免疫检查点抑制剂生物标志物在非小细胞肺癌中的研究进展
|
摘要
免疫检查点抑制剂(ICI)已成功用于晚期非小细胞肺癌(NSCLC)患者的治疗,但是大多数未经选择的NSCLC患者对ICI没有反应性。与靶向治疗不同,目前尚缺乏一个完美的生物标志物用以指导免疫治疗。免疫组化(IHC)检测程序性细胞死亡蛋白配体(PD-L1)表达是目前临床上最常用的反应性预测标志物,肿瘤突变负荷(TMB)则是另一种逐渐兴起的生物标志物。本文主要综述PD-L1、TMB以及其他一些候选标志物,如微卫星不稳定性、错配修复缺陷、肿瘤浸润淋巴细胞以及干扰素γ等,以期为今后的临床应用提供参考。
Immune checkpoint inhibitors(ICI) have been successfully used in the patients with advanced nonsmall cell lung cancer(NSCLC).However,most unselected NSCLC patients fail to respond to ICI due to lack of perfect biomarkers for guiding the immunotherapy.Currently,PD-L1 expression detecting by immune histochemistry(IHC) is the most common used predictive marker for ICI,and the tumor mutation burden(TMB) is an emerging biomarker.This review describes the biomarker PD-L1 and TMB and other potential biomarkers,such as microsatellite instability,mismatch repair,tumor infiltrating lymphocyte and interferon-γ to provide a reference for further clinical application.
Immune checkpoint inhibitors(ICI) have been successfully used in the patients with advanced nonsmall cell lung cancer(NSCLC).However,most unselected NSCLC patients fail to respond to ICI due to lack of perfect biomarkers for guiding the immunotherapy.Currently,PD-L1 expression detecting by immune histochemistry(IHC) is the most common used predictive marker for ICI,and the tumor mutation burden(TMB) is an emerging biomarker.This review describes the biomarker PD-L1 and TMB and other potential biomarkers,such as microsatellite instability,mismatch repair,tumor infiltrating lymphocyte and interferon-γ to provide a reference for further clinical application.
引文
[1]赵沙,蒋涛,周彩存.抗PD-1/PD-L1免疫治疗疗效预测标志物在非小细胞肺癌中的研究进展[J].肿瘤,2016,36(7):823-828.
[2]Cyriac G,Gandhi L.Emerging biomarkers for immune checkpoint inhibition in lung cancer[J].Semin Cancer Biol,2018,52(Pt 2):269-277.
[3]Brahmer J,Reckamp KL,Baas P,et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer[J].N Engl J Med,2015,373(2):123-135.
[4]Borghaei H,Paz-Ares L,Horn L,et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J].N Engl J Med,2015,373(17):1627-1639.
[5]Carbone DP,Reck M,Paz-Ares L,et al.First-line nivolumab in stageⅣor recurrent non-small-cell lung cancer[J].N Engl J Med,2017,376(25):2415-2426.
[6]Garon EB,Rizvi NA,Hui R,et al.Pembrolizumab for the treatment of non-small-cell lung cancer[J].N Engl J Med,2015,372(21):2018-2028.
[7]Pai-Scherf L,Blumenthal GM,Li H,et al.FDA approval summary:pembrolizumab for treatment of metastatic non-small cell lung cancer:first-line therapy and beyond[J].Oncologist,2017,22(11):1392-1399.
[8]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(Supple 10):S244-S245.
[9]Weinstock C,Khozin S,Suzman D,et al.U.S.food and drug administration approval summary:atezolizumab for metastatic non-small cell lung cancer[J].Clin Cancer Res,2017,23(16):4534-4539.
[10]Fehrenbacher L,Spira A,Ballinger M,et al.Atezolizumab versus docetaxel for patients with previously treated non-smallcell lung cancer(POPLAR):a multicentre,open-label,phase2 randomised controlled trial[J].Lancet,2016,387(10030):1837-1846.
[11]Rittmeyer A,Barlesi F,Waterkamp D,et al.Atezolizumab versus docetaxel in patients with previously treated non-smallcell lung cancer(OAK):a phase 3,open-label,multicentre randomised controlled trial[J].Lancet,2017,389(10066):255-265.
[12]Antonia SJ,Villegas A,Daniel D,et al.Durvalumab after chemoradiotherapy in stageⅢnon-small-cell lung cancer[J].N Engl J Med,2017,377(20):1919-1929.
[13]Zhang P,Ma Y,Lv C,et al.Upregulation of programmed cell death ligand 1 promotes resistance response in nonsmallcell lung cancer patients treated with neo-adjuvant chemotherapy[J].Cancer Sci,2016,107(11):1563-1571.
[14]Herbst RS,Baas P,Kim DW,et al.Pembrolizumab versus docetaxel for previously treated,PD-L1-positive,advanced non-small-cell lung cancer(KEYNOTE-010):a randomised controlled trial[J].Lancet,2016,387(10027):1540-1550.
