综述

免疫检查点抑制剂治疗实体瘤的标志性成果

  • 张雨峤 ,
  • 梅伟健
展开
  • 1. 兰州大学第一临床医学院 (兰州 730000 )
    2. 中山大学肿瘤防治中心结直肠科 (广州 510060 )

收稿日期: 2023-09-19

  网络出版日期: 2024-03-06

基金资助

国家自然科学基金项目(82073159)

Landmark Achievements in Treating Solid Tumors with Immune Checkpoint Inhibitors

  • Yuqiao ZHANG ,
  • Weijian MEI
Expand
  • The First Clinical Medical School,Lanzhou University,Lanzhou 730000,China.

Received date: 2023-09-19

  Online published: 2024-03-06

摘要

肿瘤转移是实体瘤患者死亡的主要原因。细胞毒性化疗药物和靶向癌基因和肿瘤重要病理生理过程的靶向药物一过性诱导肿瘤退缩,但不能显著延长患者生存时间。从2011年第一个免疫检查点抑制剂(ICIs)伊匹木单抗上市以来,上市的ICIs药物已经包括CTLA-4、PD-1、PD-L1和LAG3特异性抗体四大类,在20多种实体瘤获得适应症。ICIs作为一种免疫疗法为实体瘤治疗带来革命性进步,从三方面改变了实体瘤临床实践:(1)部分晚期患者长期生存,甚至“临床治愈”。(2)依据特定标志物而不是病理类型的非特异性治疗策略,使罕见肿瘤患者及时获得治疗机会。(3)ICIs新辅助治疗策略使部分患者免于大范围的毁损性手术,从而保全器官功能和提高患者生活质量。本文通过总结多项临床研究结果,详细分析上述三项标志性成果的循证医学证据,为ICIs药物的创新性提供详实的依据。

本文引用格式

张雨峤 , 梅伟健 . 免疫检查点抑制剂治疗实体瘤的标志性成果[J]. 实用医学杂志, 2024 , 40(2) : 272 -277 . DOI: 10.3969/j.issn.1006-5725.2024.02.025

Abstract

Tumor metastasis is a primary cause of death among solid tumor patients. Interventions such as chemotherapy with cytotoxic drugs and other targeted therapies focusing on specific genes or tumorigenesis can induce tumor shrinkage in most cases. However, these interventions do not substantially prolong the lives of patients. In recent years, immunotherapy has made significant breakthroughs in treating solid tumors with the introduction of immune checkpoint inhibitors (ICIs), following the clinical use of Ipilimumab, the first anti?tumor drug with ICIs initially approved in 2011. Currently, four types of ICIs including CTLA?4, PD?1, PD?L1, and LAG3 have been clinically applied and have demonstrated specificity towards more than 20 types of solid tumors. The significance of ICIs lies in their superiority to conventional drugs in three aspects: (1) They can prolong the survival of late?stage patients and even achieve “clinical cure”; (2)They allow patients with rare tumors access a pan?tumor treatment based on specific biomarkers; and (3)They can free a majority of patients from invasive surgical approaches to preserve organ functions, thereby improving patient’s quality of life. This article provides a summary of multiple clinical research projects and explores the clinical evidence derived from the notable achievements related to the three advantages.

