免疫检查点抑制剂所致肝损伤的诊断和治疗进展
The Advancement in Diagnosis and Therapy of Liver Injury Induced by Immune Checkpoint Inhibitors
DOI: 10.12677/ACM.2021.1110680, PDF,   
作者: 沈致文, 万赤丹*:华中科技大学同济医学院附属协和医院肝胆外科,湖北 武汉
关键词: 免疫检查点抑制剂免疫不良反应肝损伤Immune Checkpoint Inhibitors Immune-Related Adverse Effects Liver Injury
摘要: 以免疫检查点抑制剂为代表的免疫疗法应用在多种进展期实体肿瘤的治疗中,展现出了良好的前景。免疫相关不良反应的发生也随着免疫检查点抑制剂的应用逐渐上升。免疫检查点抑制剂所致肝损伤是与免疫治疗相关的重要不良反应之一,可能造成严重不良预后。本篇综述主要讨论免疫检查点抑制剂相关肝损伤的流行病学,机制及诊治进展。
Abstract: The application of immunotherapy in the treatment of multiple advanced tumors, represented by immune checkpoint inhibitors (ICIs), has demonstrated promising prospects. However, the rates of immune-related adverse effects are gradually increasing with the application of ICIs. Liver injury induced by immune checkpoint inhibitors is a major adverse effect related to immunotherapy, which may lead to poor prognosis. This review aims to discuss the advancement in epidemiology, mechanism, diagnosis and therapy of ICIs-induced liver injury.
文章引用:沈致文, 万赤丹. 免疫检查点抑制剂所致肝损伤的诊断和治疗进展[J]. 临床医学进展, 2021, 11(10): 4628-4634. https://doi.org/10.12677/ACM.2021.1110680

参考文献

[1] Johnson, D.B., et al. (2016) Fulminant Myocarditis with Combination Immune Checkpoint Blockade. The New England Journal of Medicine, 375, 1749-1755. [Google Scholar] [CrossRef
[2] Morgado, M., et al. (2020) Management of the Adverse Effects of Immune Checkpoint Inhibitors. Vaccines (Basel), 8, 575. [Google Scholar] [CrossRef] [PubMed]
[3] Ramos-Casals, M., et al. (2020) Immune-Related Adverse Events of Checkpoint Inhibitors. Nature Reviews Disease Primers, 6, 38. [Google Scholar] [CrossRef] [PubMed]
[4] Bagchi, S., Yuan, R. and Engleman, E.G. (2021) Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annual Review of Pathology: Mechanisms of Disease, 16, 223-249. [Google Scholar] [CrossRef] [PubMed]
[5] Wang, R., Lin, N., Mao, B.B. and Wu, Q. (2021) The Efficacy of Immune Checkpoint Inhibitors in Advanced Hepatocellular Carcinoma: A Meta-Analysis Based on 40 Cohorts Incorporating 3697 Individuals. Journal of Cancer Research and Clinical Oncology. [Google Scholar] [CrossRef] [PubMed]
[6] Finn, R.S., et al. (2020) Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. The New England Journal of Medicine, 382, 1894-1905. [Google Scholar] [CrossRef
[7] Abu-Sbeih, H. and Wang, Y. (2020) Hepatobiliary Adverse Events. Advances in Experimental Medicine and Biology, 1244, 271-276. [Google Scholar] [CrossRef] [PubMed]
[8] Brahmer, J.R., et al. (2018) Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology, 36, 1714-1768. [Google Scholar] [CrossRef
[9] Wolchok, J.D., et al. (2017) Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. The New England Journal of Medicine, 377, 1345-1356. [Google Scholar] [CrossRef
[10] Mok, T.S.K., et al. (2019) Pembrolizumab versus Chemotherapy for Previously Untreated, PD-L1-Expressing, Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (KEYNOTE-042): A Randomised, Open-Label, Controlled, Phase 3 Trial. The Lancet, 393, 1819-1830. [Google Scholar] [CrossRef
[11] Rini, B.I., et al. (2019) Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. The New England Journal of Medicine, 380, 1116-1127. [Google Scholar] [CrossRef
[12] El-Khoueiry, A.B., et al. (2017) Nivolumab in Patients with Advanced Hepatocellular Carcinoma (CheckMate 040): An Open-Label, Non-Comparative, Phase 1/2 Dose Escalation and Expansion Trial. The Lancet, 389, 2492-2502. [Google Scholar] [CrossRef
[13] Zhu, A.X., et al. (2018) Pembrolizumab in Patients with Advanced Hepatocellular Carcinoma Previously Treated with Sorafenib (KEYNOTE-224): A Non-Randomised, Open-Label Phase 2 Trial. The Lancet Oncology, 19, 940-952. [Google Scholar] [CrossRef
