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3. 免疫检查点抑制剂
T细胞活化时，相应共抑制信号通路的免疫检查点，包括PD-1/程序性死亡分子配体-1（programmed death-ligand 1, PD-L1）和细胞毒性T淋巴细胞相关抗原4（cytotoxic T lymphocyte antigen 4, CTLA-4）的表达会增加，而ICIs通过阻断上述检查点恢复或增强机体的抗肿瘤免疫[17]。
3.1 PD-（L）1抑制剂
PD-1是表达在T细胞表面的一种重要的免疫抑制跨膜蛋白，其主要配体为PD-L1。肿瘤细胞能够表达PD-L1，与PD-1结合，导致PD-1胞质域的酪氨酸磷酸化和酪氨酸磷酸酶SHP-2的募集，使得T细胞受体（T cell receptor, TCR）信号分子去磷酸化，减弱了TCR下游的信号激活，降低了T细胞活化和细胞因子生成[18]。PD-（L）1抑制剂正是通过阻断PD-1/L1的结合，恢复机体对肿瘤细胞的免疫杀伤功能。PD-（L）1抑制剂见表1。
3.2 CTLA-4抑制剂
CTLA-4是由CTLA-4基因编码的一种跨膜蛋白，表达于活化的CD4+和CD8+ T细胞，与配体CD80（B7-1）和CD86（B7-2）结合。CTLA-4可通过竞争性抑制CD28与B7配体结合或将磷酸酶募集到CTLA-4的胞质域，降低TCR和CD28信号传导，抑制T细胞活化。其次，CTLA-4可通过细胞因子下调APC上CD80/CD86的表达，或通过胞吞作用，使CD80/CD86移出APC，从而减少CD28与B7配体的结合。再次，CTLA-4还能通过结合树突状细胞表达的CD80/CD86并诱导色氨酸降解酶吲哚胺2,3-双加氧酶（indoleamine 2, 3-dioxygenase, IDO）的表达，从而抑制T细胞应答[18]。目前国内尚无CTLA-4抗体获批上市，国外已批准CTLA-4抗体有伊匹单抗（Ipilimumab，商品名“Yervoy”）用于治疗晚期NSCLC等。
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戳“阅读原文”我们一起进步
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Cite this article as: Zhou CC, Wang J, Wang BC, et al. Chinese Experts Consensus on Immune Checkpoint Inhibitors for Non-small Cell Lung Cancer (2020 Version). Zhongguo Fei Ai Za Zhi, 2021, 24(4): 217-235. [周彩存, 王洁, 王宝成, 等. 中国非小细胞肺癌 免疫检查点抑制剂治疗专家共识（2020年版）. 中国肺癌杂志, 2021, 24(4): 217-235.] doi: 10.3779/j.issn.1009-3419.2021.101. 13
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附录：ICIs一线及二线治疗晚期NSCLC III期临床研究释义
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KEYNOTE-021G研究在晚期非鳞状NSCLC患者中评估了帕博利珠单抗联合培美曲塞/卡铂对比培美曲塞/卡铂的疗效[108]。结果显示，帕博利珠单抗联合组ORR和OS获益显著（ORR：58% vs 33%；mOS：34.5个月 vs 21.1个月，HR=0.71；3年生存率：50% vs 37%）。III期研究KEYNOTE-189对比了帕博利珠单抗联合培美曲塞/铂类较安慰剂联合培美曲塞/铂类治疗在晚期EGFR/ALK野生型非鳞NSCLC患者的疗效和安全性。