抗PD-1免疫疗法治疗肺癌伴肺结核,疗效显著?

2021/12/23 561

程序性细胞死亡1(PD-1)及其配体(PD-L1)的免疫检查点抑制剂(ICI)已经改变了各种实体恶性肿瘤,尤其是在非小细胞肺癌(NSCLC)中。[1-6]众所周知,共抑制了受体PD-1与其配体PD-L1的结合会减弱T细胞的启动、增殖和细胞毒性。[7-8]因此,肿瘤细胞通过PD-1/PD-L1轴逃避宿主免疫监视和逃避肿瘤中和。[9]近年来,抗PD-1/PD-L1单克隆抗体(mAbs)免疫治疗在NSCLC中取得突破性进展,晚期NSCLC的5年生存率由不足5%显著提高至23.2%。[10-11]


T细胞上的免疫检查点分子,如PD-1和细胞毒性T淋巴细胞抗原4(CTLA-4)在慢性传染病期间也将被上调。免疫疗法在癌症中的疗效,尤其是抗PD-1/PD-L1 mAbs能够恢复和增强T细胞的功能,引起了对免疫疗法治疗慢性感染性疾病的想法。[12]然而,越来越多的证据表明,抗PD-1/PD-L1免疫疗法会导致结核病 (TB)再激活,[13-28]这唤起了医生对免疫疗法和免疫相关不良事件(irAEs)安全性的认识。


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治疗


纳武利尤单抗、帕博利珠单抗、卡瑞利珠单抗、特瑞普利单抗、替雷利珠单抗和信迪利单抗是治疗可用的抗 PD-1 mAb。无论治疗线如何,所有这些患者都使用ICI作为单一疗法或与抗血管生成或化学疗法联合治疗。


随着免疫疗法被批准用于治疗恶性肿瘤,它确实使某些癌症免疫疗法的中位PFS达到超过10个月[4,29-33]甚至超过20个月[34]的晚期NSCLC患者受益。然而,使用 ICI 进行免疫治疗会导致免疫系统失衡,从而导致多种免疫毒性。众所周知,结核病是一种与免疫系统密切相关的传染病,被认为是肺癌的危险因素,慢性炎症和肺纤维化具有致癌作用。[35-36]



相关研究


在一项临床前研究中,[37]得出的结论是,PD-1通路对于控制TB感染后的过度炎症反应至关重要。在TB感染后,与对照组相比,PD-1缺乏小鼠肺部的显著病理特征是局灶性坏死和显性中性粒细胞浸润。此外,某些促炎细胞因子在 PD-1 缺陷小鼠中显著增加,这进一步肯定了过度炎症反应的观点。


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在临床上,一项研究显示,[15]从一名在抗PD-1免疫治疗后发展为TB的患者收集经支气管肺活检标本,组织病理学结果显示肺泡区域弥漫性淋巴细胞浸润,提示过度炎症反应。总的来说,过度的炎症反应和坏死是主要病理特征,这类似于接受抗HIV治疗的患者的免疫重建炎症综合征。[38]


此外,有项研究[39]探讨了抗PD-1免疫治疗后TB再激活的机制。首先,PD-1在TB感染的肺组织中表达,但在免疫治疗区域不表达,并且在TB感染后上调。一旦PD-1被抗 PD-1 mAb 阻断,TB生长和细胞因子分泌 [尤其是肿瘤坏死因子 α (TNF-α)] 都会增加。而这种现象会被TNF-α中和所逆转。因此,TB 中的免疫反应受 PD-1调节,PD-1阻断通过过度分泌 TNF-α 促进了 TB 生长。



结论


免疫治疗对于合并有既往治疗过的潜伏性结核感染的肺癌患者来说是相对安全的,并且免疫治疗在这一特定人群中的疗效并不逊色于没有感染结核的肺癌患者。然而,PD-1/PD-L1 的阻断与结核病的发展或再激活有关。


因此,在抗 PD-1/PD-L1免疫治疗之前使用 IGRA 筛查结核病非常重要,特别是在结核病流行地区和免疫抑制患者中。此外,由于irAE导致的抗 PD-1/PD-L1 免疫治疗的依从性差和疗效减弱,因此在合并活动性结核病感染的肺癌患者中应更加谨慎地监测 irAE。


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汇聚专业医学学术知识,提供线上线下整体解决方案

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声明:本文为医会宝编辑部原创整理,仅代表作者个人观点,希望大家理性判断,有针对性应用。


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