联合免疫治疗在晚期NSCLC中的疗效现状与前景
摘要
免疫检查点抑制剂在晚期非小细胞肺癌的治疗应用中获得显著治疗效果,延长患者的总体生存时间,为无驱动基因突变的患者提供新的治疗选择。然而,现有数据表明,仅有少数患者能从免疫治疗中获益,其可能的原因是,不同患者具有不同类型的免疫微环境。联合免疫治疗以免疫治疗为基础,通过免疫联合放化疗和靶向治疗等方式,对免疫反应中多个过程进行干预和调控,实现促进抗肿瘤免疫反应并降低耐药风险的目的。目前,免疫治疗联合化疗已经被推荐写入美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)指南,大量临床研究仍在对联合治疗的有效性及安全性进行评估。本文对近年来联合免疫治疗的研究现况及未来发展前景进行回顾与阐述。
引文
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[3] 毕良文,张丽珍,赵滑峰,等.转移性Ⅳ期非小细胞肺癌患者的生存状况及预后分析[J].实用肿瘤杂志,2018,33(5):421-425.
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[7] Shevchenko I,Karakhanova S,Soltek S,et al.Low-dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer[J].Int J Cancer,2013,133(1):98-107.
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[11] Kanwal B,Biswas S,Seminara RS,et al.Immunotherapy in advanced non-small cell lung cancer patients:ushering chemotherapy through the checkpoint inhibitors?[J].Cureus,2018,10(9):e3254.
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[13] Carbone DP,Reck M,Paz-Ares L,et al.First-line nivolumab in stage Ⅳ or recurrent non-small-cell lung cancer[J].N Engl J Med,2017,376(25):2415-2426.
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[15] Langer CJ,Gadgeel SM,Borghaei H,et al.Carboplatin and pemetrexed with or without pembrolizumab for advanced,non-squamous non-small-cell lung cancer:a randomised,phase 2 cohort of the open-label KEYNOTE-021 study[J].Lancet Oncol,2016,17(11):1497-1508.
[16] Gandhi L,Rodriguez-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.
[17] 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.
[18] Socinski MA,Jotte RM,Cappuzzo F,et al.Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC[J].N Engl J Med,2018,378(24):2288-2301.
[19] Jotte RM,Cappuzzo F,Vynnychenko I,et al.IMpower131:Primary PFS and safety analysis of a randomized phase Ⅲ study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC[J].J Clin Oncol,2018,36(Suppl 18):LBA9000.
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[21] Teng F,Kong L,Meng X,et al.Radiotherapy combined with immune checkpoint blockade immunotherapy:Achievements and challenges[J].Cancer Lett,2015,365(1):23-29.
[22] Demaria S,Golden EB,Formenti SC.Role of local radiation therapy in cancer immunotherapy[J].JAMA Oncol,2015,1(9):1325-1332.
[23] Deng L,Liang H,Burnette B,et al.Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice[J].J Clin Invest,2014,124(2):687-695.
[24] Formenti SC,Demaria S.Combining radiotherapy and cancer immunotherapy:a paradigm shift[J].J Natl Cancer Inst,2013,105(4):256-265.
[25] Postow MA,Callahan MK,Barker C A,et al.Immunologic correlates of the abscopal effect in a patient with melanoma[J].N Engl J Med,2012,366(10):925-931.
[26] Dudnik E,Yust-Katz S,Nechushtan H,et al.Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases[J].Lung Cancer,2016,98:114-117.
[27] Yuan Z,Fromm A,Ahmed KA,et al.Radiotherapy rescue of a nivolumab-refractory immune response in a patient with PD-L1-negative metastatic squamous cell carcinoma of the lung[J].J Thorac Oncol,2017,12(9):e135-136.
[28] Takamori S,Toyokawa G,Takada K,et al.Combination therapy of radiotherapy and anti-PD-1/PD-L1 treatment in non-small-cell lung cancer:a mini-review[J].Clin Lung Cancer,2018,19(1):12-16.