免疫联合组展现出绝对的疗效优势，mOS：22.0个月 vs 10.6个月（HR=0.60），3年OS率：31.3% vs 17.4%，mPFS：9.0个月 vs 4.9个月（HR=0.50）。两种治疗方案的AE相当，≥3级TRAE发生率分别为52.1% vs 42.1%，均可控。值得一提的是，不论PD-L1表达状态如何，免疫联合组患者生存均明显延长[19,20,109]。FDA及NMPA分别于2017年和2019年批准了帕博利珠单抗联合含铂双药用于晚期无驱动基因突变的非鳞NSCLC患者的一线治疗。IMpower130研究在晚期非鳞状NSCLC患者中评估了阿替利珠单抗联合白蛋白紫杉醇/卡铂对比白蛋白紫杉醇/卡铂的疗效，结果显示免疫联合化疗组显著延长mPFS（7.0个月 vs 5.5个月，HR=0.64）和mOS（18.6个月 vs 13.9个月，HR=0.79）[21]。2019年FDA批准阿替利珠单抗联合白蛋白紫杉醇/卡铂用于EGFR/ALK阴性转移性非鳞状NSCLC的一线治疗。CameL研究评估了卡瑞利珠单抗联合培美曲塞/卡铂对比单纯化疗一线治疗晚期非鳞状NSCLC的疗效和安全性，结果显示联合卡瑞利珠单抗显著延长mPFS（11.3个月 vs 8.3个月，HR=0.60）[22,23]。2020年NMPA批准卡瑞利珠单抗联合培美曲塞/卡铂用于EGFR/ALK阴性的、不可手术切除的局部晚期或转移性非鳞状NSCLC的一线治疗。ORIENT-11研究对比了信迪利单抗联合培美曲塞/铂类对比单纯化疗一线治疗EGFR/ALK阴性晚期非鳞状NSCLC的疗效和安全性，结果显示联合信迪利单抗显著延长mPFS（8.9个月 vs 5.0个月，HR=0.48）和mOS（未达 vs 未达，HR=0.61）[24]。2021年NMPA批准信迪利单抗联合培美曲塞/铂类一线治疗非鳞状NSCLC。RATIONALE 304研究结果显示，替雷利珠单抗联合培美曲塞/铂类较单纯化疗一线治疗晚期非鳞状NSCLC，显著延长mPFS（9.7个月 vs 7.6个月，HR=0.645）[25]。GEMSTONE-302研究结果显示，舒格利单抗联合培美曲塞/卡铂对比单纯化疗一线治疗IV期非鳞状NSCLC，显著延长mPFS（8.57个月 vs 5.16个月，HR=0.66）[26]。
KEYNOTE-407研究评估了帕博利珠单抗联合紫杉醇或白蛋白紫杉醇/卡铂对比化疗一线治疗晚期鳞癌NSCLC患者的疗效和安全性。与单纯化疗相比，帕博利珠单抗联合化疗组显著改善OS（mOS：17.1个月 vs 11.6个月，HR=0.71；2年生存率：37.5% vs 30.6%），在PD-L1<1%、1%-49% 和≥50%的人群中，死亡风险分别降低21%、41%和21%，不同PD-L1表达人群均有获益[27-29]。2018年美国FDA批准了帕博利珠单抗联合紫杉醇或白蛋白紫杉醇/卡铂一线治疗晚期鳞状NSCLC。KEYNOTE-407中国扩展研究同样证实了帕博利珠单抗联合化疗相对于单纯化疗改善了mOS（17.3个月 vs 12.6个月，HR=0.44）和mPFS （8.3个月 vs 4.2个月，HR=0.32）[30]。NMPA已于2019年批准该方案一线治疗转移性鳞状NSCLC。RATIONALE 307研究[31]显示，替雷利珠单抗联合紫杉醇或白蛋白紫杉醇/卡铂一线治疗晚期鳞状NSCLC较单纯化疗显著改善mPFS（7.6/7.6 个月 vs 5.5个月），HR分别为0.52和0.48。2021年NMPA批准替雷利珠单抗联合紫杉醇或白蛋白紫杉醇/卡铂一线治疗晚期鳞状NSCLC。ORIENT-12研究[32]显示，信迪利单抗联合吉西他滨/铂类较化疗一线治疗鳞状NSCLC能显著延长mPFS（5.5个月 vs 4.9个月，HR=0.54）。GEMSTONE-302研究[26]显示，舒格利单抗联合紫杉醇/卡铂对比单纯化疗一线治疗IV期鳞状NSCLC，显著延长mPFS（7.16个月 vs 4.70个月，HR=0.33）。
