晚期非小细胞肺癌免疫治疗现状及未来方向

doi:10.19401/j.cnki.1007-3639.2022.06.002

中国癌症杂志 ›› 2022, Vol. 32 ›› Issue (6): 478-486.doi: 10.19401/j.cnki.1007-3639.2022.06.002

晚期非小细胞肺癌免疫治疗现状及未来方向

苏春霞()(), 周彩存()()

同济大学附属上海市肺科医院肿瘤科,上海 200433

收稿日期:2022-05-27 修回日期:2022-06-10 出版日期:2022-06-30 发布日期:2022-07-21
通信作者: 周彩存 E-mail:susu_mail@126.com;caicunzhoudr@163.com
作者简介:苏春霞（ORCID: 0000-0003-1632-9487）,博士,主任医师,同济大学附属上海市肺科医院肿瘤科行政副主任、内科教研室副主任。E-mail: susu_mail@126.com。苏春霞,主任医师,同济大学教授、博士生导师,现任同济大学附属上海市肺科医院肿瘤科行政副主任、内科教研室副主任。在多个国际国内专业学会任职,包括2022年世界肺癌大会秘书、中国临床肿瘤学会（CSCO）患者教育专家委员会副主任委员、中华医学会肿瘤学分会青年委员、CSCO转化医学专家委员会副秘书长、CSCO免疫治疗专家委员会常务委员、上海抗癌协会青年理事会副理事长等。主持国家自然科学基金3项、申康新兴前沿技术课题等;作为执笔人撰写《CSCO免疫检查点抑制剂临床应用指南》、《CSCO免疫检查点抑制剂相关的毒性管理指南》及《上海市抗癌协会肺癌筛查指南》。以第一作者或通信作者在The Lancet Respiratory Medicine、Journal of Thoracic Oncology、NPJ Precis Oncol等SCI收录的学术期刊发表论文30余篇;主编及主译专著6部。获国家科技进步二等奖、上海科学技术进步一等奖、上海市科学技术普及个人二等奖、上海市科普教育创新奖个人二等奖等。

Current status and future directions of immunotherapy for advanced non-small cell lung cancer

SU Chunxia()(), ZHOU Caicun()()

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China

Received:2022-05-27 Revised:2022-06-10 Published:2022-06-30 Online:2022-07-21
Contact: ZHOU Caicun E-mail:susu_mail@126.com;caicunzhoudr@163.com

摘要/Abstract

摘要：

肺癌仍然是中国发病率和死亡率最高的恶性肿瘤,其中非小细胞肺癌（non-small cell lung cancer,NSCLC）约占80%以上。以靶向程序性死亡[蛋白]-1（programmed death protein-1,PD-1）或程序性死亡[蛋白]配体-1（programmed death ligand-1,PD-L1）的免疫检查点抑制剂（immune checkpoint inhibitor,ICI）为基础的治疗已成为了晚期肺癌的标准治疗手段之一。本综述将对晚期NSCLC免疫治疗的现状予以梳理,探讨现阶段面临的问题与挑战,并思考与展望未来发展方向。

关键词: 非小细胞肺癌, 免疫检查点抑制剂, 免疫治疗

Abstract:

Lung cancer remains the malignant tumor with the highest morbidity and mortality in China, among which non-small cell lung cancer (NSCLC) accounts for more than 80%. Immune checkpoint inhibitors (ICIs)-based therapy targeting programmed death protein-1 (PD-1) or its ligand programmed death ligand-1 (PD-L1) has become one of the standard treatments for advanced NSCLC. This review, with the focus on advanced NSCLC, summarized the development of immunotherapy, discussed current problems, and challenges and proposed future directions.

Key words: Non-small cell lung cancer, Immune checkpoint inhibitor, Immunotherapy

中图分类号:

R734.2

苏春霞, 周彩存. 晚期非小细胞肺癌免疫治疗现状及未来方向[J]. 中国癌症杂志, 2022, 32(6): 478-486.

SU Chunxia, ZHOU Caicun. Current status and future directions of immunotherapy for advanced non-small cell lung cancer[J]. China Oncology, 2022, 32(6): 478-486.

