程序性死亡受体1及其配体抑制剂在肺癌治疗中的研究进展
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摘要
手术、放化疗及靶向治疗已经显著提高肺癌患者的生存期,但总体疗效并不理想。随着对免疫检查点抑制剂包括程序性死亡受体1(PD-1)及其配体(PD-L1)的不断深入研究,PD-1/PD-L1抑制剂在肺癌治疗中正在书写新的篇章。然而,目前肺癌治疗中PD-1抑制剂的临床研究结果及免疫相关的不良反应等尚缺乏强有力的数据,已有的临床研究数据正在不断更新。本文综述PD-1抑制剂的作用特点、治疗肺癌的相关研究进展及不良反应。
Although the combination therapy with surgery,chemo radiotherapy and targeted therapy can significantly improve the survival of lung cancer patients,but the overall efficacy is still not satisfactory.Recently,the continuous study of immunological checkpoint inhibitors,including the programmed death receptor 1(PD-1) and its ligand(PD-L1) inhibitors are reaching a new milestone in lung cancer treatment.However,the clinical efficacy of several new PD-1 inhibitor drugs and their immune-related adverse reactions in lung cancer treatment are constantly being updated.This review describes the research progress of PD-1 inhibitors including their function characteristics,the lung cancer treatment and related adverse reactions.
Although the combination therapy with surgery,chemo radiotherapy and targeted therapy can significantly improve the survival of lung cancer patients,but the overall efficacy is still not satisfactory.Recently,the continuous study of immunological checkpoint inhibitors,including the programmed death receptor 1(PD-1) and its ligand(PD-L1) inhibitors are reaching a new milestone in lung cancer treatment.However,the clinical efficacy of several new PD-1 inhibitor drugs and their immune-related adverse reactions in lung cancer treatment are constantly being updated.This review describes the research progress of PD-1 inhibitors including their function characteristics,the lung cancer treatment and related adverse reactions.
引文
[1]Burki TK.Resistance to PD-1 blockade in melanoma[J].Lancet Oncol,2016,17(9):e376-e376.
[2]Harshman LC,Choueiri TK,Drake C,et al,Subverting the B7-H1/PD-1 pathway in advanced melanoma and kidney cancer[J].Cancer J,2014,20(4):272-280.
[3]Brayer J,Fishman M.Regression of metastatic clear cell kidney cancer with interleukin-2 treatment following nivolumab(anti-PD-1)treatment[J].J Immunother,2014,37(3):187-191.
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[14]Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy[J].Nat Rev Cancer,2012,12(4):252-264.
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[16]Mok T,Wu YL,Sadowski S,et al.Pembrolizumab(MK-3475)versus platinum-based chemotherapy for PD-L1+non-small cell lung cancer(NSCLC):randomized,open-label,phase 3KEYNOTE-042 study[J].J Thorac Oncol,2016,11(10S):S244-S245.
[17]Shen X,Zhao B.Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer:meta-analysis[J].Br Med J,2018,362:k3529-k3529.
[18]Paz-Ares L,Luft A,Vicente D,et al.Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer[J].NEngl J Med,2018,379(11):2040-2051.
[19]Antonia SJ,Villegas A,Daniel D,et al.Overall survival with durvalumab after chemoradiotherapy in stageⅢNSCLC[J].N Engl J Med,2018,doi:10.1056/NEJMoa1809697.
[20]Horn L,Mansfield AS,Szczesna A,et al.First-line atezolizumab plus chemotherapy in extensive-stage smallcell lung cancer[J].N Engl J Med,2018,doi:10.1056/NEJMoa1809064.
[21]Horn L,Gettinger SN,Gordon,et al.Safety and clinical activity of atezolizumab monotherapy in metastatic non-smallcell lung cancer:final results from a phaseⅠstudy[J].Eur JCancer,2018,101:201-209.
[22]Hui R,Garon EB,Goldman JW,et al.Pembrolizumab as firstline therapy for patients with PD-L1-positive advanced nonsmall cell lung cancer:a phase 1 trial[J].Ann Oncol,2017,28(4):874-881.
[23]Langer CJ,Gadgeel SM,Borghaei H,et al.Carboplatin and pemetrexed with or without pembrolizumab for advanced,nonsquamous non-small-cell lung cancer:a randomised,phase2 cohort of the open-label KEYNOTE-021 study[J].Lancet Oncol,2016,17(11):1497-1508.
[24]Borghaei H,Brahmer J,Horn L,et al.P2.35:nivolumab vs docetaxel in advanced NSCLC:CheckMate 017/0572-Y update and exploratory cytokine profile analysis:track:immunotherapy[J].J Thorac Oncol,2016,11(10S):S237-S238.
[25]Vokes EE,Ready N,Felip E,et al.Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer(CheckMate 017 and CheckMate 057):3-year update and outcomes in patients with liver metastases[J].Ann Oncol,2018,29(4):959-965.
