|
|
免疫检查点抑制剂不良反应的诊断与处理
|
Abstract:
近十年，免疫疗法的兴起为癌症病人带来了福音，特别是免疫检查点抑制剂(Immune checkpoint inhibitors, ICIs)彻底开拓了癌症治疗的新局面。免疫疗法的主要目标是使抗肿瘤细胞恢复和加强免疫识别及消除恶性肿瘤细胞的能力，其中以细胞毒性T淋巴细胞相关蛋白4 (Cytotoxic T lymphocyte associated antigen4, CTLA-4)和程序性死亡蛋白-1 (Programmed death protein1, PD-1)、程序性死亡蛋白配体-1 (Programmed death protein ligand-1, PD-L1)为代表药物。随着越来越多ICIs药物在临床获批使用，获益同时，伴随的是产生一系列的免疫相关不良事件(Immune-related adverse events, irAEs)，临床约40%的肿瘤患者使用ICIs后会出现皮疹、肺炎、结肠炎、肝炎、甲状腺炎等各种irAEs。其中皮肤、肠道、内分泌、肺部和肌肉骨骼系统的irAEs相对常见，而心血管、血液、肾脏、神经和眼部的irAEs则较为少见，因此需要临床医生高度警惕。本文对ICIs引起的相关不良反应，按系统分类进行综述，目的使临床医生对irAEs的临床表现、诊断与处理以全面了解。
Over the past decade, the emergence of immunotherapy has brought new hope to cancer patients, particularly as immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment. The primary objective of immunotherapy is to restore and enhance the ability of antitumor cells to recognize and eliminate malignant cells, with cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), programmed death protein-1 (PD-1), and programmed death protein ligand-1 (PD-L1) serving as representative therapeutic targets. However, alongside the increasing clinical approval and utilization of ICIs, their benefits are accompanied by a spectrum of immune-related adverse events (irAEs). Approximately 40% of cancer patients receiving ICIs develop various irAEs, including rash, pneumonitis, colitis, hepatitis, and thyroiditis. Cutaneous, gastrointestinal, endocrine, pulmonary, and musculoskeletal irAEs are relatively common, while cardiovascular, hematologic, renal, neurological, and ocular irAEs occur less frequently, necessitating heightened clinical vigilance. This review systematically categorizes and summarizes ICI-associated adverse reactions by affected organ systems, aiming to provide clinicians with a comprehensive understanding of the clinical manifestations, diagnosis, and management of irAEs.
| [1] | Martins, F., Sofiya, L., Sykiotis, G.P., Lamine, F., Maillard, M., Fraga, M., et al. (2019) Adverse Effects of Immune-Checkpoint Inhibitors: Epidemiology, Management and Surveillance. Nature Reviews Clinical Oncology, 16, 563-580. https://doi.org/10.1038/s41571-019-0218-0 |
| [2] | 梅文通, 王雪莹, 邢晓芳, 等. 肿瘤免疫治疗进展及前沿方向[J]. 中国科学基金, 2025, 39(1): 60-69. |
| [3] | Wright, J.J., Powers, A.C. and Johnson, D.B. (2021) Endocrine Toxicities of Immune Checkpoint Inhibitors. Nature Reviews Endocrinology, 17, 389-399. https://doi.org/10.1038/s41574-021-00484-3 |
| [4] | Ramos-Casals, M., Brahmer, J.R., Callahan, M.K., Flores-Chávez, A., Keegan, N., Khamashta, M.A., et al. (2020) Immune-Related Adverse Events of Checkpoint Inhibitors. Nature Reviews Disease Primers, 6, Article No. 38. https://doi.org/10.1038/s41572-020-0160-6 |
| [5] | 李哲, 孙一琦, 何超然, 等. 某院PD-1免疫检查点抑制剂致不良反应的发生情况及分析[J]. 中南药学, 2021, 19(9): 1942-1946. |
| [6] | Quach, H.T., Johnson, D.B., LeBoeuf, N.R., Zwerner, J.P. and Dewan, A.K. (2021) Cutaneous Adverse Events Caused by Immune Checkpoint Inhibitors. Journal of the American Academy of Dermatology, 85, 956-966. https://doi.org/10.1016/j.jaad.2020.09.054 |
