恶性黑素瘤免疫检查点抑制疗法研究进展

doi:10.35541/cjd.20190407

中华皮肤科杂志 ›› 2020, Vol. 53 ›› Issue (10): 841-845.doi: 10.35541/cjd.20190407

恶性黑素瘤免疫检查点抑制疗法研究进展

陈奕鹤骆丹

南京医科大学第一附属医院江苏省人民医院皮肤科，南京 210029

收稿日期:2019-03-19 修回日期:2020-01-09 发布日期:2020-09-30
通讯作者: 骆丹 E-mail:daniluo2005@163.com
基金资助:
国家自然科学基金（81771512）

Immune checkpoint inhibitor therapy for malignant melanoma

Chen Yihe, Luo Dan

Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China

Received:2019-03-19 Revised:2020-01-09 Published:2020-09-30
Contact: Luo Dan E-mail:daniluo2005@163.com
Supported by:
National Natural Science Foundation of China（81771512）

摘要/Abstract

摘要： 【摘要】免疫检查点抑制剂在过去几年中已成为许多恶性黑素瘤患者的重要治疗选择，其旨在恢复并促进效应T细胞特异性识别和杀伤肿瘤细胞的功能，系统性增强全身的抗肿瘤免疫反应，对于手术切除后具有高复发风险或处于疾病晚期（不可切除或存在转移）的患者都是较好的治疗选择。目前免疫检查点抑制的主要目标是程序性死亡受体 1与细胞毒性T淋巴细胞相关抗原4，它们分别是中枢和外周免疫耐受的两个关键受体。本文主要讨论不同免疫检查点抑制剂的临床效应、可能存在的药物反应性预测标志物与相关不良反应。

关键词: 痣和黑素瘤, 免疫检查点, 程序性细胞死亡受体1, CTLA-4抗原, 生物学标记, 药理学, 药物毒性, 免疫检查点抑制剂

Abstract: 【Abstract】 Immune checkpoint inhibitors （ICIs） have become an important treatment option for many patients with malignant melanoma in the past few years. ICIs can restore and promote the function of effector T cells to specifically recognize and kill tumor cells, and systemically enhance anti-tumor immune response of the body, so they are a good treatment option for patients who have a high risk of recurrence after surgery or are at an advanced stage of disease （unresectable or metastatic melanoma）. The main targets of current ICIs are programmed death receptor 1 and cytotoxic T lymphocyte-associated antigen 4, which are two key receptors for central and peripheral immune tolerance respectively. This review mainly discusses clinical efficacy of different ICIs, possible biomarkers of response to ICIs and ICI-related adverse reactions.

Key words: Nevi and melanomas, Immune checkpoint, Programmed cell death 1 receptor, CTLA-4 antigen, Biomarkers, pharmacological, Drug toxicity, Immune checkpoint inhibitors

陈奕鹤骆丹. 恶性黑素瘤免疫检查点抑制疗法研究进展[J]. 中华皮肤科杂志, 2020,53(10):841-845. doi:10.35541/cjd.20190407

Chen Yihe, Luo Dan. Immune checkpoint inhibitor therapy for malignant melanoma[J]. Chinese Journal of Dermatology, 2020, 53(10): 841-845.doi:10.35541/cjd.20190407