KEYNOTE-024研究显示帕博利珠单抗在PD-L1≥50%的驱动基因阴性晚期NSCLC人群中，帕博利珠单抗治疗较标准含铂化疗的PFS（HR=0.50）与OS（HR=0.62）都得到了显著改善，帕博利珠单抗组5年生存率达31.9%，明显高于化疗组（16.3%），且任何级别的TRAE（76.6% vs 90.0%）和≥3级的TRAE发生率少于化疗组（31.2% vs 53.3%）[33,34]。2016年FDA批准帕博利珠单抗用于PD-L1≥50%的驱动基因阴性晚期NSCLC的一线治疗。KEYNOTE-042研究[67]进一步探索了帕博利珠单抗单药一线治疗PD-L1≥1%的NSCLC患者的效果，结果显示帕博利珠单抗组的mOS均优于单独化疗组，其中PD-L1≥50%的人群的疗效最为显著。随访数据[35]显示，PD-L1≥1%的患者经帕博利珠单抗单药一线治疗的3年OS率可达25%。KEYNOTE-042中国人群数据同样证实了一线帕博利珠单抗单药较化疗在各PD-L1表达（≥50%; ≥20%; ≥1%）人群中均有mOS获益（≥50%：24.5个月 vs 13.8个月，HR=0.63；≥1%：20.2个月 vs 13.5个月，HR=0.67），反应持续时间（duration of response, DOR）超15个月，且安全性可控[36]。该研究将帕博利珠单抗治疗的优势人群由PD-L1≥50%扩展至PD-L1≥1%的驱动基因阴性晚期NSCLC人群，2019年FDA和NMPA批准了帕博利珠单抗单药一线治疗适应证。IMpower110研究探索了阿替利珠单抗相比铂类联合培美曲塞或吉西他滨用于经PD-L1筛选的驱动基因阴性IV期NSCLC初治患者的疗效和安全性，结果显示阿替利珠单抗较化疗显著改善TC3/IC3患者的mOS（20.2个月 vs 14.7个月，HR=0.76）[37,38]。2020年FDA批准阿替利珠单抗用于一线治疗NSCLC，限用于TC3/IC3人群。CheckMate 026研究探索了纳武利尤单抗对比含铂化疗一线治疗PD-L1≥5%的晚期NSCLC，结果显示纳武利尤单抗相比标准化疗未能延长PFS和OS[39]。并非所有的免疫单药作为驱动基因阴性的NSCLC一线治疗均能使患者获益，临床实践中还需要根据临床研究的数据及国内获批适应证的情况进行合理选择。
IMpower150研究是探索抗血管生成治疗结合化疗的基础上联合免疫治疗的疗效，对比阿替利珠单抗+贝伐珠单抗+卡铂+紫杉醇（ABCP）、阿替利珠单抗+卡铂+紫杉醇（ACP）与标准治疗贝伐珠单抗+卡铂+紫杉醇（BCP）用于未经化疗的转移性非鳞状NSCLC患者的疗效及安全性。结果显示，ABCP组（阿替利珠单抗+贝伐珠单抗+卡铂+紫杉醇）对比BCP组（贝伐珠单抗+卡铂+紫杉醇）OS获益明显（19.5个月 vs 14.7个月，HR=0.80），而ACP方案（阿替利珠单抗+卡铂+紫杉醇）未显著优于BCP方案[40,41]。2018年FDA批准ABCP方案用于转移性非鳞状NSCLC的一线治疗。ABCP方案同时也增加了3级-4级AE发生率，临床应用时需要充分评估获益及潜在风险。
CheckMate 227研究Ia部分结果显示，纳武利尤单抗联合伊匹单抗的一线双免治疗较化疗能显著改善PD-L1≥1%的晚期NSCLC患者OS（mOS：17.1个月 vs 14.9个月，HR=0.79），3年生存率达33%[42]。2020年FDA批准了纳武利尤单抗联合伊匹单抗的双免疫组合方案治疗驱动基因阴性的PD-L1≥1%的晚期NSCLC。CheckMate 9LA研究[44]结果显示，无论PD-L1表达水平，纳武利尤单抗和伊匹单抗的双免疫联合加含铂化疗对比化疗一线治疗晚期NSCLC能显著延长OS（15.6个月 vs 10.9个月，HR=0.66）和PFS（6.7个月 vs 5.0个月，HR=0.68）。2020年FDA批准纳武利尤单抗和伊匹单抗联合2周期含铂化疗一线治疗EGFR/ALK阴性晚期NSCLC。考虑到KEYNOTE 598研究在PD-L1 TPS≥50%人群中显示帕博利珠单抗联合伊匹单抗未优于帕博利珠单抗单药治疗，在该人群中选择PD-1（L1）联合CTLA-4的双免疫方案需要慎重[43]。
