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Progress in the Treatment of Non-small Cell Lung Cancer with Immune Checkpoint Inhibitors
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摘要: 肺癌是全球范围内发病率及死亡率极高的恶性肿瘤，其中以非小细胞肺癌(non-small cell lung cancer，NSCLC)最为常见。NSCLC的传统治疗主要依靠化学药物，近年来免疫治疗成为NSCLC治疗的热点，并取得了令人瞩目的进展。大量新型生物免疫制剂被开发并应用于临床，其中免疫检查点抑制剂的应用最广、疗效最为肯定。本文将对近年NSCLC免疫治疗生物标志物研究现状及进展进行阐述，以期提高免疫治疗精准度，更好地指导NSCLC患者的个体化治疗。Abstract: Lung cancer is a malignant tumor with high incidence rate and mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common malignancy. The traditional treatment of NSCLC mainly depends on chemical drugs. In recent years, immunotherapy has become a hot spot in the treatment of NSCLC and made remarkable progress. The overall objective remission rate of immunotherapy for NSCLC patients is about 20%. A large number of new biological immune agents have been developed and applied in clinic. Among them, immune checkpoint inhibitor (ICI) has the widest application and the most positive effect on NSCLC. This paper summarizes the research status and progress of immunotherapy biomarkers of NSCLC in recent years, with the hope of improving the accuracy of immunotherapy and better guiding individualized treatment of NSCLC patients.
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Keywords:
- non-small cell lung cancer /
- immunotherapy /
- CTLA-4 /
- PD-1 /
- PD-L1
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肺癌作为发病率及死亡率极高的恶性肿瘤，其中以NSCLC最为常见，死亡率居恶性肿瘤首位。当前NSCLC的治疗通常采用以铂类药物为主的双药化疗，在治疗上存在一定的局限性且不良反应较多，因此需探索更为有效的治疗方式。近年来，随着细胞毒性T淋巴细胞相关蛋白4(cytotoxic T-lymphocyte-associated protein 4，CTLA-4)、程序性死亡[蛋白]-1(programmed death-1，PD-1)及其配体-1(programmed death-ligand 1，PD-L1)等免疫检查点及相关抑制剂的发展与研究的深入，免疫治疗显示出良好的发展前景，为肿瘤治疗开启了新时代。在所有NSCLC患者中，不区分治疗人群，客观缓解率为20%左右，中位缓解时间为12个月左右[1-4]。而针对PD-L1阳性患者，客观缓解率为45%左右[5]。为获得更好的治疗效果，改善患者预后，本文对近年新兴的NSCLC免疫治疗靶点及其靶点药物研究进展进行阐述，以期对NSCLC的免疫治疗临床实践提供参考，为NSCLC患者提供治疗新策略。
1. 免疫检查点及作用机制
免疫检查点是一类免疫抑制性分子，可调节机体的免疫激活程度，免疫检查点分子的表达和功能异常是癌症(包括肺癌)发生的重要原因之一[6]。因此，修复免疫检查点异常已成为肿瘤治疗的重要选择。