[26]Killock D.Lung cancer:frontline nivolumab-CheckMate026 ends in stalemate[J].Nat Rev Clin Oncol,2017,14(8):458-459.
[27]Horinouchi H.KEYNOTE-010:flash of a supernova(immune-checkpoint inhibitors)in second-line non-small cell lung cancer[J].J Thorac Dis,2017,9(11):4187-4190.
[28]Brahmer JR,Rodriguez-Abreu D,Robinson AG,et al.Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced,PD-L1-positive NSCLC(KEYNOTE-024):a multicentre,international,randomised,open-label phase 3 trial[J].Lancet Oncol,2017,18(12):1600-1609.
[29]Rusch VW,Chaft J,Hellmann M.KEYNOTE-024:unlocking a pathway to lung cancer cure?[J].J Thorac Cardiovasc Surg,2018,155(4):1777-1780.
[30]De Lima Lopes G,Wu YL,Sadowski S,et al.P2.43:pembrolizumab vs platinum-based chemotherapy for PD-L1+NSCLC:phase 3,randomized,open-label KEYNOTE-042(NCT02220894):track:immunotherapy[J].J Thorac Oncol,2016,11(10):S244-S245.
[31]Ferrara R,Mezquita L,Texier M,et al.Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy[J].J Am Med Assoc Oncol,2018,4(11):1543-1552.
[32]Tachihara M,Negoro S,Inoue T,et al.Efficacy of anti-PD-1/PD-L1 antibodies after discontinuation due to adverse events in non-small cell lung cancer patients(HANSHIN 0316)[J].Bio Med Cent Cancer,2018,18(1):946-946.
[33]Andruska N,Mahapatra L,Hebbard C,et al.Severe pneumonitis refractory to steroids following anti-PD-1immunotherapy[J].Br Med J Case Rep,2018,doi:10.11 36/bcr-2018-225937.
[34]Wang DY,Salem JE,Cohen JV,et al.Fatal toxic effects associated with immune checkpoint inhibitors:a systematic review and meta-analysis[J].J Am Med Assoc Oncol,2018,doi:10.1001/jamaoncol.2018.3923.
[35]You W,Liu M,Miao JD,et al.A network meta-analysis comparing the efficacy and safety of anti-PD-1 with antiPD-L1 in non-small cell lung cancer[J].J Cancer,2018,9(7):1200-1206.
[2]Harshman LC,Choueiri TK,Drake C,et al,Subverting the B7-H1/PD-1 pathway in advanced melanoma and kidney cancer[J].Cancer J,2014,20(4):272-280.
[3]Brayer J,Fishman M.Regression of metastatic clear cell kidney cancer with interleukin-2 treatment following nivolumab(anti-PD-1)treatment[J].J Immunother,2014,37(3):187-191.
[4]Harvey RD.Immunologic and clinical effects of targeting PD-1 in lung cancer[J].Clin Pharmacol Ther,2014,96(2):214-223.
[5]Ansell SM,Lesokhin AM,Borrello I,et al.PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma[J].N Engl J Med,2015,372(4):311-319.
[6]Kroemer G,Galluzzi L.Immunotherapy of hematological cancers:PD-1 blockade for the treatment of Hodgkin's l ymp h oma[J].O n c o immu n o l o g y,2 0 1 5,4(6):e1008853-e1008853.
[7]Sonpavde G.PD-1 and PD-L1 inhibitors as salvage therapy for urothelial carcinoma[J].N Engl J Med,2017,376(11):1073-1074.
[8]Thoma C.Urothelial carcinoma:targeting PD-1 in advanced disease[J].Nat Rev Urol,2017,14(3):133-133.
[9]Zandberg DP,Strome SE.The role of the PD-L1:PD-1pathway in squamous cell carcinoma of the head and neck[J].Oral Oncol,2014,50(7):627-632.
[10]Ghiotto M,Gauthier L,Serriari N,et al.PD-L1 and PD-L2differ in their molecular mechanisms of interaction with PD-1[J].Int Immunol,2010,22(8):651-660.
[11]Sanmamed MF,Chen L.A Paradigm shift in cancer immunotherapy:from enhancement to normalization[J].Cell,2018,175(2):313-326.
[12]Lee JY,Na II,Jang SH,et al.Differences in clinical presentation of non-small cell lung cancer in never-smokers versus smokers[J].J Thorac Dis,2013,5(6):758-763.
[13]Norum J,Nieder C.Tobacco smoking and cessation and PD-L1inhibitors in non-small cell lung cancer(NSCLC):a review of the literature[J].ESMO Open,2018,3(6):e000406-e000406.
[14]Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy[J].Nat Rev Cancer,2012,12(4):252-264.