[14] Duffy, A.G., et al. (2017) Tremelimumab in Combination with Ablation in Patients with Advanced Hepatocellular Carcinoma. Journal of Hepatology, 66, 545-551. [Google Scholar] [CrossRef] [PubMed]
[15] Kitagataya, T., et al. (2020) Prevalence, Clinical Course, and Predictive Factors of Immune Checkpoint Inhibitor Monotherapy-Associated Hepatitis in Japan. Journal of Gastroenterology and Hepatology, 35, 1782-1788. [Google Scholar] [CrossRef] [PubMed]
[16] De Martin, E., Michot, J.-M., Rosmorduc, O., Guettier, C. and Samuel, D. (2020) Liver Toxicity as a Limiting Factor to the Increasing Use of Immune Checkpoint Inhibitors. JHEP Reports, 2, Article ID: 100170. [Google Scholar] [CrossRef] [PubMed]
[17] Daniello, L., et al. (2021) Therapeutic and Prognostic Implications of Immune-Related Adverse Events in Advanced Non-Small-Cell Lung Cancer. Frontiers in Oncology, 11, Article ID: 703893. [Google Scholar] [CrossRef] [PubMed]
[18] Zhong, L., Wu, Q., Chen, F.C., Liu, J.J. and Xie, X.H. (2021) Immune-Related Adverse Events: Promising Predictors for Efficacy of Immune Checkpoint Inhibitors. Cancer Immunology, Immunotherapy, 70, 2559-2576. [Google Scholar] [CrossRef] [PubMed]
[19] Yokohama, K., et al. (2020) Liver Dysfunction Is Associated with Poor Prognosis in Patients after Immune Checkpoint Inhibitor Therapy. Scientific Reports, 10, Article No. 14470. [Google Scholar] [CrossRef] [PubMed]
[20] Affolter, T., et al. (2019) Inhibition of Immune Checkpoints PD-1, CTLA-4, and IDO1 Coordinately Induces Immune-Mediated Liver Injury in Mice. PLoS ONE, 14, e0217276. [Google Scholar] [CrossRef] [PubMed]
[21] Fessas, P., et al. (2019) Immunotoxicity from Checkpoint Inhibitor Therapy: Clinical Features and Underlying Mechanisms. Immunology, 159, 167-177. [Google Scholar] [CrossRef] [PubMed]
[22] Mizuno, K., et al. (2020) Real World Data of Liver Injury Induced by Immune Checkpoint Inhibitors in Japanese Patients with Advanced Malignancies. Journal of Gastroenterology, 55, 653-661. [Google Scholar] [CrossRef] [PubMed]
[23] Zen, Y., et al. (2020) Immune-Related Adverse Reactions in the Hepatobiliary System: Second-Generation Check-Point Inhibitors Highlight Diverse Histological Changes. Histopathology, 76, 470-480. [Google Scholar] [CrossRef] [PubMed]
[24] Pi, B., et al. (2021) Immune-Related Cholangitis Induced by Immune Checkpoint Inhibitors: A Systematic Review of Clinical Features and Management. European Journal of Gastroenterology & Hepatology. [Google Scholar] [CrossRef
[25] Kawakami, H., et al. (2017) Imaging and Clinicopathological Features of Nivolumab-Related Cholangitis in Patients with Non-Small Cell Lung Cancer. Investigational New Drugs, 35, 529-536. [Google Scholar] [CrossRef] [PubMed]
[26] Onoyama, T., et al. (2020) Programmed Cell Death-1 Inhibitor-Related Sclerosing Cholangitis: A Systematic Review. World Journal of Gastroenterology, 26, 353-365. [Google Scholar] [CrossRef] [PubMed]
[27] Takinami, M., et al. (2021) Comparison of Clinical Features between Immune-Related Sclerosing Cholangitis and Hepatitis. Investigational New Drugs. [Google Scholar] [CrossRef] [PubMed]
[28] Denaro, N., et al. (2021) Unusual Fatal Outcome Following Administration of a Combination of Anti-PD1 and Anti-CTLA4 in Metastatic Renal Cell Carcinoma: Liver Toxicity Case Report and a Literature Review. European Journal of Case Reports in Internal Medicine, 8, Article ID: 002639. [Google Scholar] [CrossRef] [PubMed]
[29] Suzman, D.L., Pelosof, L., Rosenberg, A. and Avigan, M.I. (2018) Hepatotoxicity of Immune Checkpoint Inhibitors: An Evolving Picture of Risk Associated with a Vital Class of Immunotherapy Agents. Liver International, 38, 976-987. [Google Scholar] [CrossRef] [PubMed]