1.1 CTLA-4
CTLA-4与CD80/CD86结合抑制T细胞活化，发挥负向免疫应答调节作用。调节性T(regulatory T，Treg)细胞可通过CTLA-4依赖的胞啃作用降低CD80/CD86表达，从而抑制抗原提呈细胞的T细胞刺激活性，以及通过增加PD-1和效应T细胞的PD-L1活性从而对T细胞产生双重抑制作用。因此，联合阻断CTLA-4和PD-1/PD-L1可能协同阻碍调Treg细胞介导的免疫抑制，从而有效增强肿瘤免疫[7]。
1.2 PD-1及PD-L1
PD-1及PD-L1主要在T细胞活化后表达，其功能与CTLA-4相似。由于PD-L1主要在肿瘤细胞表面表达，PD-1与PD-L1的结合主要发生在肿瘤免疫微环境中，因此使用PD-1及PD-L1抑制剂引起的自身免疫副作用较小[8]。多项临床试验研究证明，相较于CTLA-4抗体，PD-1及PD-L1抗体发生副反应的风险低且具有更好的抗肿瘤活性[9]。KEYNOTE-24研究显示，对于PD-L1高表达的驱动基因阴性的晚期NSCLC，PD-1治疗相较于化疗一线治疗展现出更好的总生存率(overall survival，OS)及5年生存率[9]。
1.3 其他免疫检查点
淋巴细胞激活基因-3(lymphocyte-activation Gene-3，LAG-3)可在Treg细胞及失能的CD4+Th细胞上表达并与主要组织相容性复合体Ⅱ类分子结合，从而抑制CD4+T细胞活性。研究表明，LAG-3不仅在NSCLC患者的肿瘤浸润淋巴细胞中高表达，而且在肿瘤细胞中异位表达[10]。此外，在NSCLC患者中肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte，TIL)高表达LAG-3，可能与PD-1/PD-L1轴不敏感有关[11-12]。晚期NSCLC患者EGFR-TKI治疗失败后，LAG-3表达水平显著上调。
T细胞免疫球蛋白ITIM结构域(T cell immunoglobulin and ITIM domains，TIGIT)是一种在免疫细胞上表达的免疫检查点蛋白，在多种T细胞和自然杀伤细胞上高表达，通过与激活性受体CD226竞争性结合CD155从而抑制淋巴细胞激活[13-15]。在肿瘤细胞表面(包括NSCLC细胞)，通常高表达CD155以抑制淋巴细胞对其的杀伤作用。
T淋巴细胞免疫球蛋白黏蛋白-3(T cell immunoglobulin domain and mucin domain-3，TIM-3)是一种负调控免疫检查点，存在于多种T细胞(包括Treg细胞)、树突状细胞、B细胞、巨噬细胞、自然杀伤细胞和肥大细胞中[16]。TIM-3在NSCLC中高表达并通过介导T细胞耗竭抑制抗肿瘤免疫[17-18]。
此外，文献报道还存在一些其他免疫检查点与NSCLC可能相关。如最新临床前研究发现，部分NSCLC患者癌细胞表面可表达Adenosine 5'-Diphos-phate (ADP)-Ribosyltransferase-1(ART1)并介导Notch胞内结构域(notch intracellular domain，NICD)以抵抗机体CD8+ T细胞浸润[19]。蛋白酪氨酸磷酸酶1B(protein tyrosine phosphatase-1B，PTP-1B)是另一种新的细胞内免疫检查点分子，PTP-1B高表达可抑制T细胞的增殖和杀伤力，进而促进肿瘤生长[20]。白细胞分化抗原(cluster of differentiation，CD)272是在T细胞及B细胞上表达的免疫检查点分子，当CD272与白细胞上的疱疹病毒侵入介导因子(herpes virus entry mediator，HVEM)结合后，可抑制B细胞和T细胞的活化[21]。CD276属于细胞表面受体B7家族，与髓系细胞触发受体2结合，可抑制或增强T细胞的活性[21]。CD278表达于T细胞群和各种先天免疫细胞，与其同族配体CD275结合后，引起Treg细胞扩增，释放白细胞介素(interleukin，IL)-10以抑制B细胞活化[21]。
2. 免疫检查点抑制剂
免疫检查点抑制剂(immune checkpoint inhibitor，ICI)类药物通过解除NSCLC的免疫抑制，激活机体自身免疫应答，从而发挥抗肿瘤作用。此外，ICI单独或联合化疗进一步扩大了NSCLC患者姑息治疗药物的选择，并有效延长部分晚期NSCLC患者的生存期[22-23]。但并非所有患者对ICI治疗反应良好，甚至部分患者可能出现严重副反应。因此，针对不同类型的NSCLC患者应选用不同的ICI以达到最佳治疗效果[24]。
2.1 抗CTLA-4治疗
