摘要:免疫检查点抑制剂属于单抗类药物,不同于传统的癌症治疗方法,其通过作用于免疫检查点进而获得疗 效,是临床上一种新的尝试。但由于免疫系统过度激活,导致的毒副反应多累及皮肤、胃肠道、肺、内分泌器 官、肝等,虽大多为轻度,但少数中重度毒副反应较易危及生命。因而,对于毒副反应的早期诊断和适当临床管 理显得尤为重要。论文重点对免疫检查点抑制剂在应用过程中的常见毒副反应和管理作一综述,以最大程度保障 其应用的安全性。
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[1] 魏后忆,牛亦农.免疫检查点抑制剂在膀胱癌中的应用[J].肿瘤综 合治疗电子杂志,2020,6(4):69-74
[2] SANMAMED MF, CHEN L. A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization [J]. Cell, 2019,176(3):677
[3] KHOJA L, DAY D, WEI- WU CHEN T, et al. Tumour- and class- specific patterns of immune- related adverse events of immune checkpoint inhibitors: a systematic review [J]. Ann Oncol, 2017,28(10):2377-2385
[4] 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
[5] 付恩锋,王艳,王洁.70例非小细胞肺癌患者免疫检查点抑制剂不 良反应分析及护理对策[J].护理学报,2020,27(14):68-70
[6] EIGENTLER TK, HASSEL JC, BERKING C, et al. Diagnosis, monitoring and management of immune- related adverse drug reactions of anti- PD- 1 antibody therapy [J]. Cancer Treat Rev, 2016,45:7-18
[7] CHAMPIAT S, LAMBOTTE O, BARREAU E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper [J]. Ann Oncol, 2016,27(4):559-574
[8] BRAHMER JR, LACCHETTI C, THOMPSON JA. Management of Immune- Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary [J]. J Oncol Pract, 2018,14(4):247- 249
[9] WILLIAMS KJ, GRAUER DW, HENRY DW, et al. Corticosteroids for the management of immune- related adverse events in patients receiving checkpoint inhibitors [J]. J Oncol Pharm Pract, 2019,25(3):544-550
[10] CURRY JL, TETZLAFF MT, NAGARAJAN P, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy [J]. J Cutan Pathol, 2017,44 (2):158-176
[11] BOUTROS C, TARHINI A, ROUTIER E, et al. Safety profiles of anti- CTLA- 4 and anti- PD- 1 antibodies alone and in combination [J]. Nat Rev Clin On, 2016,13 (8):473-486
[12] KUNIMASA K, ISEI T, NAKAMURA H, et al. Proliferative CD8(+) PD-1(+) T- cell infiltration in a pembrolizumab- induced cutaneous adverse reaction [J]. Invest New Drugs, 2018,36(6):1138-1142
[13] FUJII T, COLEN RR, BILEN MA, et al. Incidence of immune- related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience [J]. Invest New Drugs, 2018,36(4):638-646
[14] WOLCHOK JD, SEIGEL C, WEBER JS, et al. Management of Immune- Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline [J]. J Clin Oncol, 2018,36(17):1714-1768
[15] DE LA ROCHEFOUCAULD J, NOËL N, LAMBOTTE O. Management of immune- related adverse events associated with immune checkpoint inhibitors in cancer patients: a patient- centred approach [J]. Int Emerg Med, 2020,15(4): 587-598
[16] PRIEUX- KLOTZ C, DIOR M, DAMOTTE D, et al. Immune Checkpoint Inhibitor- Induced Colitis: Diagnosis and Management [J]. Targ Oncol, 2017,12(3):301-308
[17] GEUKES FOPPEN MH, ROZEMAN EA, VAN WILPE S, et al. Immune checkpoint inhibition- related colitis: symptoms, endoscopic features, histology and response to management[J]. ESMO Open, 2018,3(1):e278
[18] 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
[19] SOULARUE E, LEPAGE P, COLOMBEL JF, et al. Enterocolitis due to immune checkpoint inhibitors: a systematic review [J]. Gut, 2018,67(11):2056-2067
[20] ROBERT C, RIBAS A, WOLCHOK JD, et al. Antiprogrammed- death- receptor- 1 treatment with pembrolizumab in ipilimumab- refractory advanced melanoma: a randomised dose- comparison cohort of a phase 1 trial [J]. Lancet, 2014,384(9948):1109-1117
