免疫检查点抑制剂相关多器官不良反应研究进展

摘要/Abstract

摘要：

免疫检查点抑制剂（ICI）是一把疗效与不良反应并存的“双刃剑”，为肿瘤患者带来临床获益的同时，免疫相关不良反应（irAE）不容忽视。尤其是ICI导致的多器官不良反应（MO-irAE），临床表现尤为复杂，危重患者占比较高，临床认识和重视不足，管理相对困难，可能危及患者生命。合理应用激素等免疫调节剂、积极对症支持治疗、开展严密监测和长期随访是控制MO-irAE的关键措施。患者的临床特征、外周血指标及遗传易感性等因素在一定程度上能预测MO-irAE的发生发展。全面把握MO-irAE的临床表现、干预措施及转归预后等情况，深入了解其潜在的分子机制和预测因子，有助于有效控制MO-irAE，提高患者临床获益。

关键词:肿瘤,免疫检查点抑制剂,不良反应,免疫相关多器官不良反应

Abstract:

Tumor immune checkpoint inhibitors （ICIs） present a dual nature，offering therapeutic benefits alongside possible toxic side effects. Despite their significant clinical advantages，immune-related adverse events （irAEs） are major concern. In particular，the multi-organ irAEs （MO-irAEs） caused by ICIs present complex clinical manifestations，affecting a high proportion of critically ill patients. There is a lack of clinical awareness and attention towards these adverse events，making management relatively difficult，thus potentially threatening the life of patients. Reasonable application of hormones and immune modulators，along with symptomatic and supportive treatment，as well as careful monitoring and long-term follow-up are crucial measures to control MO-irAEs. Clinical characteristics，peripheral blood indicators，and genetic predisposition can serve as predictive markers for MO-irAEs occurrence and progression to some extent. A comprehensive understanding of clinical features，intervention measures，prognosis，potential molecular mechanisms and predictive factors of MO-irAEs can help to effectively control MO-irAEs，ultimately improving patient outcomes.

Key words:Neoplasms,Immune checkpoint inhibitors,Adverse events,Multi-organ irAEs

王秋实, 徐瑞涛, 李松, 褚佳慧, 刘联. 免疫检查点抑制剂相关多器官不良反应研究进展[J]. 国际肿瘤学杂志, 2024, 51(8): 510-514.

Wang Qiushi, Xu Ruitao, Li Song, Chu Jiahui, Liu Lian. Research progress of immune checkpoint inhibitor-related multi-organ adverse events[J]. Journal of International Oncology, 2024, 51(8): 510-514.

