PD-1/PD-L1在小细胞肺癌中的临床研究进展
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摘要
小细胞肺癌(small cell lung cancer,SCLC)恶性程度高,具有强侵袭性、快速增长及早期转移等特点。初始治疗对化疗和放疗较敏感,但易复发且预后差。免疫检测点抑制剂程序性死亡分子-1(programmed death-1,PD-1)和程序性死亡分子1配体(pro-grammed death-ligand 1,PD-L1)拮抗剂,通过激活T细胞对肿瘤细胞的免疫应答,在SCLC的临床研究中均获得了很好的疗效,有望成为治疗SCLC的主要手段。本文旨在阐述PD-1/PD-L1抑制剂在SCLC治疗中的研究进展,同时,比较肿瘤突变负荷(tumormutation burden,TMB)与PD-L1表达作为生物标记物在SCLC的作用。
Small-cell lung cancer(SCLC) has a high degree of malignancy and is characterized by strong invasiveness, rapid growth, and early metastasis. SCLC is sensitive to initial treatment with chemotherapy and radiotherapy, but it can easily relapse and has a poor prognosis. Both programmed death-1(PD-1) and programmed cell death-ligand 1(PD-L1) antagonists activate the immune response of tumor cells by activating T cells, and have shown exciting curative effects in clinical studies of SCLC, thereby becoming powerful po‐tential agents to treat SCLC in the future. This article aims to illustrate the progress of PD-1/PD-L1 inhibitors in the treatment of SCLC,as well as the role of PD-L1 expression and tumor mutation burden(TMB) as a biomarker in SCLC.
Small-cell lung cancer(SCLC) has a high degree of malignancy and is characterized by strong invasiveness, rapid growth, and early metastasis. SCLC is sensitive to initial treatment with chemotherapy and radiotherapy, but it can easily relapse and has a poor prognosis. Both programmed death-1(PD-1) and programmed cell death-ligand 1(PD-L1) antagonists activate the immune response of tumor cells by activating T cells, and have shown exciting curative effects in clinical studies of SCLC, thereby becoming powerful po‐tential agents to treat SCLC in the future. This article aims to illustrate the progress of PD-1/PD-L1 inhibitors in the treatment of SCLC,as well as the role of PD-L1 expression and tumor mutation burden(TMB) as a biomarker in SCLC.
引文
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[9] Zou W, Wolchok JD, Chen L. PD-L1(B7-H1)and PD-1 pathwayblockade for cancer therapy:Mechanisms, response biomarkers, andcombi‐nations[J]. Sci Transl Med, 2016, 8(328):328rv4.
[10] Ameratunga M, Asadi K, Lin X, et al. PD-L1 and tumor infiltrating lymphocytes as prognostic markers in resected NSCLC[J]. PLoS One.,2016, 11(4):e0153954.
[11] Li Z, Dong P, Ren M, et al. PD-L1 expression is associated with tumor FOXP3(+)regulatory T-cell infiltration of breast cancer and poor prognosis of patient[J]. J Cancer, 2016, 7(7):784-793.
[12] Faraj SF, Munari E, Guner G, et al. Assessment of tumoral PD-L1 ex‐pression and intratumoral CD8+T cells in urothelial carcinoma[J].Urology, 2015, 85(3):703.e1-6.
[13] Saresella M, Rainone V, Al-Daghri NM, et al. The PD-1/PD-L1 pathway in human pathology[J]. Curr Mol Med, 2012, 12(3):259-267.
[14] Ma W, Gilligan BM, Yuan J, et al. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy[J]. J Hematol Oncol, 2016, 9(1):47.
[15] Yan F, Pang J, Peng Y, et al. Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells[J]. PLoS One, 2016, 11(9):e0162925.
[16] Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus in advanced nonsquamous non-small-cell lung cancer[J]. N Engl J Med, 2015, 373(17):1627-1639.
[17] 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.
[18] Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer(Check Mate 032):a multicentre, open-label, phase 1/2 trial[J]. Lancet Oncol, 2016, 17(7):883-895.