[29] Tang C,Welsh JW,De Groot P,et al.Ipilimumab with stereotactic ablative radiation therapy:phase Ⅰ results and immunologic correlates from peripheral T cells[J].Clin Cancer Res,2017,23(6):1388-1396.
[30] Shaverdian N,Lisberg AE,Bornazyan K,et al.Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer:a secondary analysis of the KEYNOTE-001 phase 1 trial[J].Lancet Oncol,2017,18(7):895-903.
[31] Tsao AS,Scagliotti GV,Bunn PA,et al.Scientific advances in lung cancer 2015[J].J Thorac Oncol,2016,11(5):613-638.
[32] Akbay EA,Koyama S,Carretero J,et al.Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors[J].Cancer Discov,2013,3(12):1355-1363.
[33] Rizvi NA,Chow LQ,Borghaei H.Safety and response with nivolumab (anti-PD-1;BMS-936558,ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC[J].ASCO Meeting Abstracts,2014,32(Suppl 15):8022.
[34] Gibbons DL,Chow LQ,Kim DW,et al.57O Efficacy,safety and tolerability of MEDI4736 (durvalumab[D]),a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody,combined with gefitinib (G):A phase Ⅰ expansion in TKI-na?ve patients (pts) with EGFR mutant NSCLC[J].J Thorac Oncol,2016,11(Suppl 4):S79.
[35] Ahn MJ,Yang J,Yu H,et al.136O Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer:Results from the TATTON phase Ⅰb trial[J].J Thorac Oncol,2016,11(Suppl 4):S115.
[36] Hellmann MD,Rizvi NA,Goldman JW,et al.Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012):results of an open-label,phase 1,multicohort study[J].Lancet Oncol,2017,18(1):31-41.
[37] Gubens MA,Sequist LV,Stevenson J,et al.Phase Ⅰ/Ⅱ study of pembrolizumab (pembro) plus ipilimumab (ipi) as second-line therapy for NSCLC:KEYNOTE-021 cohorts D and H[J].ASCO Meeting Abstracts,2016,34(Suppl 15):9027.
[38] Antonia S,Goldberg SB,Balmanoukian A,et al.Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer:a multicentre,phase 1b study[J].Lancet Oncol,2016,17(3):299-308.
[39] Kleponis J,Skelton R,Zheng L.Fueling the engine and releasing the break:combinational therapy of cancer vaccines and immune checkpoint inhibitors[J].Cancer Biol Med,2015,12(3):201-208.
[40] Remy-Ziller C,Thioudellet C,Hortelano J,et al.Sequential administration of MVA-based vaccines and PD-1/PD-L1-blocking antibodies confers measurable benefits on tumor growth and survival:Preclinical studies with MVA-betaGal and MVA-MUC1 (TG4010) in a murine tumor model[J].Hum Vaccin Immunother,2018,14(1):140-145.
[41] Chen J,Chen Y,Feng F,et al.Programmed cell death protein-1/programmed death-ligand 1 blockade enhances the antitumor efficacy of adoptive cell therapy against non-small cell lung cancer[J].J Thorac Dis,2018,10(12):6711-6721.
[42] Ruella M,Barrett DM,Kenderian SS,et al.Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies[J].J Clin Invest,2016,126(10):3814-3826.
[43] Zeltsman M,Dozier J,Mcgee E,et al.CAR T-cell therapy for lung cancer and malignant pleural mesothelioma[J].Transl Res,2017,187:1-10.
[2] Goldstraw P,Crowley J,Chansky K,et al.The IASLC Lung Cancer Staging Project:proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours[J].J Thorac Oncol,2007,2(8):706-714.
[3] 毕良文,张丽珍,赵滑峰,等.转移性Ⅳ期非小细胞肺癌患者的生存状况及预后分析[J].实用肿瘤杂志,2018,33(5):421-425.