参考文献 50

[1]	ZHENG R S,, ZHANG S W,, ZENG H M, et al. Cancer incidence and mortality in China, 2016[J]. J Natl Cancer Cent, 2022, 2(1): 1-9.
[2]	MOLINA J R,, YANG P,, CASSIVI S D, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship[J]. Mayo Clin Proc, 2008, 83(5): 584-594. doi: 10.1016/S0025-6196(11)60735-0
[3]	YANG C Y,, YANG J C H,, YANG P C. Precision management of advanced non-small cell lung cancer[J]. Annu Rev Med, 2020, 71: 117-136. doi: 10.1146/annurev-med-051718-013524
[4]	RECK M,, RODRÍGUEZ-ABREU D,, ROBINSON A G, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small cell lung cancer[J]. N Engl J Med, 2016, 375(19): 1823-1833. doi: 10.1056/NEJMoa1606774
[5]	BRAHMER J R,, RODRIGUEZ-ABREU D,, ROBINSON A G, et al. LBA51 KEYNOTE-024 5-year OS update: first-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%[J]. Ann Oncol, 2020, 31: S1181-S1182.
[6]	HERBST R S,, GIACCONE G,, DE MARINIS F, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC[J]. N Engl J Med, 2020, 383(14): 1328-1339. doi: 10.1056/NEJMoa1917346
[7]	JASSEM J,, DE MARINIS F,, GIACCONE G, et al. Updated overall survival analysis from IMpower110: atezolizumab versus platinum-based chemotherapy in treatment-naive programmed death-ligand 1-selected NSCLC[J]. J Thorac Oncol, 2021, 16(11): 1872-1882. doi: 10.1016/j.jtho.2021.06.019
[8]	SEZER A,, KILICKAP S,, GÜMÜŞ M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial[J]. Lancet, 2021, 397(10274): 592-604. doi: 10.1016/S0140-6736(21)00228-2
[9]	RECK M,, RODRÍGUEZ-ABREU D,, ROBINSON A G, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small cell lung cancer with PD-L1 tumor proportion score ≥ 50[J]. J Clin Oncol, 2021, 39(21): 2339-2349. doi: 10.1200/JCO.21.00174
[10]	HWANG D M,, ALBAQER T,, SANTIAGO R C, et al. Prevalence and heterogeneity of PD-L1 expression by 22C3 assay in routine population-based and reflexive clinical testing in lung cancer[J]. J Thorac Oncol, 2021, 16(9): 1490-1500. doi: 10.1016/j.jtho.2021.03.028
[11]	GANDHI L,, RODRÍGUEZ-ABREU D,, GADGEEL S, et al. Pembrolizumab plus chemotherapy in metastatic non-small cell lung cancer[J]. N Engl J Med, 2018, 378(22): 2078-2092. doi: 10.1056/NEJMoa1801005
[12]	GADGEEL S,, GARASSINO M C,, ESTEBAN E, et al. KEYNOTE-189: OS update and progression after the next line of therapy (PFS2) with pembrolizumab + chemotherapy for metastatic nonsquamous NSCLC[J]. J Thorac Oncol, 2019, 14(11): S1153.
[13]	PAZ-ARES L,, LUFT A,, VICENTE D, et al. Pembrolizumab plus chemotherapy for squamous non-small cell lung cancer[J]. N Engl J Med, 2018, 379(21): 2040-2051. doi: 10.1056/NEJMoa1810865
[14]	PAZ-ARES L,, VICENTE D,, TAFRESHI A, et al. A randomized, placebo-controlled trial of pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: Protocol-specified final analysis of KEYNOTE-407[J]. J Thorac Oncol, 2020, 15(10): 1657-1669. doi: 10.1016/j.jtho.2020.06.015
[15]	ZHOU C C,, CHEN G Y,, HUANG Y C, et al. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial[J]. Lancet Respir Med, 2021, 9(3): 305-314. doi: 10.1016/S2213-2600(20)30365-9
[16]	YANG Y P,, WANG Z H,, FANG J, et al. Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (oncology program by innovent anti-PD-1-11)[J]. J Thorac Oncol, 2020, 15(10): 1636-1646. doi: 10.1016/j.jtho.2020.07.014
[17]	YANG Y P,, SUN J Y,, WANG Z H, et al. Updated overall survival data and predictive biomarkers of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC in the phase 3 ORIENT-11 study[J]. J Thorac Oncol, 2021, 16(12): 2109-2120. doi: 10.1016/j.jtho.2021.07.015