[15]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.
[16]Socinski MA,Jotte RM,Cappuzzo F,et al.Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC[J].NEngl J Med,2018,378(24):2288-2301.
[17]Snyder A,Makarov V,Merghoub T,et al.Genetic basis for clinical response to CTLA-4 blockade in melanoma[J].NEngl J Med,2014,371(23):2189-2199.
[18]Rizvi NA,Hellmann MD,Snyder A,et al.Cancer immunology.Mutational landscape determines sensitivity to PD-1blockade in non-small cell lung cancer[J].Science,2015,348(6230):124-128.
[19]Kowanetz M,Zou W,Shames D,et al.Tumor mutation burden(TMB)is associated with improved efficacy of atezolizumab in 1L and 2L+NSCLC patients[J].J Thorac Oncol,2017,12(1):S321-S322.
[20]Peters S,Creelan B,Hellmann MD,et al.Abstract CT082:impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer:an exploratory analysis of CheckMate 026[J].Cancer Res,2017,doi:10.11 58/1538-7445.
[21]Gandara DR,Paul SM,Kowanetz M,et al.Blood-based tumor mutational burden as a predictor of clinical benefit in nonsmallcell lung cancer patients treated with atezolizumab[J].Nat Med,2018,24(9):1441-1448.
[22]Mok TSK,Gadgeel S,Kim ES,et al.Blood first line ready screening trial(B-F1RST)and blood first assay screening trial(BFAST)enable clinical development of novel blood based biomarker assays for tumor mutational burden(TMB)and somatic mutations in 1L advanced or metastatic NSCLC[J].Ann Oncol,2017,28(Suppl 5):v494-v495.
[23]Rashdan S,Minna JD,Gerber DE.Lung cancer immunotherapy biomarkers:refine not reject[J].Lancet Respir Med,2018,6(6):472-478.
[24]Hellmann MD,Ciuleanu TE,Pluzanski A,et al.Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden[J].N Engl J Med,2018,378(22):2093-2104.
[25]Ramalingairn SS,Hellmann MD,Awad MM,et al.Tumor mutational burden(TMB)as a biomarker for clinical benefit from dual immune checkpoint blockade with nivolumab(nivo)+ipilimumab(ipi)in first-line(1L)non-small cell lung cancer(NSCLC):identification of TMB cutoff from CheckMate 568[J].Cancer Res,2018,78(13 Supplement):CT078-CT078.
[26]Overman MJ,Lonardi S,Wong KYM,et al.Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repairdeficient/microsatellite instability-high metastatic colorectal cancer[J].J Clin Oncol,2018,36(8):773-779.
[27]Geng Y,Shao Y,He W,et al.Prognostic role of tumor-infiltrating lymphocytes in lung cancer:a meta-analysis[J].Cell Physiol Biochem,2015,37(4):1560-1571.
[28]Simoni Y,Becht E,Fehlings M,et al.Bystander CD8(+)Tcells are abundant and phenotypically distinct in human tumour infiltrates[J].Nature,2018,557(7706):575-579.
[29]Garcia-Diaz A,Shin DS,Moreno BH,et al.Interferon receptor signaling pathways regulating PD-L1 and PD-L2expression[J].Cell Rep,2017,19(6):11 89-1201.
[30]Karachaliou N,Gonzalez-Cao M,Crespo G,et al.Interferon gamma,an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients[J].Ther Adv Med Oncol,2018,doi:10.11 77/1758834017749748.
[2]Cyriac G,Gandhi L.Emerging biomarkers for immune checkpoint inhibition in lung cancer[J].Semin Cancer Biol,2018,52(Pt 2):269-277.
[3]Brahmer J,Reckamp KL,Baas P,et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer[J].N Engl J Med,2015,373(2):123-135.
[4]Borghaei H,Paz-Ares L,Horn L,et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J].N Engl J Med,2015,373(17):1627-1639.
[5]Carbone DP,Reck M,Paz-Ares L,et al.First-line nivolumab in stageⅣor recurrent non-small-cell lung cancer[J].N Engl J Med,2017,376(25):2415-2426.
[6]Garon EB,Rizvi NA,Hui R,et al.Pembrolizumab for the treatment of non-small-cell lung cancer[J].N Engl J Med,2015,372(21):2018-2028.
[7]Pai-Scherf L,Blumenthal GM,Li H,et al.FDA approval summary:pembrolizumab for treatment of metastatic non-small cell lung cancer:first-line therapy and beyond[J].Oncologist,2017,22(11):1392-1399.
[8]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(Supple 10):S244-S245.
[9]Weinstock C,Khozin S,Suzman D,et al.U.S.food and drug administration approval summary:atezolizumab for metastatic non-small cell lung cancer[J].Clin Cancer Res,2017,23(16):4534-4539.
