常见肺损伤类型

简介

纳武利尤单抗是一种免疫检查点阻断剂，主要用于治疗表皮生长因子受体（EGFR）突变阴性和间变性淋巴瘤激酶（ALK）阴性，先前接受含铂化疗方案后疾病进展或不能耐受的局部晚期或转移性非小细胞肺癌（NSCLC）；治疗先前接受含铂化疗方案治疗时或治疗后疾病进展且肿瘤程序性死亡分子-配体1（PD-L1）表达阳性（定义为表达PD-L1的肿瘤细胞≥1%）的复发性或转移性头颈部鳞状细胞癌（SCCHN）；治疗先前接受过两种或两种以上全身性治疗方案的晚期或复发性胃或胃食管连接部腺癌。

背景

纳武利尤单抗是一种人类IgG4单克隆抗体，可与PD-1受体结合，阻断其与PD-L1和PD-L2之间的相互作用，阻断PD-1通路介导的免疫抑制反应，包括抗肿瘤免疫反应。除上述获批的适应症之外，目前还存在超说明书用药，用于治疗既往接受过索拉菲尼治疗的肝癌病人；伴淋巴结转移的黑色素瘤或完全切除病人伴转移的黑色素瘤的辅助治疗；治疗不可切除或转移性黑色素瘤(合并伊匹单抗)或单药治疗治疗BRAF V600野生型不可切除或转移性黑色素瘤或BRAF V600突变阳性病人的不能切除或转移黑色素瘤；治疗错配修复缺陷(dMMR)或微卫星高度不稳定(MSI-H)的转移性结直肠癌；治疗中高危晚期肾细胞癌(联合伊匹单抗或单药用于曾接收过抗血管生成治疗的病人)；以及复发或进展的霍奇金淋巴瘤的治疗。纳武利尤单抗（商品名：欧狄沃（Opdivo)）为40mg（10mg/ml），100mg（10mg/ml）两种规格的注射液。常见不良反应包括：咳嗽、上呼吸道感染等呼吸系统不良反应；中性粒细胞减少等血液系统不良反应；输液相关反应、超敏反应；甲状腺功能减退、甲状腺功能亢进等内分泌相关不良反应；周围神经病变、头痛、头晕等神经系统不良反应；恶心、腹泻等胃肠道不良反应；皮疹、瘙痒、白癜风、皮肤干燥、红斑、脱发等皮肤不良反应；骨骼肌肉疼痛、关节疼痛等肌肉骨骼不良反应；以及疲乏、体重下降、高血压等不良反应。

肺毒性

目前关于纳武利尤单抗相关的肺毒性大多基于临床试验结果以及个案报道，基于肺癌的临床试验数据表明，纳武利尤单抗导致的免疫相关性肺炎的发生率为4.6-6.2%，在肺癌中，纳武利尤单抗所致的病人死亡相较于其他肿瘤中更为常见。免疫相关性肺炎通常在PD-1治疗后几个月出现，但是个案报道中有病人在使用PD-1之后立即出现。     

基于文献报道纳武利尤单抗与以下肺疾病有关：间质性肺疾病、急性间质性肺炎、机化性肺炎(急性纤维素性机化性肺炎（AFOP）)、过敏性肺炎、非特异性间质性肺炎（NSIP）、细支气管炎、肺炎、肺结核、肉芽肿性肺炎、急性呼吸窘迫综合征、嗜酸粒细胞性肺炎、放射性复发性肺炎（RRP）、弥漫性肺泡出血、支气管痉挛、胸腔积液、肺动脉高压、呼吸困难（纳武利尤单抗导致吉兰-巴雷综合征、重症肌无力、肌炎累及呼吸肌）、结节脉络膜性肉芽肿、血管炎。

损伤机制

纳武利尤单抗导致肺损伤的机制目前尚未完全阐明，有研究认为可能与纳武利尤单抗阻断PD-1/PD-L1信号通路，导致肺间质免疫细胞（主要是细胞毒性T淋巴细胞）过度激活有关，识别肺组织来源抗原。但仍有待进一步研究。

用药结果和药物管理

目前关于对于免疫检查点抑制剂相关肺毒性（肺炎）的治疗，2021年CSCO免疫检查点抑制剂相关的毒性管理指南中建议 对于G2-G4级的肺毒性，以激素治疗为基础，必要时可以考虑使用英夫利西单抗静脉滴注、吗替麦考酚酯、静脉注射丙种球蛋白治疗。

对于纳武利尤导致的其他肺毒性大多基于个案报道，目前尚无公认的治疗方案推荐，个案中大多在停用纳武利尤单抗的基础上联合使用激素治疗，必要时使用英夫利西单抗、利妥昔单抗、环磷酰胺等药物治疗，但病人转归个体差异较大，大部分病人症状控制、好转，小部分病人治疗后死亡。

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