| [7] | Collins, L.K., Chapman, M.S., Carter, J.B. and Samie, F.H. (2017) Cutaneous Adverse Effects of the Immune Checkpoint Inhibitors. Current Problems in Cancer, 41, 125-128. https://doi.org/10.1016/j.currproblcancer.2016.12.001 |
| [8] | Thompson, J.A., Schneider, B.J., Brahmer, J., Achufusi, A., Armand, P., Berkenstock, M.K., et al. (2022) Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network, 20, 387-405. https://doi.org/10.6004/jnccn.2022.0020 |
| [9] | Malviya, N., Tattersall, I.W., Leventhal, J. and Alloo, A. (2020) Cutaneous Immune-Related Adverse Events to Checkpoint Inhibitors. Clinics in Dermatology, 38, 660-678. https://doi.org/10.1016/j.clindermatol.2020.06.011 |
| [10] | Kröner, P.T., Mody, K. and Farraye, F.A. (2019) Immune Checkpoint Inhibitor–related Luminal GI Adverse Events. Gastrointestinal Endoscopy, 90, 881-892. https://doi.org/10.1016/j.gie.2019.09.009 |
| [11] | Lui, R.N. and Chan, S.L. (2021) Management of Gastrointestinal Side Effects of Immune Checkpoint Inhibitors. Clinical Gastroenterology and Hepatology, 19, 2262-2265. https://doi.org/10.1016/j.cgh.2021.06.038 |
| [12] | Rocha, M., Correia de Sousa, J., Salgado, M., Araújo, A. and Pedroto, I. (2018) Management of Gastrointestinal Toxicity from Immune Checkpoint Inhibitor. GE—Portuguese Journal of Gastroenterology, 26, 268-274. https://doi.org/10.1159/000494569 |
| [13] | Rajha, E., Chaftari, P., Kamal, M., Maamari, J., Chaftari, C. and Yeung, S.J. (2019) Gastrointestinal Adverse Events Associated with Immune Checkpoint Inhibitor Therapy. Gastroenterology Report, 8, 25-30. https://doi.org/10.1093/gastro/goz065 |
| [14] | Jin, K., Wang, S., Ying, X., Lan, H., Lv, J., Zhang, L., et al. (2020) Immune-Mediated Adverse Effects of Immune-Checkpoint Inhibitors and Their Management in Cancer. Immunology Letters, 221, 61-71. https://doi.org/10.1016/j.imlet.2020.02.008 |
| [15] | Ball, S., Ghosh, R.K., Wongsaengsak, S., Bandyopadhyay, D., Ghosh, G.C., Aronow, W.S., et al. (2019) Cardiovascular Toxicities of Immune Checkpoint Inhibitors: JACC Review Topic of the Week. Journal of the American College of Cardiology, 74, 1714-1727. https://doi.org/10.1016/j.jacc.2019.07.079 |
| [16] | Drobni, Z.D., Alvi, R.M., Taron, J., Zafar, A., Murphy, S.P., Rambarat, P.K., et al. (2020) Association between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaque. Circulation, 142, 2299-2311. https://doi.org/10.1161/circulationaha.120.049981 |
| [17] | Delaunay, M., Prévot, G., Collot, S., Guilleminault, L., Didier, A. and Mazières, J. (2019) Management of Pulmonary Toxicity Associated with Immune Checkpoint Inhibitors. European Respiratory Review, 28, Article ID: 190012. https://doi.org/10.1183/16000617.0012-2019 |
| [18] | Baik, A.H., Tsai, K.K., Oh, D.Y. and Aras, M.A. (2021) Mechanisms and Clinical Manifestations of Cardiovascular Toxicities Associated with Immune Checkpoint Inhibitors. Clinical Science, 135, 703-724. https://doi.org/10.1042/cs20200331 |