[10]Fehrenbacher L,Spira A,Ballinger M,et al.Atezolizumab versus docetaxel for patients with previously treated non-smallcell lung cancer(POPLAR):a multicentre,open-label,phase2 randomised controlled trial[J].Lancet,2016,387(10030):1837-1846.
[11]Rittmeyer A,Barlesi F,Waterkamp D,et al.Atezolizumab versus docetaxel in patients with previously treated non-smallcell lung cancer(OAK):a phase 3,open-label,multicentre randomised controlled trial[J].Lancet,2017,389(10066):255-265.
[12]Antonia SJ,Villegas A,Daniel D,et al.Durvalumab after chemoradiotherapy in stageⅢnon-small-cell lung cancer[J].N Engl J Med,2017,377(20):1919-1929.
[13]Zhang P,Ma Y,Lv C,et al.Upregulation of programmed cell death ligand 1 promotes resistance response in nonsmallcell lung cancer patients treated with neo-adjuvant chemotherapy[J].Cancer Sci,2016,107(11):1563-1571.
[14]Herbst RS,Baas P,Kim DW,et al.Pembrolizumab versus docetaxel for previously treated,PD-L1-positive,advanced non-small-cell lung cancer(KEYNOTE-010):a randomised controlled trial[J].Lancet,2016,387(10027):1540-1550.
[15]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.
[16]Socinski MA,Jotte RM,Cappuzzo F,et al.Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC[J].NEngl J Med,2018,378(24):2288-2301.
[17]Snyder A,Makarov V,Merghoub T,et al.Genetic basis for clinical response to CTLA-4 blockade in melanoma[J].NEngl J Med,2014,371(23):2189-2199.
[18]Rizvi NA,Hellmann MD,Snyder A,et al.Cancer immunology.Mutational landscape determines sensitivity to PD-1blockade in non-small cell lung cancer[J].Science,2015,348(6230):124-128.
[19]Kowanetz M,Zou W,Shames D,et al.Tumor mutation burden(TMB)is associated with improved efficacy of atezolizumab in 1L and 2L+NSCLC patients[J].J Thorac Oncol,2017,12(1):S321-S322.
[20]Peters S,Creelan B,Hellmann MD,et al.Abstract CT082:impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer:an exploratory analysis of CheckMate 026[J].Cancer Res,2017,doi:10.11 58/1538-7445.
[21]Gandara DR,Paul SM,Kowanetz M,et al.Blood-based tumor mutational burden as a predictor of clinical benefit in nonsmallcell lung cancer patients treated with atezolizumab[J].Nat Med,2018,24(9):1441-1448.
[22]Mok TSK,Gadgeel S,Kim ES,et al.Blood first line ready screening trial(B-F1RST)and blood first assay screening trial(BFAST)enable clinical development of novel blood based biomarker assays for tumor mutational burden(TMB)and somatic mutations in 1L advanced or metastatic NSCLC[J].Ann Oncol,2017,28(Suppl 5):v494-v495.
[23]Rashdan S,Minna JD,Gerber DE.Lung cancer immunotherapy biomarkers:refine not reject[J].Lancet Respir Med,2018,6(6):472-478.
[24]Hellmann MD,Ciuleanu TE,Pluzanski A,et al.Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden[J].N Engl J Med,2018,378(22):2093-2104.
[25]Ramalingairn SS,Hellmann MD,Awad MM,et al.Tumor mutational burden(TMB)as a biomarker for clinical benefit from dual immune checkpoint blockade with nivolumab(nivo)+ipilimumab(ipi)in first-line(1L)non-small cell lung cancer(NSCLC):identification of TMB cutoff from CheckMate 568[J].Cancer Res,2018,78(13 Supplement):CT078-CT078.
[26]Overman MJ,Lonardi S,Wong KYM,et al.Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repairdeficient/microsatellite instability-high metastatic colorectal cancer[J].J Clin Oncol,2018,36(8):773-779.
[27]Geng Y,Shao Y,He W,et al.Prognostic role of tumor-infiltrating lymphocytes in lung cancer:a meta-analysis[J].Cell Physiol Biochem,2015,37(4):1560-1571.
[28]Simoni Y,Becht E,Fehlings M,et al.Bystander CD8(+)Tcells are abundant and phenotypically distinct in human tumour infiltrates[J].Nature,2018,557(7706):575-579.
[29]Garcia-Diaz A,Shin DS,Moreno BH,et al.Interferon receptor signaling pathways regulating PD-L1 and PD-L2expression[J].Cell Rep,2017,19(6):11 89-1201.
[30]Karachaliou N,Gonzalez-Cao M,Crespo G,et al.Interferon gamma,an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients[J].Ther Adv Med Oncol,2018,doi:10.11 77/1758834017749748.