参考文献

1 WANG D R , WU X L , SUN Y L .Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response[J]. Signal Transduct Target Ther, 2022,7(1):331. doi:10.1038/s41392-022-01136-2
2 BUDIMIR N , THOMAS G D , DOLINA J S , et al . Reversing T-cell Exhaustion in Cancer: Lessons Learned from PD-1/PD-L1 Immune Checkpoint Blockade[J]. Cancer Immunol Res, 2022 Feb;10(2):146-153. doi:10.1158/2326-6066.cir-21-0515
3 SHARMA P , GOSWAMI S , RAYCHAUDHURI D , et al .Immune checkpoint therapy-current perspectives and future directions[J]. Cell, 2023,186(8):1652-1669. doi:10.1016/j.cell.2023.03.006
4 KORMAN A J , GARRETT-THOMSON S C , LONBERG N . The?foundations?of?immune checkpoint?blockade?and the?ipilimumab?approval?decennial[J]. Nat Rev Drug Discov, 2022,21(7):509-528. doi:10.1038/s41573-021-00345-8
5 TANG Q , CHEN Y , LI X , et al . The role of?PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers[J].Front Immunol, 2022,13:964442. doi:10.3389/fimmu.2022.964442
6 TAWBI H A , SCHADENDORF D , LIPSON E J , et al .Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced?Melanoma[J]. N Engl J Med,2022,386(1):24-34. doi:10.1056/nejmoa2109970
7 SCHADENDORF D , HODI F S , ROBERT C , et al .Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma[J].J Clin Oncol, 2015,33(17):1889-94. doi:10.1200/jco.2014.56.2736
8 WOLCHOK J D , CHIARION-SILENI V , GONZALEZ R , et al .Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma[J].J Clin Oncol, 2022, 40(2):127-137. doi:10.1200/jco.21.02229
9 ROBERT C , CARLINO M S , MCNEIL C , et al . Seven-Year Follow-Up of the Phase III?KEYNOTE-006?Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma[J].J Clin Oncol, 2023, 41(24):3998-4003. doi:10.1200/jco.22.01599
10 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
11 DE CASTRO G J R , KUDABA I , WU Y L , et al . Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score ≥ 1% in the KEYNOTE-042 Study[J]. J Clin Oncol, 2023,41(11):1986-1991. doi:10.1200/jco.21.02885
12 BRAHMER J R , LEE J S , CIULEANU T E , et al .Five-Year?Survival?Outcomes?With?Nivolumab?Plus?Ipilimumab?Versus?Chemotherapy?as?First-Line?Treatment?for?Metastatic?Non-Small-Cell?Lung?Cancer?in?CheckMate?227[J]. J Clin Oncol, 2023,41(6):1200-1212. doi:10.1200/jco.22.01503
13 NOVELLO S , KOWALSKI D M , LUFT A , et al .Pembrolizumab?Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III?KEYNOTE-407?Study[J]. J Clin Oncol, 2023,41(11):1999-2006. doi:10.1200/jco.22.01990
14 GARASSINO M C , GADGEEL S , SPERANZA G , et al . Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3?KEYNOTE-189?Study[J]. J Clin Oncol, 2023,41(11):1992-1998. doi:10.1200/jco.22.01989
15 SPIGEL D R , FAIVRE-FINN C , GRAY J E , et al . Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer[J]. J Clin Oncol, 2022,40(12):1301-1311. doi:10.1200/jco.21.01308
16 MANSINHO A , FERNANDES R M , CARNEIRO A V .Histology-Agnostic?Drugs: A?Paradigm?Shift-A Narrative Review[J]. Adv Ther,2023,40(4):1379-1392. doi:10.1007/s12325-022-02362-4
17 MARABELLE A , FAKIH M , LOPEZ J , et al . Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study[J]. Lancet Oncol, 2020,21(10):1353-1365. doi:10.1016/s1470-2045(20)30445-9
18 MCGRAIL D J , PILIé P G , RASHID N U , et al . High?tumor?mutation?burden? fails?to?predict?immune?checkpoint?blockade?response?across?all?cancer?types[J].Ann Oncol, 2021,32(5):661-672. doi:10.1016/j.annonc.2021.02.006
