Advances in Dynamic Monitoring of Immune Checkpoint Inhibitors as the Prognostic Markers for Advanced Non-small Cell Lung Cancer
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摘要: 免疫检查点抑制剂在晚期非小细胞肺癌中的应用显著提高了患者的生存获益,但存在治疗反应率低等临床问题。免疫检查点抑制剂治疗是肿瘤-免疫系统交互对话、动态变化的过程,纵向监测生物标志物变化,有助于消除个体间的差异,提供肿瘤时空异质性信息。本文将从肿瘤细胞源性、免疫微环境源性及多指标联合三方面对免疫检查点抑制剂治疗晚期非小细胞肺癌预后标志物动态监测的相关研究进展进行综述。Abstract: The use of immune checkpoint inhibitors(ICIs) in advanced non-small cell lung cancer(NSCLC) significantly improves survival, but it has clinical problems such as low response rate. Treatment of tumor with ICIs is a dynamic change that involves the process of tumor-immune system interaction. Vertical monitoring of dynamic changes of biomarkers is helpful to eliminate individual differences and to provide information on spatiotemporal heterogeneity of tumors. This paper reviews the biomarkers of advanced NSCLC, covering the aspects of treatment with ICIs from tumor cell origin, immune microenvironmental source and joint indicators.作者贡献:代丽源负责文献检索、论文撰写及修订;韩晓红、石远凯负责论文选题和审校。利益冲突:所有作者均声明不存在利益冲突
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表 1 ICIs治疗晚期NSCLC预后标志物动态监测相关研究
标志物 治疗方式 样本量(n) 检测内容 监测方法 临床效应 参考文献 ctDNA nivolumab 14 基因等位频率AF 靶向测序(53个基因) PD [25] 抗PD-1单药/联合ICIs治疗 28 突变体等位基因分数MAF 高通量基因测序 PR、PFS、OS [26] pembrolizumab 12 bTMB、最大体细胞等位基因频率MSAF、肿瘤克隆结构 靶向测序(329个基因) PFS、肿瘤进展 [27] nivolumab/pembrolizumab/atezolizumab 34 KRAS突变 微滴式数字PCR PFS、OS、肿瘤进展 [28] CTC nivolumab 24 PD-L1+ CTCs 循环肿瘤细胞检测体系(Cell Search System) PD、CB [29] CD4+ T细胞亚群 atezolizumab/nivolumab/pembrolizumab 70 CD28- CD4+ T细胞 流式细胞术 HPD [30] CD8+ T细胞亚群 pembrolizumab/nivolumab 36 表达CX3CR1的CD8+T细胞 流式细胞术 ORR、PFS、OS [31] TCR nivolumab 4 TCR克隆性 单细胞RNA测序 肿瘤进展 [32] nivolumab 21 TCR克隆性 TCR测序 MPR [33] nivolumab 40 PD-1+CD8+T细胞 流式细胞术TCR测序 PFS [34] NLR nivolumab 101 NLR 全自动血液分析仪 PFS [35] nivolumab/pembrolizumab 19 NLR 全自动血液分析仪 TTF [36] LMR nivolumab 162 LMR 全自动血液分析仪 ORR、PFS、OS [37] IL-8 nivolumab/pembrolizumab 19 IL-8 酶联免疫吸附试验 假性进展 [38] IL-6 nivolumab/pembrolizumab/atezolizumab/durvalumab 47 IL-6 酶联免疫吸附试验 PFS [39] ctDNA、TCR nivolumab/pembrolizumab/联合ICIs治疗 38 ctDNA、TCR克隆性 靶向错误矫正测序 PFS、OS [40] bTMB、CD8+T细胞亚群、ctDNA 抗PD-1单药/联合ICIs治疗 99 ctDNA、CD8+ T细胞 高通量测序流式细胞术 PFS [41] NSCLC:非小细胞肺癌;ctDNA:循环肿瘤DNA;PD-1:程序性死亡蛋白-1;ICIs:免疫检查点抑制剂;CTC:循环肿瘤细胞;PD-L1:程序性死亡[蛋白]配体-1;NLR:中性粒细胞/淋巴细胞比值;LMR:淋巴细胞/单核细胞比值;IL-8:白细胞介素-8;TCR:T细胞受体;bTMB:血液肿瘤突变负荷;DCB:持久临床获益;PR:部分缓解;PFS:无进展生存期;OS:总生存期;PD:疾病进展;CB:临床获益;HPD:超进展;ORR:客观缓解率;MPR:病理部分缓解;TTF:达到治疗失败时间 -
[1] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71: 209-249. doi: 10.3322/caac.21660 [2] Gridelli C, Rossi A, Carbone DP, et al. Non-small-cell lung cancer[J]. Nat Rev Dis Primers, 2015, 1: 15009. doi: 10.1038/nrdp.2015.9 [3] Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer[J]. Nature, 2018, 553: 446-454. doi: 10.1038/nature25183 [4] 周彩存, 王洁, 王宝成, 等. 中国非小细胞肺癌免疫检查点抑制剂治疗专家共识(2020年版)[J]. 