参考文献50

[1]	Bajwa R, Cheema A, Khan T, et al. Adverse effects of immune checkpoint inhibitors (programmed death-1 inhibitors and cytotoxic T-lymphocyte-associated protein-4 inhibitors): results of a retrospective study[J].J Clin Med Res,2019,11(4): 225-236. DOI:10.14740/jocmr3750. pmid:30937112
[2]	Naidoo J, Murphy C, Atkins MB, et al. Society for Immunotherapy of Cancer (SITC) consensus definitions for immune checkpoint inhibitor-associated immune-related adverse events (irAEs) terminology[J].J Immunother Cancer,2023,11(3): e006398. DOI:10.1136/jitc-2022-006398.
[3]	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(12): 1952-1956. DOI:10.1001/jamaoncol.2020.5012. pmid:33119034
[4]	Shimozaki K, Sukawa Y, Beppu N, et al. Multiple immune-related adverse events and anti-tumor efficacy: real-world data on various solid tumors[J].Cancer Manag Res,2020,12: 4585-4593. DOI:10.2147/CMAR.S247554. pmid:32606951
[5]	Ng KYY, Tan SH, Tan JJE, et al. Impact of immune-related adverse events on efficacy of immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma[J].Liver Cancer,2022,11(1): 9-21. DOI:10.1159/000518619. pmid:35222504
[6]	Freites-Martinez A, Santana N, Arias-Santiago S, et al. Using the Common Terminology Criteria for Adverse Events (CTCAE-version 5.0) to evaluate the severity of adverse events of anticancer therapies[J].Actas Dermosifiliogr (Engl Ed),2021,112(1): 90-92. DOI:10.1016/j.adengl.2019.05.021.
[7]	Kichenadasse G, Miners JO, Mangoni AA, et al. Multiorgan immune-related adverse events during treatment with atezolizumab[J].J Natl Compr Canc Netw,2020,18(9): 1191-1199. DOI:10.6004/jnccn.2020.7567.
[8]	Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota[J].Science,2015,350(6264): 1079-1084. DOI:10.1126/science.aad1329. pmid:26541610
[9]	Vastarella M, Fabbrocini G, Sibaud V. Hyperkeratotic skin adverse events induced by anticancer treatments: a comprehensive review[J].Drug Saf,2020,43(5): 395-408. DOI:10.1007/s40264-020-00907-6.
[10]	Aldrich J, Pundole X, Tummala S, et al. Inflammatory myositis in cancer patients receiving immune checkpoint inhibitors[J].Arthritis Rheumatol,2021,73(5): 866-874. DOI:10.1002/art.41604.
[11]	Thompson LL, Krasnow NA, Chang MS, et al. Patterns of cutaneous and noncutaneous immune-related adverse events among patients with advanced cancer[J].JAMA Dermatol,2021,157(5): 577-582. DOI:10.1001/jamadermatol.2021.0326. pmid:33760001
[12]	Hu YZ, Lu WC, Tang BR, et al. Urinary incontinence as a possible signal of neuromuscular toxicity during immune checkpoint inhibitor treatment: case report and retrospective pharmacovigilance study[J].Front Oncol,2022,12: 954468. DOI:10.3389/fonc.2022.954468.
[13]	Yin N, Liu XA, Ye XJ, et al. PD-1 inhibitor therapy causes multisystem immune adverse reactions: a case report and literature review[J].Front Oncol,2022,12: 961266. DOI:10.3389/fonc.2022.961266.
[14]	Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis[J].JAMA Oncol,2018,4(12): 1721-1728. DOI:10.1001/jamaoncol.2018.3923. pmid:30242316
[15]	Xie X, Wang L, Li Y, et al. Multi-organ immune-related adverse event is a risk factor of immune checkpoint inhibitor-associated myocarditis in cancer patients: a multi-center study[J].Front Immunol,2022,13: 879900. DOI:10.3389/fimmu.2022.879900.
[16]	Chen Y, Chen Y, Xie J, et al. Multisystem immune-related adverse events due to toripalimab: two cases-based review[J].Front Cardiovasc Med,2022,9: 1036603. DOI:10.3389/fcvm.2022.1036603.
[17]	Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma[J].Lancet,2021,398(10304): 1002-1014. DOI:10.1016/S0140-6736(21)01206-X. pmid:34509219
[18]	Pathak R, Katel A, Massarelli E, et al. Immune checkpoint inhibitor-induced myocarditis with myositis/myasthenia gravis overlap syndrome: a systematic review of cases[J].Oncologist,2021,26(12): 1052-1061. DOI:10.1002/onco.13931. pmid:34378270
[19]	Faje AT, Lawrence D, Flaherty K, et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma[J].Cancer,2018,124(18): 3706-3714. DOI:10.1002/cncr.31629. pmid:29975414
[20]	Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4[J].J Clin Oncol,2005,23(25): 6043-6053. DOI:10.1200/JCO.2005.06.205. pmid:16087944
[21]	Laparra A, Kfoury M, Champiat S, et al. Multiple immune-related toxicities in cancer patients treated with anti-programmed cell death protein 1 immunotherapies: a new surrogate marker for clinical trials?[J].Ann Oncol,2021,32(7): 936-937. DOI:10.1016/j.annonc.2021.04.006. pmid:33865965
[22]	Tomoaia R, Beyer RS, Pop D, et al. Fatal association of fulminant myocarditis and rhabdomyolysis after immune checkpoint blockade[J].Eur J Cancer,2020,132: 224-227. DOI:10.1016/j.ejca.2020.03.003. pmid:32336614
[23]	Fa'ak F, Buni M, Falohun A, et al. Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events[J].J Immunother Cancer,2023,11(6): e006814. DOI:10.1136/jitc-2023-006814.
[24]	Hryniewicki AT, Wang C, Shatsky RA, et al. Management of immune checkpoint inhibitor toxicities: a review and clinical guideline for emergency physicians[J].J Emerg Med,2018,55(4): 489-502. DOI:10.1016/j.jemermed.2018.07.005. pmid:30120013
[25]	Williams MD, Braun LA, Cooper LM, et al. Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care[J].Crit Care,2004,8(5): R291-R298. DOI:10.1186/cc2893.