[21] GEUKES FOPPEN MH, ROZEMAN EA, VAN WILPE S, et al. Immune checkpoint inhibition- related colitis: symptoms, endoscopic features, histology and response to management[J]. ESMO Open, 2018,3(1):e278
[22] WEBER JS, YANG JC, ATKINS MB, et al. Toxicities of Immunotherapy for the Practitioner [J]. J Clin Oncol, 2015,33(18):2092-2099
[23] BERGQVIST V, HERTERVIG E, GEDEON P, et al. Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis [J]. Cancer Immunol Immunother, 2017, 66(5):581-592
[24] WANG Y, WIESNOSKI DH, HELMINK BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor- associated colitis [J]. Nat Med, 2018, 24(12):1804-1808
[25] NAIDOO J, WANG X, WOO KM, et al. Pneumonitis in Patients Treated With Anti- Programmed Death-1/Programmed Death Ligand 1 Therapy [J]. J Clin Oncol, 2017, 35(7):709-717
[26] KHUNGER M, RAKSHIT S, PASUPULETI V, et al. Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death- Ligand 1 Inhibitors in NonSmall Cell Lung Cancer: A Systematic Review and MetaAnalysis of Trials [J]. Chest, 2017,152(2):271-281
[27] CHUZI S, TAVORA F, CRUZ M, et al. Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor- related pneumonitis [J]. Cancer Manag Res, 2017,9:207-213
[28] MA K, LU Y, JIANG S, et al. The Relative Risk and Incidence of Immune Checkpoint Inhibitors Related Pneumonitis in Patients With Advanced Cancer: A Meta-Analysis [J]. Front Pharmacol, 2018,9:1430
[29] 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
[30] HUFFMAN BM, KOTTSCHADE LA, KAMATH PS, et al. Hepatotoxicity After Immune Checkpoint Inhibitor Therapy in Melanoma [J]. Am J Clin Oncol, 2018,41(8): 760-765
[31] 张文,王旭升,刘云霞,等.免疫检查点抑制剂致免疫介导性肝损 伤研究进展[J].药物不良反应杂志,2021,23(1):30-34
[32] THOMPSON JA, SCHNEIDER BJ, BRAHMER J, et al. Management of Immunotherapy- Related Toxicities, Version 1. 2019, NCCN Clinical Practice Guidelines in Oncology [J]. JNCCN, 2019,17(3):255-289
[33] PARLATI L, VALLET- PICHARD A, BATISTA R, et al. Incidence of grade 3- 4 liver injury under immune checkpoints inhibitors: A retrospective study [J]. J Hepatol, 2018,69(6):1396-1397
[34] PEERAPHATDIT T B, WANGJ, ODENWALD MA, et al. Hepatotoxicity From Immune Checkpoint Inhibitors: A Systematic Review and Management Recommendation [J]. Hepatol, 2020,72(1):315-329
[35] RUGGERI RM, CAMPENNÌ A, GIUFFRIDA G, et al. Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know) [J]. J End Invest, 2019,42(7):745-756
[36] WEBER JS, POSTOW M, LAO CD, et al. Management of Adverse Events Following Treatment With AntiProgrammed Death- 1 Agents [J]. Oncol, 2016,21(10): 1230-1240
[37] CHANG L, BARROSO- SOUSA R, TOLANEY SM, et al. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints [J]. Endocr Rev, 2019,40(1): 17-65
[38] CUKIER P, SANTINI FC, SCARANTI M, et al. Endocrine side effects of cancer immunotherapy [J]. Endocr Relat Cancer, 2017,24(12):T331-T347
[39] ORLOV S, SALARI F, KASHAT L, et al. Induction of Painless Thyroiditis in Patients Receiving Programmed Death 1 Receptor Immunotherapy for Metastatic Malignancies [J]. J Clin Endocrinol Metabol, 2015,100(5):1738- 1741
[40] YAMAUCHI I, SAKANE Y, FUKUDA Y, et al. Clinical Features of Nivolumab- Induced Thyroiditis: A Case Series Study [J]. Thyroid, 2017,27(7):894-901