伊匹木单抗(Ipilimumab)是一种CTLA-4单抗，可增强T细胞活化增殖能力而发挥抗肿瘤作用。需注意的是，患者应用Ipilimumab后易发生炎症副反应(15%~30%)，因此临床上治疗NSCLC时常将Ipilimumab与其他药物联合应用[8, 25]。研究显示，无论PD-L1肿瘤比例评分(tumor proportion score，TPS)如何，Ipilimumab治疗NSCLC均显示出良好疗效[26]。此外，Formenti等[27]报道了Ipilimumab联合姑息性放疗治疗NSCLC的临床效果，发现放疗增强了Ipilimumab对CTLA-4的阻断作用。Ⅱ期临床试验(NCT00527735)研究表明，化疗阶段性使用Ipilimumab方案较全程使用Ipilimumab及对照组患者的中位无进展生存期(progression free survival，PFS)明显改善[28]。基于上述研究结果，Ipilimumab可能成为具有发展前景的治疗方法。目前多个临床试验(CTR20200425、CTR20180929、CTR20170541)正在进行Ⅲ期NSCLC同步放化疗联合的随机对照研究。另一款IBI310(抗CTLA-4单抗)联合信迪利单抗治疗晚期或转移性NSCLC的Ⅰb期研究正在开展中(CTR20212823)。
曲美木单抗(Tremelimumab)是一种人源化CTLA-4 IgG2单克隆抗体，Tremelimumab通过抑制CTLA-4从而增强T细胞活性。目前，关于NSCLC患者的德瓦鲁单抗(Durvalumab)+Tremelimumab联合化疗研究(NCT02000947，Ⅰb期)证实，Durvalumab+Tremelimumab联合治疗NSCLC表现出良好的抗肿瘤效果，且不受PD-L1表达水平的影响。
卡度尼利单抗(Cadonilimab)是一种PD-1/CTLA-4双特异性抗体，近期获得国家药品监督管理局药品审评中心(center for drug evaluation，CDE)的临床试验许可，其适应证为晚期NSCLC患者。重组人源化PD-L1/CTLA-4双特异性单域抗体Fc融合蛋白注射液(KN046)可同时阻断PD-L1和CTLA-4，目前国内正在开展针对NSCLC患者的Ⅱ和Ⅲ期临床试验研究(CTR20211540，Ⅱ/Ⅲ期；CTR20201294，Ⅲ期；CTR20191219，Ⅲ期；CTR20190195，Ⅱ期)。此外，姜春娟等[29]利用可降解材料ZIF-8在KN046研究的基础上开发了一款新型药物KN046@19F-ZIF-8，使得KN046在体内复杂环境中保存其活性成分并输送至肿瘤细胞进行快速释放，从而达到高特异性免疫杀伤肿瘤细胞的目的。体外实验及动物实验研究均表明，相较于KN046，KN046@19F-ZIF-8有效提高了药物在肿瘤内的免疫应答率并降低其毒副作用，具有良好的抗肿瘤疗效[29]，为免疫联合疗法的临床应用提供了新的研发策略。
2.2 抗PD-1及PD-L1治疗
帕博利珠单抗(Pembrolizumab/ Keytruda)是一种以PD-1为靶点的单克隆抗体，可与PD-1受体结合，阻断其与PD-L1和PD-L2之间的相互作用，被批准用于NSCLC免疫联合疗法的一线治疗。研究表明，在PD-L1 TPS大于50%的NSCLC患者治疗过程中，将Pembrolizumab加入联合化疗可进一步改善患者的晚期预后[30-32]。KEYNOTE-001临床试验纳入了495例NSCLC患者，Pembrolizumab单药治疗的客观缓解率(objective response rate，ORR)和缓解持续时间均有改善，当PD-L1表达≥50%时，Pembrolizumab的治疗效果改善更明显[1, 33]。KEYNOTE-010、KEYNOTE-024和KEYNOTE-042研究表明，Pembrolizumab单药治疗改善了PD-L1阳性NSCLC患者的预后，并与较少的不良事件相关[34]。基于该研究，美国食品药品监督管理局(Food and Drug Administration, FDA)批准Pembrolizumab用于PD-L1表达≥50% 且上皮生长因子受体(epidermal growth factor receptor，EGFR)或间变性淋巴瘤激酶(anaplasticlymphoma kinase，ALK)基因突变阴性NSCLC患者的一线治疗。但值得注意的是，接受Pembrolizumab治疗的部分NSCLC患者出现肾小管间质性肾炎、IgA肾病等肾脏损伤[35]或出现伪疾病进展，即肿瘤治疗缩小后的假性进展[36]，未来应扩大样本量进一步开展研究。