中国肺癌杂志, 2021, 24: 217-235. https://www.cnki.com.cn/Article/CJFDTOTAL-FAIZ202104001.htm Zhou CC, Wang J, Wang BC, et al. Chinese Experts Consensus on Immune Checkpoint Inhibitors for Non-small Cell Lung Cancer (2020 Version)[J]. Zhongguo Feiai Zazhi, 2021, 24: 217-235. https://www.cnki.com.cn/Article/CJFDTOTAL-FAIZ202104001.htm [5] Rizvi H, Sanchez-Vega F, La K, et al. Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing[J]. J Clin Oncol, 2018, 36: 633-641. [6] Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria[J]. Clin Cancer Res, 2009, 15: 7412-7420. doi: 10.1158/1078-0432.CCR-09-1624 [7] Champiat S, Dercle L, Ammari S, et al. Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1[J]. Clin Cancer Res, 2017, 23: 1920-1928. doi: 10.1158/1078-0432.CCR-16-1741 [8] Kas B, Talbot H, Ferrara R, et al. Clarification of Definitions of Hyperprogressive Disease During Immunotherapy for Non-Small Cell Lung Cancer[J]. JAMA Oncol, 2020, 6: 1039-1046. doi: 10.1001/jamaoncol.2020.1634 [9] Shankar B, Zhang J, Naqash AR, et al. Multisystem Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors for Treatment of Non-Small Cell Lung Cancer[J]. JAMA Oncol, 2020, 6: 1952-1956. doi: 10.1001/jamaoncol.2020.5012 [10] Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Block-ade[J]. N Engl J Med, 2018, 378: 158-168. doi: 10.1056/NEJMra1703481 [11] Gettinger SN, Horn L, Gandhi L, et al. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer[J]. J Clin Oncol, 2015, 33: 2004-2012. doi: 10.1200/JCO.2014.58.3708 [12] Nishino M, Ramaiya NH, Chambers ES, et al. Immune-related response assessment during PD-1 inhibitor therapy in advanced non-small-cell lung cancer patients[J]. J Immunother Cancer, 2016, 4: 84. doi: 10.1186/s40425-016-0193-2 [13] Katz SI, Hammer M, Bagley SJ, et al. Radiologic Pseudoprogression during Anti-PD-1 Therapy for Advanced Non-Small Cell Lung Cancer[J]. J Thorac Oncol, 2018, 13: 978-986. doi: 10.1016/j.jtho.2018.04.010 [14] Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics[J]. Lancet Oncol, 2017, 18: e143-e152. doi: 10.1016/S1470-2045(17)30074-8 [15] 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]. JAMA Oncol, 2018, 4: 1543-1552. doi: 10.1001/jamaoncol.2018.3676 [16] Champiat S, Dercle L, Ammari S, et al. Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1[J]. Clin Cancer Res, 2017, 23: 1920-1928. doi: 10.1158/1078-0432.CCR-16-1741 [17] Haratani K, Hayashi H, Chiba Y, et al. Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer[J]. JAMA Oncol, 2018, 4: 374-378. doi: 10.1001/jamaoncol.2017.2925 [18] Michaelidou K, Agelaki S, Mavridis K. Molecular markers related to immunosurveillance as predictive and monitoring tools in non-small cell lung cancer: recent accomplishments and future promises[J]. Expert Rev Mol Diagn, 2020, 20: 335-344. doi: 10.1080/14737159.2020.1724785 [19] Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, res-ponse biomarkers, and combinations[J]. Sci Transl Med, 2016, 8: 328rv4. [20] Ren X, Kang B, Zhang Z. Understanding tumor ecosystems by single-cell sequencing: promises and limitations[J]. Genome Biol, 2018, 19: 211. doi: 10.1186/s13059-018-1593-z [21] Andor N, Graham TA, Jansen M, et al. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity[J]. Nat Med, 2016, 22: 105-113. doi: 10.1038/nm.3984 [22] Binnewies M, Roberts EW, Kersten K, et al. Unders-tanding the tumor immune microenvironment (TIME) for effective therapy[J]. Nat Med, 2018, 24: 541-550. doi: 10.1038/s41591-018-0014-x [23] Lesterhuis WJ, Bosco A, Millward MJ, et al. Dynamic versus static biomarkers in cancer immune checkpoint blockade: unravelling complexity[J]. Nat Rev Drug Discov, 2017, 16: 264-272. doi: 10.1038/nrd.2016.233 [24] Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies[J]. Nat Rev Clin Oncol, 2018, 15: 81-94. doi: 10.1038/nrclinonc.2017.166 [25] Iijima Y, Hirotsu Y, Amemiya K, et al. Very early response of circulating tumour-derived DNA in plasma predicts efficacy of nivolumab treatment in patients with non-small cell lung cancer[J]. Eur J Cancer, 2017, 86: 349-357. doi: 10.1016/j.ejca.2017.09.004 [26] Goldberg SB, Narayan A, Kole AJ, et al. Early Assess-ment of Lung Cancer Immunotherapy Response via Circulat-ing Tumor DNA[J]. Clin Cancer Res, 2018, 24: 1872-1880. doi: 10.1158/1078-0432.CCR-17-1341 [27] Li L, Wang Y, Shi W, et al. Serial ultra-deep sequencing of circulating tumor DNA reveals the clonal evolution in non-small cell lung cancer patients treated with anti-PD1 immunotherapy[J]. Cancer Med, 2019, 8: 7669-7678. doi: 10.1002/cam4.2632 [28] Zulato E, Attili I, Pavan A, et al. Early assessment of KRAS mutation in cfDNA correlates with risk of progression and death in advanced non-small-cell lung cancer[J]. Br J Cancer, 2020, 123: 81-91. doi: 10.1038/s41416-020-0833-7 [29] Nicolazzo C, Raimondi C, Mancini M, et al. Monitoring PD-L1 positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor Nivolumab[J]. Sci Rep, 2016, 6: 31726. doi: 10.1038/srep31726 [30] Arasanz H, Zuazo M, Bocanegra A, et al. Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics[J]. Cancers (Basel), 2020, 12: 344. doi: 10.3390/cancers12020344 [31] Kim CG, Hong MH, Kim KH, et al. Dynamic changes in circulating PD-1(+)CD8(+) T lymphocytes for predicting treatment response to PD-1 blockade in patients with non-small-cell lung cancer[J]. Eur J Cancer, 2021, 143: 113-126. doi: 10.1016/j.ejca.2020.10.028 [32] Zhang F, Bai H, Gao R, et al. Dynamics of peripheral T cell clones during PD-1 blockade in non-small cell lung cancer[J]. Cancer Immunol Immunother, 2020, 69: 2599-2611. doi: 10.1007/s00262-020-02642-4 [33] Zhang J, Ji Z, Caushi JX, et al. Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non-Small Cell Lung Cancer[J]. Clin Cancer Res, 2020, 26: 1327-1337. doi: 10.1158/1078-0432.CCR-19-2931 [34] Han J, Duan J, Bai H, et al. TCR Repertoire Diversity of Peripheral PD-1(+)CD8(+) T Cells Predicts Clinical Outcomes after Immunotherapy in Patients with Non-Small Cell Lung Cancer[J]. Cancer Immunol Res, 2020, 8: 146-154. doi: 10.1158/2326-6066.CIR-19-0398 [35] Nakaya A, Kurata T, Yoshioka H, et al. Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab[J]. Int J Clin Oncol, 2018, 23: 634-640. doi: 10.1007/s10147-018-1250-2 [36] Kiriu T, Yamamoto M, Nagano T, et al. The time-series behavior of neutrophil-to-lymphocyte ratio is useful as a predictive marker in non-small cell lung cancer[J]. PLoS One, 2018, 13: e0193018. doi: 10.1371/journal.pone.0193018 [37] Sekine K, Kanda S, Goto Y, et al. Change in the lymphocyte-to-monocyte ratio is an early surrogate marker of the efficacy of nivolumab monotherapy in advanced non-small-cell lung cancer[J]. Lung Cancer, 2018, 124: 179-188. doi: 10.1016/j.lungcan.2018.08.012 [38] Sanmamed MF, Perez-Gracia JL, Schalper KA, et al. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients[J]. Ann Oncol, 2017, 28: 1988-1995. doi: 10.1093/annonc/mdx190 [39] Keegan A, Ricciuti B, Garden P, et al. Plasma IL-6 changes correlate to PD-1 inhibitor responses in NSCLC[J]. J Immunother Cancer, 2020, 8: e000678. doi: 10.1136/jitc-2020-000678 [40] Anagnostou V, Forde PM, White JR, et al. Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer[J]. Cancer Res, 2019, 79: 1214-1225. doi: 10.1158/0008-5472.CAN-18-1127 [41] Nabet BY, Esfahani MS, Moding EJ, et al. Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition[J]. Cell, 2020, 183: 363-376.e313. doi: 10.1016/j.cell.2020.09.001 [42] Heitzer E, Haque IS, Roberts CES, et al. Current and future perspectives of liquid biopsies in genomics-driven oncology[J]. Nat Rev Genet, 2019, 20: 71-88. doi: 10.1038/s41576-018-0071-5 [43] Guibert N, Delaunay M, Lusque A, et al. PD-L1 expression in circulating tumor cells of advanced non-small cell lung cancer patients treated with nivolumab[J]. Lung Cancer, 2018, 120: 108-112. doi: 10.1016/j.lungcan.2018.04.001 [44] Tamminga M, de Wit S, Hiltermann TJN, et al. Circulat-ing tumor cells in advanced non-small cell lung cancer patients are associated with worse tumor response to checkpoint inhibitors[J]. J Immunother Cancer, 2019, 7: 173. doi: 10.1186/s40425-019-0649-2 [45] Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer[J]. N Engl J Med, 2012, 366: 2443-2454. doi: 10.1056/NEJMoa1200690 [46] Tumeh PC, Harview CL, Yearley JH, et al. PD-1 block-ade induces responses by inhibiting adaptive immune resistance[J]. Nature, 2014, 515: 568-571. doi: 10.1038/nature13954 [47] Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy[J]. Lancet Oncol, 2016, 17: e542-e551. doi: 10.1016/S1470-2045(16)30406-5 [48] Janning M, Kobus F, Babayan A, et al. Determination of PD-L1 Expression in Circulating Tumor Cells of NSCLC Patients and Correlation with Response to PD-1/PD-L1 Inhibitors[J]. Cancers(Basel), 2019, 11: 835. [49] Papadaki MA, Sotiriou AI, Vasilopoulou C, et al. Optimization of the Enrichment of Circulating Tumor Cells for Downstream Phenotypic Analysis in Patients with Non-Small