[18]	LU S,, WANG J,, YU Y, et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): a randomized phase 3 trial[J]. J Thorac Oncol, 2021, 16(9): 1512-1522. doi: 10.1016/j.jtho.2021.05.005
[19]	ZHOU C,, REN S,, CHEN J, et al. Camrelizumab or placebo plus carboplatin and paclitaxel as first-line treatment for advanced squamous NSCLC (CameL-sq): a randomized, double-blind, multicenter, phase Ⅲ trial[J]. J Thorac Oncol, 2021, 16(4): S748.
[20]	WANG J,, LU S,, HU C, et al. Updated analysis of tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment of advanced squamous non-small cell lung cancer (SQ NSCLC)[J]. Ann Oncol, 2020, 31: S817.
[21]	ZHOU C C,, WU L,, FAN Y, et al. Sintilimab plus platinum and gemcitabine as first-line treatment for advanced or metastatic squamous NSCLC: results from a randomized, double-blind, phase 3 trial (ORIENT-12)[J]. J Thorac Oncol, 2021, 16(9): 1501-1511. doi: 10.1016/j.jtho.2021.04.011
[22]	ZHOU C C,, WANG Z P,, SUN Y P, et al. Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial[J]. Lancet Oncol, 2022, 23(2): 220-233. doi: 10.1016/S1470-2045(21)00650-1
[23]	WANG J,, WANG Z,, WU L, et al. CHOICE-01: a phase 3 study of toripalimab versus placebo in combination with first-line chemotherapy for advanced NSCLC[J]. J Thorac Oncol, 2021, 16(10): S927-S928.
[24]	RECK M,, JOTTE R,, CAPPUZZO F, et al. IMpower150: analysis of efficacy in patients (pts) with liver metastases (mets)[J]. Pneumologie, 2020, 74: S39-S39
[25]	YANG J C H,, LUFT A,, DE LA MORA JIMÉNEZ E, et al. Pembrolizumab (Pembro) with or without lenvatinib (Lenva) in first-line metastatic NSCLC with PD-L1 TPS ≥1% (LEAP-007): a phase Ⅲ, randomized, double-blind study[J]. Ann Oncol, 2021, 32: S1429-S1430.
[26]	NISHIO M,, PELED N,, ZER A, et al. Phase Ⅲ LEAP-006 safety Run-in (Part 1): 1L pembrolizumab (Pembro) + chemotherapy (Chemo) with lenvatinib (Len) for metastatic NSCLC[J]. Ann Oncol, 2020, 31: S848-S849.
[27]	REN S X,, HE J X,, FANG Y, et al. Camrelizumab plus apatinib in treatment-naive patients with advanced nonsquamous NSCLC: a multicenter, open-label, single-arm, phase 2 trial[J]. JTO Clin Res Rep, 2022, 3(5): 100312.
[28]	HAN B H,, CHEN J,, XIE Q, et al. A multicenter, randomized, phase 3 trial of penpulimab in combination with anlotinib or chemotherapy as first-line treatment in advanced NSCLC[J]. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer, 2021, 16(3): S650.
[29]	CHU T Q,, ZHONG R B,, ZHONG H, et al. Phase 1b study of sintilimab plus anlotinib as first-line therapy in patients with advanced NSCLC[J]. J Thorac Oncol, 2021, 16(4): 643-652. doi: 10.1016/j.jtho.2020.11.026
[30]	ZHAO S,, REN S X,, JIANG T, et al. Low-dose apatinib optimizes tumor microenvironment and potentiates antitumor effect of PD-1/PD-L1 blockade in lung cancer[J]. Cancer Immunol Res, 2019, 7(4): 630-643. doi: 10.1158/2326-6066.CIR-17-0640
[31]	HELLMANN M D,, PAZ-ARES L,, BERNABE CARO R, et al. Nivolumab plus ipilimumab in advanced non-small cell lung cancer[J]. N Engl J Med, 2019, 381(21): 2020-2031. doi: 10.1056/NEJMoa1910231
[32]	PAZ-ARES L G,, RAMALINGAM S S,, CIULEANU T E, et al. First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial[J]. J Thorac Oncol, 2022, 17(2): 289-308. doi: 10.1016/j.jtho.2021.09.010
[33]	PAZ-ARES L,, CIULEANU T E,, COBO M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2021, 22(2): 198-211. doi: 10.1016/S1470-2045(20)30641-0
