【协和医学杂志】非小细胞肺癌免疫检查点抑制剂治疗进展

时间:2023-09-11 16:57:52   热度:37.1℃   作者:网络

肺癌作为发病率及死亡率极高的恶性肿瘤,其中以非小细胞肺癌(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(CTLA-4)、 程序性死亡[蛋白]-1(PD-1)及其配体-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(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(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(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(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(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(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(NICD)以抵抗机体CD8+ T细胞浸润[19]

蛋白酪氨酸磷酸酶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(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(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(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(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(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(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(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(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(FDA)批准 Pembrolizumab用于PD-L1表达≥50%且上皮生长因子受体(EGFR)或间变性淋巴瘤激酶(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。

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