（nAMD）进行进一步对照评估。试验注册：中国临床试验注册中心标识符：ChiCTR2500095798。
完整摘要 · 英文原文
Persistent fluid despite intravitreal anti-vascular endothelial growth factor (VEGF) treatment remains common in neovascular age-related macular degeneration (nAMD). Regulatory T cell-derived exosomes (TregExo) have preclinical immunomodulatory activity. To evaluate the safety and maximum tolerated dose (MTD) of intravitreal autologous TregExo plus ranibizumab in refractory nAMD. Design, Setting, and Participants: Single-centre, prospective, open-label phase 1a trial using a 3+3 dose-escalation design at Hebei General Hospital. Four participants with persistent intraretinal or subretinal fluid despite at least 3 consecutive monthly intravitreal anti-VEGF injections were treated. One intravitreal injection of autologous TregExo (planned doses, 0.05, 0.5, or 1.5 mg) coformulated with ranibizumab, 0.5 mg. The primary outcome was safety and MTD determination. Dose-limiting toxicity (DLT) was prespecified as severe sterile intraocular inflammation, sustained intraocular pressure greater than 30 mm Hg, loss of more than 15 ETDRS points, or another serious ocular adverse event within 30 days. Exploratory visual and anatomic outcomes were assessed through day 90. Four participants were treated: 3 at 0.05 mg and 1 at 0.5 mg. No DLT or intraocular inflammation occurred in the 0.05-mg cohort, and intraocular pressure remained stable. Two low-dose participants improved from ETDRS scores of 3 and 9 at baseline to 35 at day 90; Patient 1 had a macular thickness reduction from 318.2 to 253.9 µm. The 0.5-mg participant developed sterile intraocular inflammation with vision loss and a large intraretinal cyst, which resolved after local corticosteroid therapy. Dose escalation was stopped, and 0.05 mg was the protocol-defined MTD. Intravitreal autologous TregExo plus ranibizumab had an identifiable dose ceiling: 0.05 mg was tolerated, whereas 0.5 mg was associated with DLT. Further controlled evaluation of lower-dose TregExo-based adjunctive therapy in refractory nAMD is warranted. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2500095798.