[34]	JOHN T,, SAKAI H,, IKEDA S, et al. First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) + chemotherapy (chemo) in Asian patients (pts) with advanced non-small cell lung cancer (NSCLC) from CheckMate 9LA[J]. Ann Oncol, 2020, 31: S847-S848.
[35]	JOHNSON M,, CHO B C,, LUFT A, et al. Durvalumab ± tremelimumab + chemotherapy as first-line treatment for mNSCLC: results from the phase 3 POSEIDON study[J]. J Thorac Oncol, 2021, 16(10): S844.
[36]	ABREU D R,, RECK M,, ŞENDUR N, et al. Pembrolizumab plus ipilimumab or placebo in previously untreated metastatic NSCLC with PD-L1 tumor proportion score ≥50%: KEYNOTE-598 3-year follow-up[J]. Ann Oncol, 2022, 33: S30-S31.
[37]	MARUHASHI T,, SUGIURA D,, OKAZAKI I M, et al. LAG-3: from molecular functions to clinical applications[J]. J Immunother Cancer, 2020, 8(2): e001014.
[38]	HODI F S,, TAWBI H A,, LIPSON E J, et al. Relatlimab (RELA) + nivolumab (NIVO) vs NIVO in previously untreated metastatic or unresectable melanoma: additional efficacy in RELATIVITY-047[J]. Ann Oncol, 2021, 32: S867-S868.
[39]	MORGENSZTERN D,, CHAUDHRY A,, IANNOTTI N, et al. RELATIVITY-104: First-line relatlimab (RELA) + nivolumab (NIVO) with chemotherapy vs NIVO with chemotherapy in stage Ⅳ or recurrent non-small cell lung cancer (NSCLC): a phase Ⅱ, randomized, double-blind study[J]. Ann Oncol, 2021, 32: S1030.
[40]	CHAUVIN J M,, ZAROUR H M. TIGIT in cancer immunotherapy[J]. J Immunother Cancer, 2020, 8(2): e000957.
[41]	CHO B C,, ABREU D R,, HUSSEIN M, et al. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study[J]. Lancet Oncol, 2022, 23(6): 781-792. doi: 10.1016/S1470-2045(22)00226-1
[42]	MARIN-ACEVEDO J A,, KIMBROUGH E O,, LOU Y Y. Next generation of immune checkpoint inhibitors and beyond[J]. J Hematol Oncol, 2021, 14(1): 45. doi: 10.1186/s13045-021-01056-8
[43]	PAZ-ARES L,, KIM T M,, VICENTE D, et al. Bintrafusp Alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in second-line treatment of patients with NSCLC: results from an expansion cohort of a phase 1 trial[J]. J Thorac Oncol, 2020, 15(7): 1210-1222. doi: 10.1016/j.jtho.2020.03.003
[44]	WU L,, CHEN B,, YAO W, et al. A phase Ⅰb/Ⅱ trial of AK104 (PD-1/CTLA-4 bispecific antibody) in combination with anlotinib in advanced NSCLC[J]. Ann Oncol, 2021, 32: S1006.
[45]	HONG M H,, CLUBB J D,, CHEN Y Y. Engineering CAR-T cells for next-generation cancer therapy[J]. Cancer Cell, 2020, 38(4): 473-488. doi: 10.1016/j.ccell.2020.07.005
[46]	QU J J,, MEI Q H,, CHEN L J, et al. Chimeric antigen receptor (CAR)-T-cell therapy in non-small cell lung cancer (NSCLC): current status and future perspectives[J]. Cancer Immunol Immunother, 2021, 70(3): 619-631. doi: 10.1007/s00262-020-02735-0
[47]	YILMAZ A,, CUI H W,, CALIGIURI M A, et al. Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy[J]. J Hematol Oncol, 2020, 13(1): 168. doi: 10.1186/s13045-020-00998-9
[48]	GOULDING J,, BLUM R,, HANCOCK B, et al. Abstract 1591: FT536: preclinical development of a novel off-the-shelf CAR-MICA/B NK cell immunotherapy combined with radiation and antibody treatments as a first-of-kind pan-cancer targeting strategy[J]. Cancer Res, 2021, 81(13_Supplement): 1591. doi: 10.1158/1538-7445.AM2021-1591
[49]	HEMMINKI O,, DOS SANTOS J M,, HEMMINKI A. Oncolytic viruses for cancer immunotherapy[J]. J Hematol Oncol, 2020, 13(1): 84. doi: 10.1186/s13045-020-00922-1
[50]	SAXENA M,, VAN DER BURG S H,, MELIEF C J M, et al. Therapeutic cancer vaccines[J]. Nat Rev Cancer, 2021, 21(6): 360-378. doi: 10.1038/s41568-021-00346-0