KEYNOTE-001研究探索帕博利珠单抗治疗晚期NSCLC的疗效与安全性。数据显示PD-L1表达与帕博利珠单抗疗效相关，帕博利珠单抗治疗安全性可控[110]。在此研究基础上，KEYNOTE-010研究纳入PD-L1≥1%且既往接受过至少一种化疗方案的局部晚期或转移性NSCLC患者，对比帕博利珠单抗与多西他赛的疗效。结果显示，无论是帕博利珠单抗标准剂量2 mg/kg组还是高剂量10 mg/kg组的OS，均明显优于多西他赛组（10.4个月 vs 12.7个月 vs 8.5个月）。随访结果显示，PD-L1≥50%的患者接受帕博利珠单抗治疗较化疗 OS明显延长（mOS：16.9个月 vs 8.2个月，HR=0.55；5年OS率：25.0% vs 8.2%）。PD-L1≥1%的患者中，同样也观察到了帕博利珠单抗治疗的OS获益，5年OS率可达15.6%[45,46]。基于上述研究，FDA批准了帕博利珠单抗二线治疗既往接受过至少一种化疗的PD-L1≥1%的局部晚期或转移性NSCLC患者。KEYNOTE-033研究评估了帕博利珠单抗对比多西他赛二线治疗中国晚期NSCLC患者的疗效，在PD-L1≥50%的人群中，OS未达统计学显著性，在PD-L1≥1%的人群中，帕博利珠单抗依然显示了OS的获益趋势[111]。CheckMate 017、CheckMate 057和CheckMate 078三项III期研究显示了纳武利尤单抗单药用于二线治疗接受过含铂化疗方案的驱动基因阴性的NSCLC患者的疗效。在晚期鳞癌中，纳武利尤单抗单药较多西他赛显著改善mOS（9.2个月 vs 6.0个月，HR=0.62）[51,52]。在晚期非鳞癌中，纳武利尤单抗单药较多西他赛也能改善mOS（12.2个月 vs 9.5个月，HR=0.70）[52,53]。在中国晚期鳞癌与非鳞癌患者中，纳武利尤单抗仍然优于多西他赛（mOS：11.9个月 vs 9.5个月，HR=0.75）[49,50]，且三项研究中≥3级的AE的发生率纳武利尤单抗明显低于化疗组[49,112]。FDA及NMPA分别于2015和2018年批准纳武利尤单抗用于治疗驱动基因阴性的晚期NSCLC的二线治疗。POPLAR研究（II期）[113] 和OAK研究（III期）[47,48]分别评估了PD-L1抗体阿替利珠单抗二线治疗复发性局部晚期或转移性NSCLC的患者的疗效和安全性。研究显示，与多西他赛治疗组相比，阿替利珠单抗可显著提高患者的mOS（POPLAR：12.6个月 vs 9.7个月，HR=0.76；OAK：13.3个月 vs 9.8个月，HR=0.78）[48]。2016年，FDA批准阿替利珠单抗单药二线治疗晚期NSCLC，无论PD-L1的表达水平。JAVELIN Lung 200研究中单药Avelumab作为二线疗法治疗晚期PD-L1阳性NSCLC较多西他赛并未获得改善OS的阳性结果[114]。
5.1 PD-L1表达
PD-1是表达在T细胞表面的一种重要的免疫抑制跨膜蛋白，其主要配体为PD-L1。肿瘤细胞能够表达PD-L1，与PD-1结合，导致PD-1胞质域的酪氨酸磷酸化和酪氨酸磷酸酶SHP-2的募集，使得T细胞受体（T cell receptor, TCR）信号分子去磷酸化，减弱了TCR下游的信号激活，降低了T细胞活化和细胞因子生成[18]。PD-（L）1抑制剂正是通过阻断PD-1/L1的结合，恢复机体对肿瘤细胞的免疫杀伤功能。PD-（L）1抑制剂见表1
4.3 早期NSCLC的新辅助/辅助免疫治疗