[4] Lynch TJ,Bondarenko I,Luft A,et al.Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage ⅢB/Ⅳ non-small-cell lung cancer:results from a randomized,double-blind,multicenter phase Ⅱ study[J].J Clin Oncol,2012,30(17):2046-2054.
[5] Morgensztern D,Herbst RS.Nivolumab and pembrolizumab for non-small cell lung cancer[J].Clin Cancer Res,2016,22(15):3713-3717.
[6] Hannani D,Sistigu A,Kepp O,et al.Prerequisites for the antitumor vaccine-like effect of chemotherapy and radiotherapy[J].Cancer J,2011,17(5):351-358.
[7] Shevchenko I,Karakhanova S,Soltek S,et al.Low-dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer[J].Int J Cancer,2013,133(1):98-107.
[8] Suzuki E,Kapoor V,Jassar AS,et al.Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity[J].Clin Cancer Res,2005,11(18):6713-6721.
[9] Ma Y,Adjemian S,Mattarollo SR,et al.Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells[J].Immunity,2013,38(4):729-741.
[10] GalluzzI L,Buque A,Kepp O,et al.Immunological effects of conventional chemotherapy and targeted anticancer agents[J].Cancer Cell,2015,28(6):690-714.
[11] Kanwal B,Biswas S,Seminara RS,et al.Immunotherapy in advanced non-small cell lung cancer patients:ushering chemotherapy through the checkpoint inhibitors?[J].Cureus,2018,10(9):e3254.
[12] Rizvi NA,Hellmann MD,Brahmer JR,et al.Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer[J].J Clin Oncol,2016,34(25):2969-2979.
[13] Carbone DP,Reck M,Paz-Ares L,et al.First-line nivolumab in stage Ⅳ or recurrent non-small-cell lung cancer[J].N Engl J Med,2017,376(25):2415-2426.
[14] Borghaei H,Hellmann MD,Paz-Ares LG,et al.Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with < 1% tumor PD-L1 expression:results from CheckMate 227[J].J Clin Oncol,2018,36(Suppl 18):9001.
[15] Langer CJ,Gadgeel SM,Borghaei H,et al.Carboplatin and pemetrexed with or without pembrolizumab for advanced,non-squamous non-small-cell lung cancer:a randomised,phase 2 cohort of the open-label KEYNOTE-021 study[J].Lancet Oncol,2016,17(11):1497-1508.
[16] Gandhi L,Rodriguez-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.
[17] 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.
[18] Socinski MA,Jotte RM,Cappuzzo F,et al.Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC[J].N Engl J Med,2018,378(24):2288-2301.
[19] Jotte RM,Cappuzzo F,Vynnychenko I,et al.IMpower131:Primary PFS and safety analysis of a randomized phase Ⅲ study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC[J].J Clin Oncol,2018,36(Suppl 18):LBA9000.
[20] National Comprehensive Cancer Network.NCCN clinical practice guidelines in oncology-non-small cell lung cancer (version 3.2019)[EB/OL].(2019-01-18)[2019-03-08].https://www.nccn.org/professionals/physician_gls/default.aspx
[21] Teng F,Kong L,Meng X,et al.Radiotherapy combined with immune checkpoint blockade immunotherapy:Achievements and challenges[J].Cancer Lett,2015,365(1):23-29.
[22] Demaria S,Golden EB,Formenti SC.Role of local radiation therapy in cancer immunotherapy[J].JAMA Oncol,2015,1(9):1325-1332.
[23] Deng L,Liang H,Burnette B,et al.Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice[J].J Clin Invest,2014,124(2):687-695.
[24] Formenti SC,Demaria S.Combining radiotherapy and cancer immunotherapy:a paradigm shift[J].J Natl Cancer Inst,2013,105(4):256-265.
[25] Postow MA,Callahan MK,Barker C A,et al.Immunologic correlates of the abscopal effect in a patient with melanoma[J].N Engl J Med,2012,366(10):925-931.
[26] Dudnik E,Yust-Katz S,Nechushtan H,et al.Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases[J].Lung Cancer,2016,98:114-117.