[30] Couey, M.A., et al. (2019) Delayed Immune-Related Events (DIRE) after Discontinuation of Immunotherapy: Diagnostic Hazard of Autoimmunity at a Distance. Journal for ImmunoTherapy of Cancer, 7, Article No. 165. [Google Scholar] [CrossRef] [PubMed]
[31] Tsung, I., et al. (2019) Liver Injury Is Most Commonly Due to Hepatic Metastases Rather than Drug Hepatotoxicity during Pembrolizumab Immunotherapy. Alimentary Pharmacology & Therapeutics, 50, 800-808. [Google Scholar] [CrossRef] [PubMed]
[32] Slawinski, G., et al. (2020) Immune Checkpoint Inhibitors and Cardiac Toxicity in Patients Treated for Non-Small Lung Cancer: A Review. International Journal of Molecular Sciences, 21, 7195. [Google Scholar] [CrossRef] [PubMed]
[33] Vani, V., Regge, D., Cappello, G., Gabelloni, M. and Neri, E. (2020) Imaging of Adverse Events Related to Checkpoint Inhibitor Therapy. Diagnostics (Basel), 10, 216. [Google Scholar] [CrossRef] [PubMed]
[34] Michot, J.M., et al. (2016) Immune-Related Adverse Events with Immune Checkpoint Blockade: A Comprehensive Review. European Journal of Cancer, 54, 139-148. [Google Scholar] [CrossRef] [PubMed]
[35] Xu, Y., Fu, Y., Zhu, B., Wang, J. and Zhang, B.C. (2020) Predictive Biomarkers of Immune Checkpoint Inhibitors-Related Toxicities. Frontiers in Immunology, 11, 2023. [Google Scholar] [CrossRef] [PubMed]
[36] Shahabi, V., et al. (2013) Gene Expression Profiling of Whole Blood in Ipilimumab-Treated Patients for Identification of Potential Biomarkers of Immune-Related Gastrointestinal Adverse Events. Journal of Translational Medicine, 11, 75. [Google Scholar] [CrossRef] [PubMed]
[37] Valpione, S., et al. (2018) Sex and Interleukin-6 Are Prognostic Factors for Autoimmune Toxicity Following Treatment with Anti-CTLA4 Blockade. Journal of Translational Medicine, 16, 94. [Google Scholar] [CrossRef] [PubMed]
[38] Chaput, N., et al. (2019) Baseline Gut Microbiota Predicts Clinical Response and Colitis in Metastatic Melanoma Patients Treated with Ipilimumab. Annals of Oncology, 30, 2012. [Google Scholar] [CrossRef] [PubMed]
[39] Pollack, M.H., et al. (2018) 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. Annals of Oncology, 29, 250-255. [Google Scholar] [CrossRef] [PubMed]
[40] Weber, J., et al. (2016) Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab. Cancer Immunology Research, 4, 345-353. [Google Scholar] [CrossRef
[41] Simonaggio, A., et al. (2019) Evaluation of Readministration of Immune Checkpoint Inhibitors after Immune-Related Adverse Events in Patients with Cancer. JAMA Oncology, 5, 1310-1317. [Google Scholar] [CrossRef] [PubMed]
[42] Puzanov, I., et al. (2017) Managing Toxicities Associated with Immune Checkpoint Inhibitors: Consensus Recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. Journal for ImmunoTherapy of Cancer, 5, 95. [Google Scholar] [CrossRef] [PubMed]
[43] Gauci, M.L., et al. (2018) Immune-Related Hepatitis with Immunotherapy: Are Corticosteroids Always Needed? Journal of Hepatology, 69, 548-550. [Google Scholar] [CrossRef] [PubMed]
[44] De Martin, E., et al. (2018) Characterization of Liver Injury Induced by Cancer Immunotherapy Using Immune Checkpoint Inhibitors. Journal of Hepatology, 68, 1181-1190. [Google Scholar] [CrossRef] [PubMed]
[45] Lombardi, A. and Mondelli, M.U. (2019) Review Article: Immune Checkpoint Inhibitors and the Liver, from Therapeutic Efficacy to Side Effects. Alimentary Pharmacology & Therapeutics, 50, 872-884. [Google Scholar] [CrossRef] [PubMed]
[46] Araujo, D.V., et al. (2021) Real World Outcomes and Hepatotoxicity of Infliximab in the Treatment of Steroid-Refractory Immune-Related Adverse Events. Current Oncology, 28, 2173-2179. [Google Scholar] [CrossRef] [PubMed]