[19] Kalemkerian GP, Loo BW Jr, Akerley W, et al. NCCN Guidelines Insights:Small Cell Lung Cancer, Version 2.2018[J]. J Natl Compr Canc Netw,2018, 16(10):1171-1182.
[20] Hellmann MD, Ott PA, Zugazagoitia J, et al. Nivolumab(nivo)±ipilim‐umab(ipi)in advanced small-cell lung cancer(SCLC):First report of a randomized expansion cohort from CheckMate 032[Abstract]. J Clin Oncol, 2017, 35(15):8503.
[21] Ott PA,Fernandez MEE,Hiret S, et al. Pembrolizumab(MK-3475)in patients with extensive-stage small cell lung cancer:preliminary safety and efficacy results from KEYNOTE-028[Abstract]. J Clin Oncol, 2015,33:7502.
[22] Chung HC, Lopez-Martin JA, Kao SC, et al. Phase 2 study of pembro‐lizumab in advanced small-cell lung cancer(SCLC):KEYNOTE-158[abstract]. J Clin Oncol, 2018, 36:8506.
[23] Sequist LV, Chiang A, Gilbert J, et al. Clinical activity, safety and pre‐dictive biomarkers results from a phase Ia atezolizumab(atezo)trial in extensive-stage small cell lung cancer(ES-SCLC)[J]. Ann Oncol, 2016,27(6):493-496.
[24] Horn L, Mansfield AS, Szcz?sna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer[J]. N Engl J Med, 2018, 379(23):2220-2229.
[25] Wang W, Shen G, Wu S, et al. PD-1 mRNA expression in peripheral blood cells and its modulation characteristics in cancer patients[J].Oncotarget, 2017, 8(31):50782-50791.
[26]李慧,刘岩,柳影,柳菁菁,赵丹丹,王莹,程颖.CTLA-4、PD-1和PD-L1在小细胞肺癌外周血中的分布及临床意义[J].中国肺癌杂志,2017,20(11):755-760.
[27] Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Muta‐tional landscape determines sensitivity to PD-1 blockade in nonsmall cell lung cancer[J]. Science, 2015, 348(6230):124-128.
[28] Peters S, Creelan B, Hellmann MD, et al. Abstrat 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[abstract]. Cancer Res, 2017, 77:CT082.
[29] Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilim‐umab in lung cancer with a high tumor mutational burden[J]. N Engl J Med, 2018, 378(22):2093-2104.
[30] Hellmann MD, Callahan MK, Awad MM, et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer[J]. Cancer Cell, 2018, 33(5):853-861。
[2] Kalemkerian GP, Akerley W, Bogner P, et al. Small cell lung cancer[J].J Natl Compr Canc Netw, 2013, 11(1):78-98.
[3] Pesch B, Kendzia B, Gustavsson P, et al. Cigarette smoking and lung cancer-relative risk estimates for the major histological types from a pooled analysis of case-control studies[J]. Int J Cancer, 2012, 131(5):1210-1219.
[4] Owonikoko TK, Behera M, Chen Z, et al. A systematic analysis of ef‐ficacy of second-line chemotherapy in sensitive and refractory smallcell lung cancer[J]. J Thorac Oncol, 2012, 7(5):866-872.
[5] Behera M, Ragin C, Kim S, et al. Trends, predictors, and impact of systemic chemotherapy in small cell lung cancer patients between1985 and 2005[J]. Cancer, 2016, 122(1):50-60.
[6] Varghese AM, Zakowski MF, Yu HA, et al. Small-cell lung cancers in patients who never smoked cigarettes[J]. J Thorac Oncol, 2014, 9(6):892-896.
[7] CChalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden[J].Genome Med, 2017, 9(1):34.
[8] Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatchrepair deficiency[J]. N Engl J Med, 2015, 372(26):2509-2520.
[9] Zou W, Wolchok JD, Chen L. PD-L1(B7-H1)and PD-1 pathwayblockade for cancer therapy:Mechanisms, response biomarkers, andcombi‐nations[J]. Sci Transl Med, 2016, 8(328):328rv4.