[15]Gettinger S,Hellmann MD,Chow LQM,et al.Nivolumab plus erlotinib in patients with EGFR-mutant advanced NSCLC[J].J Thorac Oncol,2018,13(9):1245-1247.
[16]Mok T,Wu YL,Sadowski S,et al.Pembrolizumab(MK-3475)versus platinum-based chemotherapy for PD-L1+non-small cell lung cancer(NSCLC):randomized,open-label,phase 3KEYNOTE-042 study[J].J Thorac Oncol,2016,11(10S):S244-S245.
[17]Shen X,Zhao B.Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer:meta-analysis[J].Br Med J,2018,362:k3529-k3529.
[18]Paz-Ares L,Luft A,Vicente D,et al.Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer[J].NEngl J Med,2018,379(11):2040-2051.
[19]Antonia SJ,Villegas A,Daniel D,et al.Overall survival with durvalumab after chemoradiotherapy in stageⅢNSCLC[J].N Engl J Med,2018,doi:10.1056/NEJMoa1809697.
[20]Horn L,Mansfield AS,Szczesna A,et al.First-line atezolizumab plus chemotherapy in extensive-stage smallcell lung cancer[J].N Engl J Med,2018,doi:10.1056/NEJMoa1809064.
[21]Horn L,Gettinger SN,Gordon,et al.Safety and clinical activity of atezolizumab monotherapy in metastatic non-smallcell lung cancer:final results from a phaseⅠstudy[J].Eur JCancer,2018,101:201-209.
[22]Hui R,Garon EB,Goldman JW,et al.Pembrolizumab as firstline therapy for patients with PD-L1-positive advanced nonsmall cell lung cancer:a phase 1 trial[J].Ann Oncol,2017,28(4):874-881.
[23]Langer CJ,Gadgeel SM,Borghaei H,et al.Carboplatin and pemetrexed with or without pembrolizumab for advanced,nonsquamous non-small-cell lung cancer:a randomised,phase2 cohort of the open-label KEYNOTE-021 study[J].Lancet Oncol,2016,17(11):1497-1508.
[24]Borghaei H,Brahmer J,Horn L,et al.P2.35:nivolumab vs docetaxel in advanced NSCLC:CheckMate 017/0572-Y update and exploratory cytokine profile analysis:track:immunotherapy[J].J Thorac Oncol,2016,11(10S):S237-S238.
[25]Vokes EE,Ready N,Felip E,et al.Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer(CheckMate 017 and CheckMate 057):3-year update and outcomes in patients with liver metastases[J].Ann Oncol,2018,29(4):959-965.
[26]Killock D.Lung cancer:frontline nivolumab-CheckMate026 ends in stalemate[J].Nat Rev Clin Oncol,2017,14(8):458-459.
[27]Horinouchi H.KEYNOTE-010:flash of a supernova(immune-checkpoint inhibitors)in second-line non-small cell lung cancer[J].J Thorac Dis,2017,9(11):4187-4190.
[28]Brahmer JR,Rodriguez-Abreu D,Robinson AG,et al.Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced,PD-L1-positive NSCLC(KEYNOTE-024):a multicentre,international,randomised,open-label phase 3 trial[J].Lancet Oncol,2017,18(12):1600-1609.
[29]Rusch VW,Chaft J,Hellmann M.KEYNOTE-024:unlocking a pathway to lung cancer cure?[J].J Thorac Cardiovasc Surg,2018,155(4):1777-1780.
[30]De Lima Lopes G,Wu YL,Sadowski S,et al.P2.43:pembrolizumab vs platinum-based chemotherapy for PD-L1+NSCLC:phase 3,randomized,open-label KEYNOTE-042(NCT02220894):track:immunotherapy[J].J Thorac Oncol,2016,11(10):S244-S245.
[31]Ferrara R,Mezquita L,Texier M,et al.Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy[J].J Am Med Assoc Oncol,2018,4(11):1543-1552.
[32]Tachihara M,Negoro S,Inoue T,et al.Efficacy of anti-PD-1/PD-L1 antibodies after discontinuation due to adverse events in non-small cell lung cancer patients(HANSHIN 0316)[J].Bio Med Cent Cancer,2018,18(1):946-946.
[33]Andruska N,Mahapatra L,Hebbard C,et al.Severe pneumonitis refractory to steroids following anti-PD-1immunotherapy[J].Br Med J Case Rep,2018,doi:10.11 36/bcr-2018-225937.
[34]Wang DY,Salem JE,Cohen JV,et al.Fatal toxic effects associated with immune checkpoint inhibitors:a systematic review and meta-analysis[J].J Am Med Assoc Oncol,2018,doi:10.1001/jamaoncol.2018.3923.
[35]You W,Liu M,Miao JD,et al.A network meta-analysis comparing the efficacy and safety of anti-PD-1 with antiPD-L1 in non-small cell lung cancer[J].J Cancer,2018,9(7):1200-1206.