免疫治疗也在早期NSCLC患者中进行着积极的探索。目前多项I期/II期研究的结果显示了良好的免疫应答和临床获益，尽管这些研究的入组人群、治疗方案、治疗周期等存在差异[58]。CheckMate 159、LCMC3、PRINCEPS、TOP1501、IoNESCO及ChicTR-OIC-17013726等免疫单药新辅助研究入组I期-IIIb期NSCLC患者，治疗1个-3个周期，病理学显著缓解率（major pathologic response, MPR）为14%-45%[59-62]。免疫联合化疗（NADIM、NCT02716038、SAKK 16/14）新辅助研究入组Ib期-IIIa期的患者，治疗2个-4个周期，其中，NADIM的MPR达到85.36%，病理学完全缓解（pathologic complete response, pCR）达到71.4%，其余两项研究的MPR在60%左右[63-65]。双免（NEOSTAR）新辅助纳入I期-IIIa期的患者，治疗3个周期，MPR率为24%[66]。免疫新辅助治疗后手术延迟率低，总体平均手术切除率为88.70%，未增加手术难度及围术期风险，手术并发症的平均发生率为20.6%，多数预后良好[58]。KEYNOTE-671、CheckMate 816、IMpower030、Checkmate 77T、AEGEAN等多项III期研究也在进行中。
4.1.3 III期不可切除的NSCLC免疫治疗 见表6。
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主要证据来源：度伐利尤单抗用于不可切除III期NSCLC同步放化疗后的巩固治疗（PACIFIC），FDA和NMPA批准。
PACIFIC研究在接受含铂同步放化疗后未发生疾病进展的III期不可切除的NSCLC患者中评估了度伐利尤单抗巩固治疗对比安慰剂的疗效。结果显示，度伐利尤单抗对比安慰剂治疗显著延长OS（47.5个月 vs 29.1个月，HR=0.71）和生存率（4年：49.6% vs 36.3%）[54,55]。目前FDA和NMPA批准度伐利尤单抗用于不可切除III期NSCLC同步放化疗后的巩固治疗。
4.2 驱动基因突变阳性NSCLC
对于驱动基因阳性的NSCLC进行免疫治疗目前尚缺乏充分证据。IMpower150是第一个在亚组中显示ICIs对表皮生长因子受体（epidermal growth factor receptor, EGFR）阳性患者有临床获益的研究。针对EGFR阳性亚组的进一步分析显示，阿替利珠单抗+贝伐珠单抗+化疗组较贝伐珠单抗联合化疗组具有PFS获益（10.2个月 vs 7.1个月，HR=0.56），且OS获益在EGFR敏感突变NSCLC患者中更明显（29.4个月 vs 18.1个月，HR=0.60）[56]。CT18 II期临床研究中探索了特瑞普利单抗联合化疗用于EGFR-TKI治疗失败的EGFR突变阳性T790M阴性晚期NSCLC患者的疗效和安全性，客观缓解率（objective response rate, ORR）达50.0%，mPFS达7.0个月[57]。针对EGFR阳性晚期NSCLC，国内外免疫联合抗血管生成或化疗的多项研究（KEYNOTE-789、Checkmate-722、ORIENT-31和TREASURE）正在进行中，有望探索出新的治疗方案。
4.1.2 晚期NSCLC二线免疫治疗 见表4。
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主要证据来源：①纳武利尤单抗单药（CheckMate 017, CheckMate 057, CheckMate 078），不论PD-L1表达，FDA与NMPA批准；②帕博利珠单抗单药（KEYNOTE-010），PD-L1≥1%，FDA批准；③阿替利珠单抗单药（OAK），不论PD-L1表达，FDA批准（表5）。
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4. NSCLC的免疫治疗
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4.1 驱动基因突变阴性NSCLC