[27] Yuan Z,Fromm A,Ahmed KA,et al.Radiotherapy rescue of a nivolumab-refractory immune response in a patient with PD-L1-negative metastatic squamous cell carcinoma of the lung[J].J Thorac Oncol,2017,12(9):e135-136.
[28] Takamori S,Toyokawa G,Takada K,et al.Combination therapy of radiotherapy and anti-PD-1/PD-L1 treatment in non-small-cell lung cancer:a mini-review[J].Clin Lung Cancer,2018,19(1):12-16.
[29] Tang C,Welsh JW,De Groot P,et al.Ipilimumab with stereotactic ablative radiation therapy:phase Ⅰ results and immunologic correlates from peripheral T cells[J].Clin Cancer Res,2017,23(6):1388-1396.
[30] Shaverdian N,Lisberg AE,Bornazyan K,et al.Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer:a secondary analysis of the KEYNOTE-001 phase 1 trial[J].Lancet Oncol,2017,18(7):895-903.
[31] Tsao AS,Scagliotti GV,Bunn PA,et al.Scientific advances in lung cancer 2015[J].J Thorac Oncol,2016,11(5):613-638.
[32] Akbay EA,Koyama S,Carretero J,et al.Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors[J].Cancer Discov,2013,3(12):1355-1363.
[33] Rizvi NA,Chow LQ,Borghaei H.Safety and response with nivolumab (anti-PD-1;BMS-936558,ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC[J].ASCO Meeting Abstracts,2014,32(Suppl 15):8022.
[34] Gibbons DL,Chow LQ,Kim DW,et al.57O Efficacy,safety and tolerability of MEDI4736 (durvalumab[D]),a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody,combined with gefitinib (G):A phase Ⅰ expansion in TKI-na?ve patients (pts) with EGFR mutant NSCLC[J].J Thorac Oncol,2016,11(Suppl 4):S79.
[35] Ahn MJ,Yang J,Yu H,et al.136O Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer:Results from the TATTON phase Ⅰb trial[J].J Thorac Oncol,2016,11(Suppl 4):S115.
[36] Hellmann MD,Rizvi NA,Goldman JW,et al.Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012):results of an open-label,phase 1,multicohort study[J].Lancet Oncol,2017,18(1):31-41.
[37] Gubens MA,Sequist LV,Stevenson J,et al.Phase Ⅰ/Ⅱ study of pembrolizumab (pembro) plus ipilimumab (ipi) as second-line therapy for NSCLC:KEYNOTE-021 cohorts D and H[J].ASCO Meeting Abstracts,2016,34(Suppl 15):9027.
[38] Antonia S,Goldberg SB,Balmanoukian A,et al.Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer:a multicentre,phase 1b study[J].Lancet Oncol,2016,17(3):299-308.
[39] Kleponis J,Skelton R,Zheng L.Fueling the engine and releasing the break:combinational therapy of cancer vaccines and immune checkpoint inhibitors[J].Cancer Biol Med,2015,12(3):201-208.
[40] Remy-Ziller C,Thioudellet C,Hortelano J,et al.Sequential administration of MVA-based vaccines and PD-1/PD-L1-blocking antibodies confers measurable benefits on tumor growth and survival:Preclinical studies with MVA-betaGal and MVA-MUC1 (TG4010) in a murine tumor model[J].Hum Vaccin Immunother,2018,14(1):140-145.
[41] Chen J,Chen Y,Feng F,et al.Programmed cell death protein-1/programmed death-ligand 1 blockade enhances the antitumor efficacy of adoptive cell therapy against non-small cell lung cancer[J].J Thorac Dis,2018,10(12):6711-6721.
[42] Ruella M,Barrett DM,Kenderian SS,et al.Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies[J].J Clin Invest,2016,126(10):3814-3826.
[43] Zeltsman M,Dozier J,Mcgee E,et al.CAR T-cell therapy for lung cancer and malignant pleural mesothelioma[J].Transl Res,2017,187:1-10.