Cell Lung Cancer Treated with Anti-PD-1 Immunotherapy[J]. Cancers (Basel), 2020, 12: 1556. doi: 10.3390/cancers12061556 [50] Guibert N, Delaunay M, Lusque A, et al. PD-L1 expression in circulating tumor cells of advanced non-small cell lung cancer patients treated with nivolumab[J]. Lung Cancer, 2018, 120: 108-112. doi: 10.1016/j.lungcan.2018.04.001 [51] Kagamu H, Kitano S, Yamaguchi O, et al. CD4(+) T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy[J]. Cancer Immunol Res, 2020, 8: 334-344. doi: 10.1158/2326-6066.CIR-19-0574 [52] Yamauchi T, Hoki T, Oba T, et al. T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors[J]. Nat Commun, 2021, 12: 1402. doi: 10.1038/s41467-021-21619-0 [53] Kidman J, Principe N, Watson M, et al. Characteristics of TCR Repertoire Associated With Successful Immune Checkpoint Therapy Responses[J]. Front Immunol, 2020, 11: 587014.2 [54] Chiffelle J, Genolet R, Perez MA, et al. T-cell repertoire analysis and metrics of diversity and clonality[J]. Curr Opin Biotechnol, 2020, 65: 284-295. doi: 10.1016/j.copbio.2020.07.010 [55] Mezquita L, Auclin E, Ferrara R, et al. Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non-Small Cell Lung Cancer[J]. JAMA Oncol, 2018, 4: 351-357. doi: 10.1001/jamaoncol.2017.4771 [56] Passiglia F, Galvano A, Castiglia M, et al. Monitoring blood biomarkers to predict nivolumab effectiveness in NSCLC patients[J]. Ther Adv Med Oncol, 2019, 11: 1758835919839928. [57] Simonaggio A, Elaidi R, Fournier L, et al. Variation in neutrophil to lymphocyte ratio (NLR) as predictor of outcomes in metastatic renal cell carcinoma (mRCC) and non-small cell lung cancer (mNSCLC) patients treated with nivolumab[J]. Cancer Immunol Immunother, 2020, 69: 2513-2522. doi: 10.1007/s00262-020-02637-1 [58] Valero C, Lee M, Hoen D, et al. Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors[J]. Nat Commun, 2021, 12: 729. doi: 10.1038/s41467-021-20935-9 [59] Liu Q, Li A, Tian Y, et al. The CXCL8-CXCR1/2 pathways in cancer[J]. Cytokine Growth Factor Rev, 2016, 31: 61-71. doi: 10.1016/j.cytogfr.2016.08.002 [60] Schalper KA, Carleton M, Zhou M, et al. Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors[J]. Nat Med, 2020, 26: 688-692. doi: 10.1038/s41591-020-0856-x [61] Yuen KC, Liu LF, Gupta V, et al. High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade[J]. Nat Med, 2020, 26: 693-698. doi: 10.1038/s41591-020-0860-1 [62] Bakouny Z, Choueiri TK. IL-8 and cancer prognosis on immunotherapy[J]. Nat Med, 2020, 26: 650-651. doi: 10.1038/s41591-020-0873-9 [63] Li JJN, Karim K, Sung M, et al. Tobacco exposure and immunotherapy response in PD-L1 positive lung cancer patients[J]. Lung Cancer, 2020, 150: 159-163. doi: 10.1016/j.lungcan.2020.10.023 [64] Lee CK, Man J, Lord S, et al. Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A Meta-Analysis[J]. J Thorac Oncol, 2017, 12: 403-407. doi: 10.1016/j.jtho.2016.10.007
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