纳武利尤单抗(Nivolumab/Opdivo)是一种可与PD-1受体结合的IgG4单克隆抗体，可阻断PD-1与PD-L1、PD-L2相互作用，解除PD-1通路介导的免疫应答抑制，被FDA批准用于系统治疗后进展的NSCLC[37]。2018年，Nivolumab在中国获批上市[2]。临床研究表明，NSCLC患者进行局部治疗(如放疗和手术切除)后，持续使用Nivolumab治疗，可缓解转移瘤的发生[38-40]。Hellmann等[41]针对Nivolumab联合Ipilimumab与化疗治疗晚期NSCLC患者的效果进行比较研究，结果显示Nivolumab联合Ipilimumab组患者的1年无进展生存率(42.6% 比13.2%)及中位PFS(7.2个月比5.5个月)均提升。在Checkmate 227 Ⅲ期临床试验中，相较于单独化疗组，Nivolumab联合Ipilimumab治疗晚期NSCLC和高肿瘤突变负荷患者的中位OS增加，Nivolumab联合化疗治疗晚期NSCLC患者的中位OS增加[42]。在Checkmate-057临床试验中，582例NSCLC患者分别应用Nivolumab和多西紫杉醇治疗，其中位OS分别为12个月和9个月，表明Nivolumab改善患者预后的情况与PD-L1表达水平呈正相关[43]。此外，目前尚未确立针对SMARCA4缺陷型NSCLC的有效治疗方法，Nivolumab可能是其潜在的有效治疗策略[44]。有文献报道，NSCLC患者应用Nivolumab后出现重症肌无力和肌病[45]，停用Nivolumab后症状缓解，推测其可能存在相应副作用，应引起重视。
度伐利尤单抗(Durvalumab/Imfinzi)是一种高亲和力抗PD-L1 IgG1单克隆抗体，可阻断PD-L1与PD-1和CD80的结合，用于治疗同步放化疗后未进展的不可切除Ⅲ期NSCLC，以及广泛期小细胞肺癌的一线治疗。在ARCTIC(NCT02352948，Ⅲ期)研究中，476例晚期NSCLC患者放、化疗后接受Durvalumab巩固治疗，结果显示接受Durvalumab治疗的患者具有更长的中位PFS，且该结果不受PD-L1表达水平的影响[46]。2018年2月，Durvalumab获批用于局部晚期放化疗后疾病尚未进展且无法手术的NSCLC患者。目前，大量Durvalumab联合治疗的Ⅲ期临床试验(NCT03003962、MYSTIC、NEPTUNE、POSEIDON)正在开展中。
阿替利珠单抗(Atezolizumab/Tecentriq)是一种以PD-L1为靶点的人源化IgG1单克隆抗体，获批用于EGFR及ALK突变为阴性、PD-L1高表达(肿瘤细胞≥50%或免疫细胞≥10%)的NSCLC一线治疗以及晚期小细胞肺癌的联合化疗。对于晚期NSCLC，Atezolizumab单药治疗可能比Atezolizumab联合化疗效果更好，在OS(RR=1.10，P=0.695)和ORR(RR=1.11，P=0.645)方面，Atezolizumab联合化疗并不优于Atezolizumab单药治疗，且接受Atezolizumab联合化疗的风险和停药创伤均显著高于Atezolizumab单药治疗[47]。POPLAR研究是针对Atezolizumabb的一项Ⅱ期临床试验[48]，研究显示Atezolizumab组患者在反应持续时间、中位持续时间等方面均优于多西紫杉醇组，表明Atezolizumab单药用于肺癌治疗的有效性，其改善程度与肿瘤细胞和TIL上PD-L1免疫组化表达程度相关，且其治疗作用在PD-L1高表达患者中更明显。
舒格利单抗(Sugemalimab)为重组抗PD-L1全人源单克隆抗体，可阻断PD-L1与PD-1和免疫细胞上的CD80相互作用，被批准用于驱动基因阴性的晚期NSCLC患者一线治疗。GEMSTONE-301是一项针对晚期无法手术切除的NSCLC患者的Ⅲ期临床试验，研究证实Sugemalimab可用于患者化疗后的巩固性治疗[49]。GEMSTONE-302 Ⅲ期临床试验分析了Sugemalimab联合化疗对既往未治疗的鳞状和非鳞状转移性NSCLC患者的中位PFS，与单独化疗相比，具有显著统计学意义和临床意义，未来有望成为临床一线用药选择[50]。
目前，在国内开展临床试验的PD-1药物包括HX008(CTR20202387，Ⅱ/Ⅲ期)、HLX10(CTR20190907，Ⅲ期)、JS001(CTR20192179，Ⅲ期)、LZM009 (CTR20191862，Ⅰb期)、特瑞普利单抗(CTR20190147，Ⅲ期；CTR20192525，其他分期)、SCT-I10A(CTR20192593，Ⅲ期)。在国内开展临床试验的PD-L1药物为ATEZOLIZUMAB(MPDL3280A注射剂；CTR20181628，Ⅲ期)。然而，一项针对PD-L1高表达、驱动基因阴性的晚期NSCLC患者的Ⅲ期随机对照研究显示，双免疫联合治疗可能不适合PD-L1高表达的NSCLC患者[51]。
2.3 其他免疫检查点抑制剂