参考文献 40

［1］	Chen DS, Mellman I. Oncology meets immunology: the cancer⁃immunity cycle［J］. Immunity, 2013,39（1）:1⁃10. doi: 10.1016/j.immuni.2013.07.012.
［2］	Lipson EJ, Drake CG. Ipilimumab: an anti⁃CTLA⁃4 antibody for metastatic melanoma［J］. Clin Cancer Res, 2011,17（22）:6958⁃6962. doi: 10.1158/1078⁃0432.CCR⁃11⁃1595.
［3］	O′Day SJ, Maio M, Chiarion⁃Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single⁃arm phase II study［J］. Ann Oncol, 2010,21（8）:1712⁃1717. doi: 10.1093/annonc/mdq013.
［4］	Hodi FS, O′Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma［J］. N Engl J Med, 2010,363（8）:711⁃723. doi: 10.1056/NEJMoa1003466.
［5］	Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double⁃blind, multicentre, phase 2, dose⁃ranging study［J］. Lancet Oncol, 2010,11（2）:155⁃164. doi: 10.1016/S1470⁃2045（09）70334⁃1.
［6］	Ascierto PA, Del Vecchio M, Robert C, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double⁃blind, multicentre, phase 3 trial［J］. Lancet Oncol, 2017,18（5）:611⁃622. doi: 10. 1016/S1470⁃2045（17）30231⁃0.
［7］	Kirkwood JM, Lorigan P, Hersey P, et al. Phase II trial of tremelimumab （CP⁃675,206） in patients with advanced refractory or relapsed melanoma［J］. Clin Cancer Res, 2010,16（3）:1042⁃1048. doi: 10.1158/1078⁃0432.CCR⁃09⁃2033.
［8］	Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing tremelimumab with standard⁃of⁃care chemotherapy in patients with advanced melanoma［J］. J Clin Oncol, 2013,31（5）:616⁃622. doi: 10.1200/JCO.2012.44.6112.
［9］	Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator⁃choice chemotherapy for ipilimumab⁃refractory melanoma （KEYNOTE⁃002）: a randomised, controlled, phase 2 trial［J］. Lancet Oncol, 2015,16（8）:908⁃918. doi: 10.1016/S1470⁃2045（15）00083⁃2.
［10］	Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma［J］. N Engl J Med, 2015,372（26）:2521⁃2532. doi: 10.1056/NEJMoa1503093.
［11］	Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open⁃label phase 3 study （KEYNOTE⁃006）［J］. Lancet, 2017,390（10105）:1853⁃1862. doi: 10.1016/S0140⁃6736（17）31601⁃X.
［12］	Hamid O, Robert C, Daud A, et al. Five⁃year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE⁃001［J］. Ann Oncol, 2019,30（4）:582⁃588. doi: 10.1093/annonc/mdz011.
［13］	Weber JS, D′Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti⁃CTLA⁃4 treatment （CheckMate 037）: a randomised, controlled, open⁃label, phase 3 trial［J］. Lancet Oncol, 2015,16（4）:375⁃384. doi: 10.1016/S1470⁃2045（15）70076⁃8.
［14］	Wolchok JD, Chiarion⁃Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma［J］. N Engl J Med, 2017,377（14）:1345⁃1356. doi: 10.1056/NEJMoa1709684.
［15］	Hodi FS, Chiarion⁃Sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma （CheckMate 067）: 4⁃year outcomes of a multicentre, randomised, phase 3 trial［J］. Lancet Oncol, 2018,19（11）:1480⁃1492. doi: 10.1016/S1470⁃2045（18）30700⁃9.
［16］	Lebbé C, Meyer N, Mortier L, et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV checkMate 511 trial［J］. J Clin Oncol, 2019,37（11）:867⁃875. doi: 10.1200/JCO.18.01998.
［17］	Meerveld⁃Eggink A, Rozeman EA, Lalezari F, et al. Short⁃term CTLA⁃4 blockade directly followed by PD⁃1 blockade in advanced melanoma patients: a single⁃center experience［J］. Ann Oncol, 2017,28（4）:862⁃867. doi: 10.1093/annonc/mdw692.
［18］	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（26）:2443⁃2454. doi: 10.1056/NEJMoa1200690.
［19］	Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab （anti⁃PD⁃1） in melanoma［J］. N Engl J Med, 2013,369（2）:134⁃144. doi: 10.1056/NEJMoa1305133.
［20］	Koster BD, de Gruijl TD, van den Eertwegh AJ. Recent developments and future challenges in immune checkpoint inhibitory cancer treatment［J］. Curr Opin Oncol, 2015,27（6）:482⁃488. doi: 10.1097/CCO.0000000000000221.