[26]	Vermeulen L, Depuydt CE, Weckx P, et al. Myositis as a neuromuscular complication of immune checkpoint inhibitors[J].Acta Neurol Belg,2020,120(2): 355-364. DOI:10.1007/s13760-020-01282-w. pmid:31993961
[27]	Johnson DB, Jakubovic BD, Sibaud V, et al. Balancing cancer immunotherapy efficacy and toxicity[J].J Allergy Clin Immunol Pract,2020,8(9): 2898-2906. DOI:10.1016/j.jaip.2020.06.028. pmid:32599218
[28]	Tang LL, Chen YP, Chen CB, et al. The Chinese Society of Clinical Oncology (CSCO) clinical guidelines for the diagnosis and treatment of nasopharyngeal carcinoma[J].Cancer Commun (Lond),2021,41(11): 1195-1227. DOI:10.1002/cac2.12218.
[29]	Roeland EJ, Bohlke K, Baracos VE, et al. Cancer cachexia: ASCO guideline rapid recommendation update[J].J Clin Oncol,2023,41(25): 4178-4179. DOI:10.1200/JCO.23.01280.
[30]	Pollack MH, Betof A, Dearden H, et al. Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma[J].Ann Oncol,2018,29(1): 250-255. DOI:10.1093/annonc/mdx642. pmid:29045547
[31]	Safa H, Johnson DH, Trinh VA, et al. Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature[J].J Immunother Cancer,2019,7(1): 319. DOI:10.1186/s40425-019-0774-y.
[32]	Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipili-mumab versus ipilimumab in untreated melanoma[J].N Engl J Med,2015,372(21): 2006-2017. DOI:10.1056/NEJMoa1414428.
[33]	Sanlorenzo M, Vujic I, Daud A, et al. Pembrolizumab cutaneous adverse events and their association with disease progression[J].JAMA Dermatol,2015,151(11): 1206-1212. DOI:10.1001/jamadermatol.2015.1916. pmid:26222619
[34]	Indini A, Di Guardo L, Cimminiello C, et al. Immune-related adverse events correlate with improved survival in patients under-going anti-PD1 immunotherapy for metastatic melanoma[J].J Cancer Res Clin Oncol,2019,145(2): 511-521. DOI:10.1007/s00432-018-2819-x. pmid:30539281
[35]	Quach HT, Dewan AK, Davis EJ, et al. Association of anti-programmed cell death 1 cutaneous toxic effects with outcomes in patients with advanced melanoma[J].JAMA Oncol,2019,5(6): 906-908. DOI:10.1001/jamaoncol.2019.0046. pmid:30998826
[36]	Naqash AR, Moey M, Cherie TX, et al. With immune checkpoint inhibitors: a pooled analysis of trials sponsored by the national cancer institute-cancer therapy evaluation program[J].J Clin Oncol,2022,40(29): 3439-3452. DOI:10.1200/JCO.22.00369.
[37]	Maslov DV, Tawagi K, Kc M, et al. Timing of steroid initiation and response rates to immune checkpoint inhibitors in metastatic cancer[J].J Immunother Cancer,2021,9(7): e002261. DOI:10.1136/jitc-2020-002261.
[38]	June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles' heel of cancer immunotherapy?[J].Nat Med,2017,23(5): 540-547. DOI:10.1038/nm.4321. pmid:28475571
[39]	Brown LJ, Weppler A, Bhave P, et al. Combination anti-PD1 and ipilimumab therapy in patients with advanced melanoma and pre-existing autoimmune disorders[J].J Immunother Cancer,2021,9(5): e002121. DOI:10.1136/jitc-2020-002121.
[40]	Halle BR, Betof WA, Zaman FY, et al. Immune checkpoint inhibitors in patients with pre-existing psoriasis: safety and efficacy[J].J immunother cancer,2021,9(10): e003066. DOI:10.1136/jitc-2021-003066.
[41]	Safi M, Ahmed H, Al-Azab M, et al. PD-1/PDL-1 inhibitors and cardiotoxicity; molecular, etiological and management outlines[J].J Adv Res,2021,29: 45-54. DOI:10.1016/j.jare.2020.09.006. pmid:33842004
[42]	Kuo AM, Kraehenbuehl L, King S, et al. Contribution of the skin-gut axis to immune-related adverse events with multi-system involvement[J].Cancers (Basel),2022,14(12): 2995. DOI:10.3390/cancers14122995.
[43]	过慈良, 江春平, 吴俊华. 肠道菌群与肿瘤免疫治疗[J].国际肿瘤学杂志,2023,50(7): 432-436. DOI:10.3760/cma.j.cn371439-20230413-00083.
[44]	Dhodapkar KM, Duffy A, Dhodapkar MV. Role of B cells in immune-related adverse events following checkpoint blockade[J].Immunol Rev,2023,318(1): 89-95. DOI:10.1111/imr.13238. pmid:37421187
[45]	Les I, Martínez M, Narro A, et al. Association of immune-related adverse events induced by nivolumab with a battery of autoantibodies[J].Ann Med,2021,53(1): 762-769. DOI:10.1080/07853890.2021.1931956. pmid:34060971
[46]	Lim SY, Lee JH, Gide TN, et al. Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1-based immunotherapy[J].Clin Cancer Res,2019,25(5): 1557-1563. DOI:10.1158/1078-0432.CCR-18-2795. pmid:30409824
[47]	Kobayashi M, Numakura K, Hatakeyama S, et al. Severe immune-related adverse events in patients treated with nivolumab for metastatic renal cell carcinoma are associated with PDCD1 polymorphism[J].Genes (Basel),2022,13(7): 1204. DOI:10.3390/genes13071204.
[48]	Sung C, An J, Lee S, et al. Integrative analysis of risk factors for immune-related adverse events of checkpoint blockade therapy in cancer[J].Nat Cancer,2023,4(6): 844-859. DOI:10.1038/s43018-023-00572-5.
[49]	Berner F, Bomze D, Lichtensteiger C, et al. Autoreactive napsin A-specific T cells are enriched in lung tumors and inflammatory lung lesions during immune checkpoint blockade[J].Sci Immunol,2022,7(75): eabn9644. DOI:10.1126/sciimmunol.abn9644. pmid:36054337
[50]	Tahir SA, Gao J, Miura Y, et al. Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities[J].Proc Natl Acad Sci U S A,2019,116(44): 22246-22251. DOI:10.1073/pnas.1908079116.