4.1.1 晚期NSCLC一线免疫治疗 见表2。
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主要证据来源：①免疫联合化疗：不论PD-L1表达：非鳞癌：帕博利珠单抗联合培美曲塞/铂类（KEYNOTE-021G, KEYNOTE-189），FDA与NMPA批准；阿替利珠单抗联合白蛋白紫杉醇/卡铂（IMpower130），FDA批准；卡瑞利珠单抗联合培美曲塞/卡铂（CameL），NMPA批准；信迪利单抗联合培美曲塞/铂类（ORIENT-11），NMPA批准；替雷利珠单抗联合培美曲塞/铂类（RATIONALE 304）；舒格利单抗联合培美曲塞/卡铂（GEMSTONE-302）；鳞癌：帕博利珠单抗联合紫杉醇或白蛋白紫杉醇/卡铂（KEYNOTE-407），FDA与NMPA批准；替雷利珠单抗联合紫杉醇或白蛋白紫杉醇/卡铂（RATIONALE 307），NMPA批准；信迪利单抗联合吉西他滨/铂类（ORIENT-12）；舒格利单抗联合紫杉醇/卡铂（GEMSTONE-302）；②单药：帕博利珠单抗（KEYNOTE-024，KEYNOTE-042），PD-L1≥1%，FDA和NMPA批准；阿替利珠单抗（IMpower110），TC3/IC3人群，FDA批准；③免疫联合化疗和抗血管：阿替利珠单抗+贝伐珠单抗+紫杉醇+卡铂（IMpower150），FDA批准；④双免疫联合治疗：纳武利尤单抗联合伊匹单抗（CheckMate 227），PD-L1≥1%，FDA批准；⑤双免疫联合化疗：纳武利尤单抗+伊匹单抗+2个周期含铂化疗（CheckMate 9LA），FDA批准（表3）。
2. 肿瘤的免疫逃逸机制
2.1 机体正常的免疫监视
在正常生理状态下，免疫系统具有“监视功能”，可精确识别“非己”成分；免疫系统可清除入侵的微生物，排斥异体移植物，还能察觉并消灭肿瘤细胞。随着免疫学研究的深入，已经证实，T淋巴细胞介导的细胞免疫是抗肿瘤免疫的主要机制。肿瘤细胞产生的新抗原被抗原递呈细胞（antigen presenting cells, APCs）摄取并加工处理，并以抗原肽-主要组织相容性复合体（major histocompatibility complex, MHC）I类/II类分子复合物的形式由APCs提呈给T细胞，使得T细胞活化、增殖、分化成肿瘤抗原特异性细胞毒性T细胞（cytotoxic T cell, CTL）。随后CTL迁移并浸润肿瘤床，并通过T细胞受体（T cell receptor, TCR）和抗原肽-MHC I类分子复合物之间的相互作用，特异性识别并杀死肿瘤细胞。肿瘤细胞凋亡后又会释放更多的肿瘤相关抗原，进一步激活更多的T细胞以进一步杀伤肿瘤[12]。
2.2 肿瘤的免疫逃逸机制和相应的治疗策略
正常情况下，机体免疫监视功能可识别并清除癌变的细胞，但肿瘤细胞有多种方法逃避免疫系统监视，最终导致肿瘤的发生和发展。肿瘤免疫逃逸机制大致可分为以下三个方面[13]：①免疫检查点：肿瘤细胞除了表达可被免疫系统识别的某些特殊抗原，还可表达多种免疫抑制性配体，与T细胞表达的抑制性受体［程序性死亡分子-1（programmed cell death protein 1, PD-1）、LAG-3、TIM-3、TIGIT、VISTA、CD244等］结合，这些共抑制分子会抑制T细胞功能。可通过阻断共抑制信号解除对T细胞的活化和增殖的抑制，从而杀死肿瘤细胞[13]。②抗原性丧失：肿瘤细胞通过丧失特异性抗原的表达来避开免疫系统的识别，从而躲避免疫系统的监视。可通过细胞工程技术改造免疫细胞，使之可以识别肿瘤细胞表面的其他特定“非己”抗原而杀死肿瘤细胞[14,15]。③免疫抑制微环境：在实体肿瘤组织内，存在多种负性调节的细胞和细胞因子，共同构成了肿瘤组织周围的免疫抑制性微环境。可通过调节免疫细胞及其分泌因子，促进血管生成等多重参与肿瘤微环境的因素实现免疫治疗[16]。
数据差根本不可能有机会发表，间接释放利好。