［21］	Yang Q, Xu Z, Zheng L, et al. Multimodal detection of PD⁃L1: reasonable biomarkers for immune checkpoint inhibitor［J］. Am J Cancer Res, 2018,8（9）:1689⁃1696.
［22］	Martens A, Wistuba⁃Hamprecht K, Geukes Foppen M, et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with Ipilimumab［J］. Clin Cancer Res, 2016,22（12）:2908⁃2918. doi: 10.1158/1078⁃0432.CCR⁃15⁃2412.
［23］	Yamazaki N, Kiyohara Y, Uhara H, et al. Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma［J］. Cancer Sci, 2017,108（5）:1022⁃1031. doi: 10.1111/cas.13226.
［24］	Chaput N, Lepage P, Coutzac C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab［J］. Ann Oncol, 2017,28（6）:1368⁃1379. doi: 10.1093/annonc/mdx108.
［25］	Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti⁃PD⁃1 immunotherapy in melanoma patients［J］. Science, 2018,359（6371）:97⁃103. doi: 10.1126/science.aan4236.
［26］	Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy［J］. J Clin Oncol, 2015, 33（17）: 1974⁃1982. doi: 10.1200/jco.2014.59.4358
［27］	Bertrand A, Kostine M, Barnetche T, et al. Immune related adverse events associated with anti⁃CTLA⁃4 antibodies: systematic review and meta⁃analysis［J］. BMC Med, 2015,13:211. doi: 10.1186/s12916⁃015⁃0455⁃8.
［28］	王雅坤, 张小田. 免疫检查点抑制剂的毒性风险分析［J］. 临床肿瘤学杂志, 2017, 22（8）: 735⁃741. doi: 10.3969/j.issn.1009⁃0460.2017.08.016.
［29］	Horvat TZ, Adel NG, Dang TO, et al. Immune⁃related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with Ipilimumab at Memorial sloan Kettering Cancer Center［J］. J Clin Oncol, 2015,33（28）:3193⁃3198. doi: 10.1200/JCO.2015.60.8448.
［30］	Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma［J］. N Engl J Med, 2015, 373（13）: 1270⁃1271. doi: 10.1056/NEJMc1509660.
［31］	Faje A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights［J］. Pituitary, 2016,19（1）:82⁃92. doi: 10.1007/s11102⁃015⁃0671⁃4.
［32］	Callahan MK, Kluger H, Postow MA, et al. Nivolumab plus Ipilimumab in patients with advanced melanoma: updated survival, response, and safety data in a phase I dose⁃escalation study［J］. J Clin Oncol, 2018,36（4）:391⁃398. doi: 10.1200/JCO.2017.72.2850.
［33］	Hwang SJ, Anforth R, Carlos G, et al. Cutaneous adverse events of new anti⁃melanoma therapies: classification and management［J］. Actas Dermosifiliogr, 2017,108（1）:6⁃16. doi: 10.1016/j.ad.2016.05.019.
［34］	Tetzlaff MT, Nagarajan P, Chon S, et al. Lichenoid dermatologic toxicity from immune checkpoint blockade therapy: a detailed examination of the clinicopathologic features［J］. Am J Dermatopathol, 2017,39（2）:121⁃129. doi: 10.1097/DAD.00000 00000000688.
［35］	Bonigen J, Raynaud⁃Donzel C, Hureaux J, et al. Anti⁃PD1⁃induced psoriasis: a study of 21 patients［J］. J Eur Acad Dermatol Venereol, 2017,31（5）:e254⁃e257. doi: 10.1111/jdv. 14011.
［36］	Barbosa NS, Wetter DA, Wieland CN, et al. Scleroderma induced by Pembrolizumab: a case series［J］. Mayo Clin Proc, 2017,92（7）:1158⁃1163. doi: 10.1016/j.mayocp.2017.03.016.
［37］	Naidoo J, Schindler K, Querfeld C, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD⁃1 and PD⁃L1［J］. Cancer Immunol Res, 2016,4（5）:383⁃389. doi: 10.1158/2326⁃6066.CIR⁃15⁃0123.
［38］	Fecher LA, Agarwala SS, Hodi FS, et al. Ipilimumab and its toxicities: a multidisciplinary approach［J］. Oncologist, 2013,18（6）:733⁃743. doi: 10.1634/theoncologist.2012⁃0483.
［39］	Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD⁃1 receptor［J］. Eur J Cancer, 2016,60:12⁃25. doi: 10. 1016/j.ejca.2016.02.010.
［40］	Hua C, Boussemart L, Mateus C, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with Pembrolizumab［J］. JAMA Dermatol, 2016,152（1）:45⁃51. doi: 10.1001/jamadermatol.2015.2707.