晚期非小细胞肺癌免疫治疗现状及未来方向

Current status and future directions of immunotherapy for advanced non-small cell lung cancer

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献 50

相关文章 15

编辑推荐

Metrics

本文评价

[1]	肖玉铃, 朱秀之, 江一舟, 邵志敏. 三阴性乳腺癌精准治疗研究的新进展与未来展望[J]. 中国癌症杂志, 2022, 32(8): 669-679.
[2]	周文斌, 谢晖, 丁强, 王水. 在乳腺癌局部精准治疗中的新进展：联合免疫治疗未来可期[J]. 中国癌症杂志, 2022, 32(8): 698-704.
[3]	许宇辰, 程蕾蕾, 王妍, 林瑾仪, 陈佳慧, 陈怡帆, 周宇红, 刘天舒, 葛均波. sST2在免疫检查点抑制剂相关不良反应风险预测中的价值[J]. 中国癌症杂志, 2022, 32(8): 712-718.
[4]	何丽媛, 王玉栋. ALK激酶域耐药突变的研究进展及未来应对策略[J]. 中国癌症杂志, 2022, 32(8): 736-746.
[5]	陈怡帆, 程蕾蕾, 沈毅辉, 张卉, 汪雪君, 许宇辰, 葛均波. 程序性死亡[蛋白]-1抑制剂诱导小鼠心肌炎模型的建立[J]. 中国癌症杂志, 2022, 32(7): 606-613.
[6]	洪雅萍, 黄韵坚, 黄漳州, 陈胜佳, 钟巧凤, 曾洪福, 庄武. EGFR突变的晚期非小细胞肺癌患者接受一代TKI靶向治疗的效果及预后预测因子分析[J]. 中国癌症杂志, 2022, 32(7): 624-634.
[7]	吴建辉, 储香玲, 王李强, 林心情, 谢晓鸿, 谢梦青, 赵静, 邓海怡, 杨伊霖, 邱桂焕, 周茂林, 孙霓, 李茹, 陈萤, 邓佳茜, 曾晨, 潘柏林, 秦茵茵, 刘明, 苏春霞, 周承志. 中国肺癌患者真实世界免疫检查点抑制剂相关性肺炎的流行病学分析[J]. 中国癌症杂志, 2022, 32(6): 469-477.
[8]	虞思来, 倪建佼, 朱正飞. 免疫治疗时代不可手术局部晚期非小细胞肺癌的治疗：现状与展望[J]. 中国癌症杂志, 2022, 32(6): 487-498.
[9]	江健韵, 应红梅. BRAF V600突变阳性的晚期黑色素瘤治疗的临床研究进展[J]. 中国癌症杂志, 2022, 32(5): 445-450.
[10]	宿佳琦, 徐文浩, 田熙, 艾合太木江·安外尔, 瞿元元, 施国海, 张海梁, 叶定伟. 肾透明细胞癌联合免疫治疗新策略——有氧糖酵解的研究进展及展望[J]. 中国癌症杂志, 2022, 32(4): 287-297.
[11]	傅圆圆, 侯润萍, 傅小龙. 基于胸部CT预测早期非小细胞肺癌淋巴道或血道转移风险的研究进展[J]. 中国癌症杂志, 2022, 32(4): 343-350.
[12]	陈光亮, 吴方恬, 曹军宁. 非特指EBV阳性弥漫大B细胞淋巴瘤的研究进展[J]. 中国癌症杂志, 2022, 32(3): 258-267.
[13]	朱逸晖, 李　婷, 胡夕春. Trastuzumab deruxtecan的临床研究进展及展望——HER2耐药患者的新希望[J]. 中国癌症杂志, 2021, 31(8): 754-761.
[14]	李海洲, 张艳炜, 许英杰, 杨　门, 张　磊, 韩京军 . miR-933调控KLF6基因影响非小细胞肺癌的作用研究[J]. 中国癌症杂志, 2021, 31(7): 581-588.
[15]	杨　佳, 刘舒媛, 王莹莹, 李盈甫, 马千里, 李　玙, 王永蓉, 李传印, 谭　芳 . 云南省汉族人群TNF-α基因多态性与非小细胞肺癌发生、发展的相关性[J]. 中国癌症杂志, 2021, 31(7): 616-628.