[10] Ameratunga M, Asadi K, Lin X, et al. PD-L1 and tumor infiltrating lymphocytes as prognostic markers in resected NSCLC[J]. PLoS One.,2016, 11(4):e0153954.
[11] Li Z, Dong P, Ren M, et al. PD-L1 expression is associated with tumor FOXP3(+)regulatory T-cell infiltration of breast cancer and poor prognosis of patient[J]. J Cancer, 2016, 7(7):784-793.
[12] Faraj SF, Munari E, Guner G, et al. Assessment of tumoral PD-L1 ex‐pression and intratumoral CD8+T cells in urothelial carcinoma[J].Urology, 2015, 85(3):703.e1-6.
[13] Saresella M, Rainone V, Al-Daghri NM, et al. The PD-1/PD-L1 pathway in human pathology[J]. Curr Mol Med, 2012, 12(3):259-267.
[14] Ma W, Gilligan BM, Yuan J, et al. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy[J]. J Hematol Oncol, 2016, 9(1):47.
[15] Yan F, Pang J, Peng Y, et al. Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells[J]. PLoS One, 2016, 11(9):e0162925.
[16] Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus in advanced nonsquamous non-small-cell lung cancer[J]. N Engl J Med, 2015, 373(17):1627-1639.
[17] 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.
[18] Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer(Check Mate 032):a multicentre, open-label, phase 1/2 trial[J]. Lancet Oncol, 2016, 17(7):883-895.
[19] Kalemkerian GP, Loo BW Jr, Akerley W, et al. NCCN Guidelines Insights:Small Cell Lung Cancer, Version 2.2018[J]. J Natl Compr Canc Netw,2018, 16(10):1171-1182.
[20] Hellmann MD, Ott PA, Zugazagoitia J, et al. Nivolumab(nivo)±ipilim‐umab(ipi)in advanced small-cell lung cancer(SCLC):First report of a randomized expansion cohort from CheckMate 032[Abstract]. J Clin Oncol, 2017, 35(15):8503.
[21] Ott PA,Fernandez MEE,Hiret S, et al. Pembrolizumab(MK-3475)in patients with extensive-stage small cell lung cancer:preliminary safety and efficacy results from KEYNOTE-028[Abstract]. J Clin Oncol, 2015,33:7502.
[22] Chung HC, Lopez-Martin JA, Kao SC, et al. Phase 2 study of pembro‐lizumab in advanced small-cell lung cancer(SCLC):KEYNOTE-158[abstract]. J Clin Oncol, 2018, 36:8506.
[23] Sequist LV, Chiang A, Gilbert J, et al. Clinical activity, safety and pre‐dictive biomarkers results from a phase Ia atezolizumab(atezo)trial in extensive-stage small cell lung cancer(ES-SCLC)[J]. Ann Oncol, 2016,27(6):493-496.
[24] Horn L, Mansfield AS, Szcz?sna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer[J]. N Engl J Med, 2018, 379(23):2220-2229.
[25] Wang W, Shen G, Wu S, et al. PD-1 mRNA expression in peripheral blood cells and its modulation characteristics in cancer patients[J].Oncotarget, 2017, 8(31):50782-50791.
[26]李慧,刘岩,柳影,柳菁菁,赵丹丹,王莹,程颖.CTLA-4、PD-1和PD-L1在小细胞肺癌外周血中的分布及临床意义[J].中国肺癌杂志,2017,20(11):755-760.
[27] Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Muta‐tional landscape determines sensitivity to PD-1 blockade in nonsmall cell lung cancer[J]. Science, 2015, 348(6230):124-128.
[28] Peters S, Creelan B, Hellmann MD, et al. Abstrat 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[abstract]. Cancer Res, 2017, 77:CT082.
[29] Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilim‐umab in lung cancer with a high tumor mutational burden[J]. N Engl J Med, 2018, 378(22):2093-2104.
[30] Hellmann MD, Callahan MK, Awad MM, et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer[J]. Cancer Cell, 2018, 33(5):853-861。