[41] SCOTT ES, LONG GV, GUMINSKI A, et al. The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma [J]. Eur J Endocrinol, 2018,178(2):173-180
[42] OLSSON- BROWN A, LORD R, SACCO J, et al. Two distinct clinical patterns of checkpoint inhibitor- induced thyroid dysfunction [J]. Endocr Connect, 2020,9(4): 318-325
[43] EGGERMONT AM, CHIARION- SILENI V, GROB JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high- risk stage III melanoma (EORTC 18071): a randomised, double- blind, phase 3 trial [J]. Lancet Oncol, 2015,16(5):522-530
[44] HORVAT TZ, ADEL NG, DANG T, et al. ImmuneRelated Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilim- umab at Memorial Sloan Kettering Cancer Center [J]. J Clin Oncol, 2015,33(28):3193-3198
[45] AGRAWAL L, BACAL A, JAIN S, et al. Immune checkpoint inhibitors and endocrine side effects, a narrative review [J]. Post Med, 2020,132(2):206-214
[46] KOTWAL A, HADDOX C, BLOCK M, et al. Immune checkpoint inhibitors: an emerging cause of insulin- dependent diabetes [J]. BMJ Open Diabetes Res Care, 2019,7(1): e591
[47] BADEN MY, IMAGAWA A, ABIRU N, et al. Characteristics and clinical course of type 1 diabetes mellitus related to anti- programmed cell death-1 therapy [J]. Diabetol Int, 2019,10(1):58-66
[48] THOMPSON JA, SCHNEIDER BJ, BRAHMER J, et al. NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1. 2020 [J]. JNCCN, 2020, 18(3):230-241
[49] BARROSO-SOUSA R, BARRY WT, GARRIDO-CASTRO AC, et al. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta- analysis [J]. JAMA Oncol, 2018,4(2):173-182
[50] WANG F, SUN X, QIN S, et al. A retrospective study of immune checkpoint inhibitor- associated myocarditis in a single center in China [J]. Chin Clin Oncol, 2020,9(2):16
[51] MOSLEHI JJ, SALEM JE, SOSMAN JA, et al. Increased reporting of fatal immune checkpoint inhibitor- associated myocarditis [J]. Lancet, 2018,391(10124):933
[52] MAHMOOD SS, FRADLEY MG, COHEN JV, et al. Myocarditis in patients treated with immune checkpoint inhibitors [J]. J Am Coll Cardiol, 2018,71(16):1755-1764
[53] KWON HJ, COTE TR, CUFFE MS, et, al. Case reports of heart failure after therapy with a tumor necrosis factro antagonist [J]. Ann Intern Med, 2003,138(10):807- 811.
苏非凡,双卫兵. 免疫检查点抑制剂的毒副反应及管理[J]. 泌尿外科杂志(电子版),2021,13(2):73-80. DOI:10.3969/j.issn.1674-7410.2021.02.017.
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近年来,随着免疫检查点抑制剂(immune checkpoint inhibitors,ICIs) 研究的进展,免疫治疗成为 肿瘤治疗的一种新的方式。阿替利珠单抗、德瓦鲁 单抗、阿利库单抗、纳武利尤单抗和帕博利珠单抗 凭借Ⅰ期和Ⅱ期临床试验中的突破性数据,迅速被 FDA 批准用于化疗失败的晚期膀胱癌患者的二线治 疗。2017年,帕博利珠单抗与阿替利珠单抗被批准 用于不适于使用铂类药物的晚期膀胱癌患者的一线 治疗[1] 。随后又陆续研发出了替雷利珠单抗等多种品 种,并且 ICIs 的治疗适应证也在不断增加。然而, ICIs 在提高肿瘤疗效的同时,也可能因其特殊的作 用机制导致免疫系统紊乱发生免疫相关不良事件 (immune- related adverse events, irAEs)。 因 此 , 正确认识 irAEs并恰当处理十分重要。
1 概述
1.1 临床表现
1.2 安全管理
1.2.1 预防
1.2.2 评估
1.2.3 治疗
1.2.4 监测
2 皮肤毒性 (dermal toxicity,DT)
2.1 临床表现
2.2 DT 管理
3 胃肠道毒性 (gastrointestinal toxicity,GT)
3.1 临床表现
3.2 GT 管理
4 肺毒性
4.1 临床表现
4.2 肺毒性管理
5 肝毒性
5.1 临床表现
5.2 肝毒性管理
6 内分泌相关毒性
6.1 甲状腺功能障碍
6.1.1 临床表现
6.1.2 管理
6.2 垂体炎
6.2.1 临床表现
6.2.2 管理
6.3 IDD
6.3.1 临床表现
6.3.2 管理
6.4 PAI
6.4.1 临床表现
6.4.2 管理
7 心脏毒性
7.1 临床表现
7.2 心脏毒性管理
8 结语与展望
8 结语与展望
相对于传统治疗手段来说,ICIs 的耐受性较 好,且大多数 irAEs是轻微症状且可逆的,早期发现 和及时干预,便可减少其毒副反应。但是药物的疗 效是因肿瘤类型和个体之间的不同是存在差异的。 对具体患者而言,并非所有患者都可获益。关于 ICIs 仍有很多有待解决的问题。如何选择合适的治 疗人群、irAEs的发生机制、评估原则、使用原则尚 不清晰,如何避免不良反应也将是今后研究的重点。
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