2.3.1 LAG-3抑制剂
晚期NSCLC患者应用LAG-3抑制剂治疗，可能获益[52]。目前，针对实体肿瘤并处于临床试验阶段的药物包括：抗LAG-3单抗(NCT2966548、NCT02817633、NCT02460224，均为Ⅰ期)、可溶性LAG-3融合蛋白(NCT03625323，Ⅱ期)及双特异性抗体(CTLA-4-LAG-3，NCT03849469，Ⅰ/Ⅱ期；PD-1-LAG-3，NCT04140500，Ⅰ期)。
2.3.2 TIGIT抑制剂
替瑞利尤单抗(Tiragolumab)是一种人源化抗TIGIT单克隆抗体，CITYSCAPE(NCT03563716)研究显示，在PD-L1高表达人群中，Tiragolumab与Atezolizumab联合用药相较于Atezolizumab单药治疗显著提高患者的ORR和PFS。多项研究显示，Tiragolumab与Atezolizumab联合用药治疗实体肿瘤有效，其中对NSCLC的治疗效果最为显著，并被美国FDA认定为突破性疗法，有望用于小细胞肺癌的治疗[53-55]。维博利单抗(Vibostolimab)是另一种TIGIT单克隆抗体，近期发布的Ⅰ期临床试验结果显示，Vibostolimab与Pembrolizumab联合用药治疗晚期NSCLC患者具有良好的耐受性和抗肿瘤活性[56-57]。
2.3.3 TIM-3抑制剂
不同抗TIM-3单克隆抗体[如考伯利单抗(Cobolimab)、LY3321367、Sabatolimab等]的早期临床试验结果显示出了安全的毒性曲线，但抗肿瘤活性仍需进一步明确[58]。据报道，PD-1抗体可导致肺癌组织的TIM-3表达增加，提示TIM-3可能是阻断PD-1抗体的标志之一，且联合应用TIM-3阻滞剂和PD-1阻滞剂较单独使用TIM-3或PD-1阻滞剂更有效[59-60]。
其他可作为潜在治疗靶点的抑制性检查点分子包括：T细胞激活抑制物免疫球蛋白可变区结构域、B7-H3(CD276)(NCT02628535，NCT03406949)、B细胞和T细胞弱化因子(BTLA或CD272)(NCT04137900)等。双特异性抗体如Cadonilimab、NK046、JNJ-61186372[61]、埃万妥单抗(Amivantamab)[62]等作为新的研究方向，由于比普通抗体具有更强的特异性，并在T细胞杀伤肿瘤细胞、脱靶毒性、临床适应证等方面具有显著优势，正被逐渐开发[63]，期待未来用于NSCLC的治疗。
3. 小结与展望
NSCLC免疫治疗药物的优势正逐渐被关注，肿瘤免疫治疗药物较传统化疗药物具有复发率低、抗肿瘤效应持久的优势，通过动员自身免疫系统，识别并破坏肿瘤细胞，减少了传统化疗药物对人体的严重副反应。与此同时，免疫治疗药物可与传统化疗药物或放疗联合应用，发挥联合治疗“1+1＞2”的作用，多种免疫治疗药物有望在临床获得更广泛的应用，其中以抗CTLA-4治疗和抗PD-1及PD-L1治疗药物最为突出。
此外，针对不同的NSCLC患者人群，主要的检测驱动基因为EGFR、ALK和ROS1等，根据中国临床肿瘤学会《小细胞肺癌诊疗指南2021》[64]中关于免疫检查点抑制剂临床应用及药物可及性的建议：(1)针对无驱动基因突变的NSCLC非鳞癌患者，一线治疗为Pembrolizumab或Atezolizumab或Pembrolizumab联合培美曲塞和铂类，二线治疗为Nivolumab，局部晚期NSCLC患者的巩固治疗应同步放化疗后使用Durvalumab。(2)针对驱动基因突变阳性的NSCLC非鳞癌患者，不推荐使用免疫治疗。(3)针对NSCLC鳞癌患者，一线治疗为Pembrolizumab或Pembrolizumab联合紫杉醇，二线治疗为Nivolumab，局部晚期NSCLC患者的巩固治疗应同步化放疗后使用Durvalumab。
尽管多种免疫治疗药物已在临床取到良好疗效，但免疫治疗药物导致的相关不良事件也引起了广泛关注，如Pembrolizumab可导致患者出现肾病或伪进展[35-36]，Nivolumab可导致患者出现重症肌无力等[45]。目前，针对免疫治疗药物的研究仍面临巨大挑战：如何更有效地选用免疫治疗药物与其他治疗方案进行联合治疗，如何更有效地控制免疫治疗相关不良事件的发生，如何更精准地确定免疫治疗的适用人群与禁忌人群，针对基因突变的肿瘤细胞如何更有效地提高治疗效果等。上述问题均需进一步关注，希望未来更多研究探索解决免疫治疗的各种问题，使患者人群获得更有效、更恰当、个体化的治疗。
作者贡献：王硕负责文献检索、论文撰写及修订；邓云天、彭欢负责论文选题及修订；张向峰负责论文审校。利益冲突：所有作者均声明不存在利益冲突 -
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