[1]	高子蕊赵培窦沅青刘萍张建中. 度普利尤单抗治疗成人结节性痒疹的疗效与安全性观察[J]. 中华皮肤科杂志, 2022, 55(7): 562-565.
[2]	施雁庭黎皓郑捷曹华. 程序性细胞死亡蛋白1及其配体通路在特发性炎症性肌病中的研究进展[J]. 中华皮肤科杂志, 2022, 55(7): 633-636.
[3]	张宁李舒李敬. 免疫检查点抑制剂和靶向药物辅助治疗可切除黑素瘤疗效的网状Meta分析[J]. 中华皮肤科杂志, 2022, 55(7): 603-609.
[4]	黄雅馨何渊民黄书莉熊霞邓永琼. 血清几丁质酶3样蛋白1水平在寻常型天疱疮中的临床意义研究[J]. 中华皮肤科杂志, 2022, 55(6): 523-527.
[5]	黄馨陈筱昀李亚萍梁兴堃张桂英周英湛意罗帅寒天廖洁月肖嵘龙海. 度普利尤单抗治疗123例特应性皮炎的疗效及安全性分析[J]. 中华皮肤科杂志, 2022, 55(6): 486-493.
[6]	高妮刘宇王雷刘玲高天文李凯. 孤立性真皮黑素瘤5例临床及组织病理分析[J]. 中华皮肤科杂志, 2022, 55(5): 408-410.
[7]	刘擘宋晓婷李若瑜赵作涛. 【开放获取】度普利尤单抗治疗特应性皮炎的疗效及安全性分析[J]. 中华皮肤科杂志, 2022, 55(4): 295-298.
[8]	李浩, 王俐韩宪伟孙彤苏芳孙晓冬韩莹杨国玲刘晓明王凯波 . 糖尿病患者服用二肽基肽酶Ⅳ抑制剂后发生大疱性类天疱疮32例临床特征分析[J]. 中华皮肤科杂志, 2022, 55(3): 213-218.
[9]	赵鹏秦小卫秦俊霞梁丽丽张馨中高杰. 斑秃患者外周血白细胞介素35的表达及其对调节性T细胞的功能调控[J]. 中华皮肤科杂志, 2022, 55(3): 224-230.
[10]	王玥严煜林. 寻常型银屑病患者171例阿维A治疗相关不良反应及停药原因分析[J]. 中华皮肤科杂志, 2022, 55(3): 242-245.
[11]	王晓雯李若瑜. 白细胞介素17相关生物制剂治疗银屑病过程中浅部真菌感染的发生及应对策略[J]. 中华皮肤科杂志, 2022, 55(3): 272-275.
[12]	董栋, 刘天一. 细胞代谢与皮肤恶性黑素瘤转移的研究进展[J]. 中华皮肤科杂志, 2022, 0(1): 20210023-e20210023.
[13]	陆佳维, 鲁严. 肿瘤坏死因子α抑制剂及其他生物制剂相关矛盾性银屑病的临床进展[J]. 中华皮肤科杂志, 2022, 0(1): 20210420-e20210420.
[14]	邹美熔汪盛. 免疫检查点抑制剂所致皮肤免疫相关不良反应的研究进展[J]. 中华皮肤科杂志, 2022, 0(1): 20201221-e20201221.
[15]	隋长霖常晓赵琪朱威. 抗肿瘤靶向和免疫治疗致银屑病研究进展[J]. 中华皮肤科杂志, 2022, 0(1): 20210442-e20210442.

恶性黑素瘤免疫检查点抑制疗法研究进展

Immune checkpoint inhibitor therapy for malignant melanoma

PDF

PDF (Mobile)

可视化

摘要/Abstract

引用本文

使用本文

参考文献 40

相关文章 15

Metrics

本文评价

推荐阅读 10