免疫检查点抑制剂所致肝脏不良反应的研究进展
DOI: 10.3969/j.issn.1001-5256.2022.01.039
利益冲突声明:所有作者均声明不存在利益冲突。
作者贡献声明:王宇负责课题设计,资料分析,撰写论文;李钊颖参与收集数据,修改论文;王宇负责拟定写作思路,刘成海、李爽指导撰写文章并最后定稿。
Research advances in adverse liver reactions caused by immune checkpoint inhibitors
-
摘要: 免疫检查点抑制剂通过阻断T淋巴细胞负性调控信号以达到增强T淋巴细胞抗肿瘤效应的同时,也可能造成免疫耐受失衡或正常免疫亢进从而导致免疫性肝炎。本文主要通过对免疫检查点抑制剂的治疗机制,导致肝损伤的不良反应机制、危险因素以及发生率等方面进行回顾分析,并且对免疫检查点抑制剂导致肝损伤的治疗方法进行初步归纳。认为免疫检查点抑制剂在促进抗肿瘤免疫的同时,由于作用机制的非肿瘤组织靶点特异性,可能造成非同质化的免疫相关的肝损伤,治疗上以恢复免疫稳态为主。因此,免疫检查点抑制剂应用患者的管理往往需要在治疗窗、毒性和特定损伤治疗之间取得平衡,并开展多学科协作。
-
关键词:
- 化学性与药物性肝损伤 /
- 免疫抑制剂 /
- 治疗学
Abstract: Immune checkpoint inhibitors can enhance the anti-tumor effect of T cells by blocking the negative regulatory signal of T cells, and meanwhile, they may also cause the imbalance of immune tolerance or normal immune hyperfunction, thus leading to immune hepatitis. This article mainly reviews the therapeutic mechanism of immune checkpoint inhibitors, their mechanism in causing the adverse reaction of liver injury, related risk factors, and incidence rate and summarizes the treatment methods for liver injury caused by immune checkpoint inhibitors. It is believed that while promoting anti-tumor immunity, immune checkpoint inhibitors may cause non-homogeneous immune-related liver injury due to the specificity of non-tumor tissue targets, and the main purpose of treatment is to restore immune homeostasis. Therefore, the management of patients using immune checkpoint inhibitors often requires a balance between treatment window, toxicity, and treatment of specific injury, as well as multidisciplinary collaboration. -
[1] PRIETO LI, BAKER DJ. Cellular senescence and the immune system in cancer[J]. Gerontology, 2019, 65(5): 505-512. DOI: 10.1159/000500683. [2] ALARD E, BUTNARIU AB, GRILLO M, et al. Advances in anti-cancer immunotherapy: Car-T cell, checkpoint inhibitors, dendritic cell vaccines, and oncolytic viruses, and emerging cellular and molecular targets[J]. Cancers (Basel), 2020, 12(7): 1826. DOI: 10.3390/cancers12071826. [3] HANAHAN D, WEINBERG RA. Hallmarks of cancer: The next generation[J]. Cell, 2011, 144(5): 646-674. DOI: 10.1016/j.cell.2011.02.013. [4] WEI SC, DUFFY CR, ALLISON JP. Fundamental mechanisms of immune checkpoint blockade therapy[J]. Cancer Discov, 2018, 8(9): 1069-1086. DOI: 10.1158/2159-8290.CD-18-0367. [5] THOMPSON JA, SCHNEIDER BJ, BRAHMER J, et al. NCCN guidelines insights: Management of immunotherapy-related toxicities, version 1.2020[J]. J Natl Compr Canc Netw, 2020, 18(3): 230-241. DOI: 10.6004/jnccn.2020.0012. [6] NISHIDA N, KUDO M. Liver damage related to immune checkpoint inhibitors[J]. Hepatol Int, 2019, 13(3): 248-252. DOI: 10.1007/s12072-018-9921-7. [7] TAN JR, HU CP. Fatal adverse events related to immune checkpoint inhibitors and the management strategies[J]. Chin J Pract Intern Med, 2020, 40(4): 340-344. DOI: 10.19538/j.nk2020040116.谭嘉蓉, 胡成平. 免疫检查点抑制剂相关致命性不良反应及管理策略[J]. 中国实用内科杂志, 2020, 40(4): 340-344. DOI: 10.19538/j.nk2020040116. [8] LI L, LI G, RAO B, et al. Landscape of immune checkpoint inhibitor-related adverse events in Chinese population[J]. Sci Rep, 2020, 10(1): 15567. DOI: 10.1038/s41598-020-72649-5. [9] HAANEN J, CARBONNEL F, ROBERT C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2017, 28(suppl_4): iv119-iv142. DOI: 10.1093/annonc/mdx225. [10] KITAGATAYA T, SUDA G, NAGASHIMA K, et al. Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan[J]. J Gastroenterol Hepatol, 2020, 35(10): 1782-1788. DOI: 10.1111/jgh.15041. [11] MIZUNO K, ITO T, ISHIGAMI M, et al. Real world data of liver injury induced by immune checkpoint inhibitors in Japanese patients with advanced malignancies[J]. J Gastroenterol, 2020, 55(6): 653-661. DOI: 10.1007/s00535-020-01677-9. [12] ALESSANDRINO F, TIRUMANI SH, KRAJEWSKI KM, et al. Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: Chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors[J]. Clin Radiol, 2017, 72(7): 521-533. DOI: 10.1016/j.crad.2017.04.003. [13] WANG W, LIE P, GUO M, et al. Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis of published data[J]. Int J Cancer, 2017, 141(5): 1018-1028. DOI: 10.1002/ijc.30678. [14] YAMAMOTO A, YANO Y, UEDA Y, et al. Clinical features of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers[J]. J Cancer Res Clin Oncol, 2021, 147(6): 1747-1756. DOI: 10.1007/s00432-020-03448-8. [15] de MARTIN E, MICHOT JM, ROSMORDUC O, et al. Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors[J]. JHEP Rep, 2020, 2(6): 100170. DOI: 10.1016/j.jhepr.2020.100170. [16] SAWADA K, HAYASHI H, NAKAJIMA S, et al. Non-alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor[J]. J Gastroenterol Hepatol, 2020, 35(6): 1042-1048. DOI: 10.1111/jgh.14889. [17] CHOWELL D, MORRIS L, GRIGG CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy[J]. Science, 2018, 359(6375): 582-587. DOI: 10.1126/science.aao4572. [18] CHENG AL, HSU C, CHAN SL, et al. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma[J]. J Hepatol, 2020, 72(2): 307-319. DOI: 10.1016/j.jhep.2019.09.025. [19] POSTOW MA, SIDLOW R, HELLMANN MD. Immune-Related adverse events associated with immune checkpoint blockade[J]. N Engl J Med, 2018, 378(2): 158-168. DOI: 10.1056/NEJMra1703481. [20] FESSAS P, POSSAMAI LA, CLARK J, et al. Immunotoxicity from checkpoint inhibitor therapy: Clinical features and underlying mechanisms[J]. Immunology, 2020, 159(2): 167-177. DOI: 10.1111/imm.13141. [21] MALNICK SDH, ABDULLAH A, NEUMAN MG. Checkpoint inhibitors and hepatotoxicity[J]. Biomedicines, 2021, 9(2): 101. DOI: 10.3390/biomedicines9020101. [22] LOMBARDI A, MONDELLI MU. Review article: Immune checkpoint inhibitors and the liver, from therapeutic efficacy to side effects[J]. Aliment Pharmacol Ther, 2019, 50(8): 872-884. DOI: 10.1111/apt.15449. [23] HSU C, MARSHALL JL, HE AR. Workup and management of immune-mediated hepatobiliary pancreatic toxicities that develop during immune checkpoint inhibitor treatment[J]. Oncologist, 2020, 25(2): 105-111. DOI: 10.1634/theoncologist.2018-0162. [24] HAGIWARA S, WATANABE T, KUDO M, et al. Clinicopathological analysis of hepatic immune-related adverse events in comparison with autoimmune hepatitis and graft-versus host disease[J]. Sci Rep, 2021, 11(1): 9242. DOI: 10.1038/s41598-021-88824-1. [25] AFFOLTER T, LLEWELLYN HP, BARTLETT DW, et al. Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice[J]. PLoS One, 2019, 14(5): e0217276. DOI: 10.1371/journal.pone.0217276. [26] LOMBARDI A, MONDELLI MU. Review article: Immune checkpoint inhibitors and the liver, from therapeutic efficacy to side effects[J]. Aliment Pharmacol Ther, 2019, 50(8): 872-884. DOI: 10.1111/apt.15449. [27] NISHIDA N, KUDO M. Liver damage related to immune checkpoint inhibitors[J]. Hepatol Int, 2019, 13(3): 248-252. DOI: 10.1007/s12072-018-9921-7. [28] de MARTIN E, MICHOT JM, PAPOUIN B, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors[J]. J Hepatol, 2018, 68(6): 1181-1190. DOI: 10.1016/j.jhep.2018.01.033. [29] KARAMCHANDANI DM, CHETTY R. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: Pathologists' perspective[J]. J Clin Pathol, 2018, 71(8): 665-671. DOI: 10.1136/jclinpath-2018-205143. [30] KAWAKAMI H, TANIZAKI J, TANAKA K, et al. Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer[J]. Invest New Drugs, 2017, 35(4): 529-536. DOI: 10.1007/s10637-017-0453-0. [31] ZEN Y, CHEN YY, JENG YM, et al. Immune-related adverse reactions in the hepatobiliary system: Second-generation check-point inhibitors highlight diverse histological changes[J]. Histopathology, 2020, 76(3): 470-480. DOI: 10.1111/his.14000. [32] ZHANG QY, CHEN LL, GAO F, et al. Pathological features of immune-mediated hepatitis due to immune checkpoint inhibitors and anti-angiogenesis targeted therapy[J]. Chin J Pathol, 2020, 49(4): 329-335. DOI: 10.3760/cma.j.cn112151-20190720-00403.章琼燕, 陈伶俐, 高峰, 等. 免疫检查点抑制剂治疗后肝功能异常的组织病理学分析[J]. 中华病理学杂志, 2020, 49(4): 329-335. DOI: 10.3760/cma.j.cn112151-20190720-00403. [33] JOHNCILLA M, MISDRAJI J, PRATT DS, et al. Ipilimumab-associated hepatitis: Clinicopathologic characterization in a series of 11 cases[J]. Am J Surg Pathol, 2015, 39(8): 1075-1084. DOI: 10.1097/PAS.0000000000000453. [34] Drug-induced Liver Disease Study Group, Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the management of drug-induced liver injury[J]. J Clin Hepatol, 2015, 31(11): 1752-1769. DOI: 10.3969/j.issn.1001-5256.2015.11.002.中华医学会肝病学分会药物性肝病学组. 药物性肝损伤诊治指南[J]. 临床肝胆病杂志, 2015, 31(11): 1752-1769. DOI: 10.3969/j.issn.1001-5256.2015.11.002. [35] ESFAHANI K, CALABRESE L. Reply to 'Personalized treatment of immune-related adverse events-balance is required'[J]. Nat Rev Clin Oncol, 2020, 17(8): 518. DOI: 10.1038/s41571-020-0401-3. [36] Guidelines Working Committee of the Chinese Society of Clinical Oncology. Guidelines for the management of toxicity related to immune checkpoint inhibitors of the Chinese Society of Clinical Oncology (CSCO)[M]. Beijing: People's Medical Publishing House, 2019: 1-116.中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)免疫检查点抑制剂相关的毒性管理指南[M]. 北京: 人民卫生出版社, 2019: 1-116. [37] POSTOW MA. Managing immune checkpoint-blocking antibody side effects[J]. Am Soc Clin Oncol Educ Book, 2015 : 76-83. DOI: 10.14694/EdBook_AM.2015.35.76. [38] LU JF, PENG Z, ZHU XG, et al. Immune checkpoint inhibitor related hepatotoxicity[J/CD]. Chin J Liver Dis (Electronic Version), 2021, 13(2): 1-5. DOI: 10.3969/j.issn.1674-7380.2021.02.001.鲁俊锋, 彭智, 朱向高, 等. 免疫检查点抑制剂相关肝毒性[J/CD]. 中国肝脏病杂志(电子版), 2021, 13(2): 1-5. DOI: 10.3969/j.issn.1674-7380.2021.02.001. [39] NAKANO K, NISHIZAWA M, FUKUDA N, et al. Mycophenolate mofetil as a successful treatment of corticosteroid-resistant immune checkpoint inhibitor-induced hepatitis[J]. Oxf Med Case Reports, 2020, 2020(4): omaa027. DOI: 10.1093/omcr/omaa027. [40] MCGUIRE HM, SHKLOVSKAYA E, EDWARDS J, et al. Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: A case report[J]. Cancer Immunol Immunother, 2018, 67(4): 563-573. DOI: 10.1007/s00262-017-2107-7. [41] ZHANG N, LIU XL, XU ZQ, et al. Research progress in relationship between tumor anti-angiogenesis and immunotherapy[J]. J Jilin Univ(Med Edit), 2021, 47(4): 1056-1063. DOI: 10.13481/j.1671-587X.20210434.张娜, 刘相良, 徐志强, 等. 肿瘤抗血管生成及其与免疫治疗关系的研究进展[J]. 吉林大学学报(医学版), 2021, 47(4): 1056-1063. DOI: 10.13481/j.1671-587X.20210434.
本文二维码
计量
- 文章访问数: 1283
- HTML全文浏览量: 227
- PDF下载量: 249
- 被引次数: 0