19 LENZ H J , VAN CUTSEM E , LUISA LIMON M , et al . First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II?CheckMate?142?Study[J]. J Clin Oncol, 2022,40(2):161-170. doi:10.1200/jco.21.01015
20 MAIO M , ASCIERTO P A , MANZYUK L , et al .Pembrolizumab?in?microsatellite?instability?high?or?mismatch?repair?deficient?cancers:?updated?analysis?from the?phase?Ⅱ?KEYNOTE-158?study[J]. Ann Oncol, 2022,33(9):929-938. doi:10.1016/j.annonc.2022.05.519
21 GOODMAN A M , SOKOL E S , FRAMPTON G M , et al .Microsatellite-Stable?Tumors?with?High?Mutational?Burden?Benefit?from?Immunotherapy[J]. Cancer Immunol Res, 2019,7(10):1570-1573. doi:10.1158/2326-6066.cir-19-0149
22 CRISAFULLI G , SARTORE-BIANCHI A , LAZZARI L , et al . Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients[J]. Cancer Discov, 2022,12(7):1656-1675. doi:10.1158/2159-8290.cd-21-1434
33 MORANO F , RAIMONDI A , PAGANI F , et al .Temozolomide Followed by Combination With Low-Dose Ipilimumab and Nivolumab in Patients With Microsatellite-Stable, O6-Methylguanine-DNA Methyltransferase-Silenced Metastatic Colorectal Cancer: The?MAYA?Trial[J]. J Clin Oncol, 2022,40(14):1562-1573. doi:10.1200/jco.21.02583
23 TOPALIAN S L , FORDE P M , EMENS L A , et al . Neoadjuvant immune checkpoint blockade: A window of opportunity to advance cancer. immunotherapy[J]. Cancer Cell, 2023,9:S1535-6108(23)00251-9. doi:10.1016/j.ccell.2023.07.011
24 CERCEK A , LUMISH M , SINOPOLI J , et al .PD-1?Blockade?in?Mismatch?Repair-Deficient,?Locally?Advanced?Rectal?Cancer[J]. N Engl J Med, 2022,386(25):2363-2376. doi:10.1056/nejmoa2201445
25 XIAO B Y , ZHANG X , CAO T Y ,et al .Neoadjuvant Immunotherapy Leads to Major Response and Low Recurrence in Localized Mismatch Repair-Deficient Colorectal Cancer[J].J Natl Compr Canc Netw, 2023,21(1):60-66.e5. doi:10.6004/jnccn.2022.7060
26 CHAKRABARTI S , GREWAL U S , VORA K B , et al . Outcome of Patients With Early-Stage Mismatch Repair Deficient Colorectal Cancer Receiving Neoadjuvant Immunotherapy: A Systematic Review[J].JCO Precis Oncol. 2023 Aug;7:e2300182. doi:10.1200/po.23.00182
27 SCHMID P , CORTES J , PUSZTAI L , et al . Pembrolizumab? for?Early?Triple-Negative?Breast?Cancer[J].N Engl J Med. 2020 Feb 27;382(9):810-821. doi:10.1056/nejmoa1910549
28 SCHMID P , CORTES J , DENT R ,et al . Event-free Survival ith?Pembrolizumab? in?Early?Triple- Negative?Breast?Cancer[J].N Engl J Med. 2022 Feb 10;386(6):556-567. doi:10.1056/nejmoa2112651
29 CASCONE T , LEUNG C H , WEISSFERDT A , et al . Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial[J]. Nat Med. 2023 Mar;29(3):593-604.
30 FORDE P M , SPICER J , LU S ,et al . Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer[J]. N Engl J Med. 2022,386(21):1973-1985. doi:10.1056/nejmoa2202170
31 CHANG J Y , LIN S H , DONG W ,et al .Stereotactic?ablative?radiotherapy?with or without?immunotherapy?for?early-stage?or?isolated?lung?parenchymal?recurrent?node-negative?non-small-cell?lung?cancer: an?open-label,?randomised,?phase?2?trial[J]. Lancet, 2023,402(10405):871-881. doi:10.1016/s0140-6736(23)01384-3
32 李思玲,商凯,黄鸿翔,等 . 放疗联合免疫治疗在非小细胞肺癌中的研究进展[J]. 实用医学杂志, 2022,38(23):3017-3022. doi:10.3969/j.issn.1006-5725.2022.23.023
34 HEGDE P S , CHEN D S .Top 10 Challenges in Cancer Immunotherapy[J]. Immunity, 2020,52(1):17-35. doi:10.1016/j.immuni.2019.12.011
文章导航

/