| [19] | Thuny, F., Naidoo, J. and Neilan, T.G. (2022) Cardiovascular Complications of Immune Checkpoint Inhibitors for Cancer. European Heart Journal, 43, 4458-4468. https://doi.org/10.1093/eurheartj/ehac456 |
| [20] | Salem, J., Allenbach, Y., Vozy, A., Brechot, N., Johnson, D.B., Moslehi, J.J., et al. (2019) Abatacept for Severe Immune Checkpoint Inhibitor-Associated Myocarditis. New England Journal of Medicine, 380, 2377-2379. https://doi.org/10.1056/nejmc1901677 |
| [21] | Cardona, Z., Sosman, J.A., Chandra, S., et al. (2023) Endocrine Side Effects of Immune Checkpoint Inhibitors. Frontiers in Endocrinology, 14, Article 1157805. https://doi.org/10.3389/fendo.2023.1157805 |
| [22] | Duan, L., Wang, L., Wang, H., Si, X., Zhang, L., Liu, X., et al. (2020) Clinical Diagnosis and Treatment of Immune Checkpoint Inhibitors‐Related Endocrine Dysfunction. Thoracic Cancer, 11, 1099-1104. https://doi.org/10.1111/1759-7714.13347 |
| [23] | Chieng, J.H.L., Htet, Z.W., Zhao, J.J., et al. (2022) Clinical Presentation of Immune-Related Endocrine Adverse Events during Immune Checkpoint Inhibitor Treatment. Cancers, 14, 2687. https://doi.org/10.3390/cancers14112687 |
| [24] | Mai, K., Fassnacht, M., Führer-Sakel, D., Honegger, J.B., Weber, M.M. and Kroiss, M. (2021) The Diagnosis and Management of Endocrine Side Effects of Immune Checkpoint Inhibitors. Deutsches Ärzteblatt international, 118, 389-396. https://doi.org/10.3238/arztebl.m2021.0143 |
| [25] | Cuzzubbo, S., Javeri, F., Tissier, M., Roumi, A., Barlog, C., Doridam, J., et al. (2017) Neurological Adverse Events Associated with Immune Checkpoint Inhibitors: Review of the Literature. European Journal of Cancer, 73, 1-8. https://doi.org/10.1016/j.ejca.2016.12.001 |
| [26] | Haugh, A.M., Probasco, J.C. and Johnson, D.B. (2020) Neurologic Complications of Immune Checkpoint Inhibitors. Expert Opinion on Drug Safety, 19, 479-488. https://doi.org/10.1080/14740338.2020.1738382 |
| [27] | Kramer, R., Zaremba, A., Moreira, A., et al. (2021) Hematological Immune Related Adverse Events after Treatment with Immune Checkpoint Inhibitors. European Journal of Cancer, 147, 170-181. |
| [28] | Shahzad, O., Thompson, N., Clare, G., Welsh, S., Damato, E. and Corrie, P. (2021) Ocular Adverse Events Associated with Immune Checkpoint Inhibitors: A Novel Multidisciplinary Management Algorithm. Therapeutic Advances in Medical Oncology, 13, 1-12. https://doi.org/10.1177/1758835921992989 |
| [29] | Chaudot, F., Sève, P., Rousseau, A., Maria, A.T.J., Fournie, P., Lozach, P., et al. (2022) Ocular Inflammation Induced by Immune Checkpoint Inhibitors. Journal of Clinical Medicine, 11, Article 4993. https://doi.org/10.3390/jcm11174993 |
| [30] | Albitar, H.A.H., Duma, N., Leventakos, K. and Gallo De Moraes, A. (2020) Pulmonary Complications Secondary to Immune Checkpoint Inhibitors. International Journal of Chronic Diseases, 2020, Article ID: 4928648. https://doi.org/10.1155/2020/4928648 |
| [31] | Cadranel, J., Canellas, A., Matton, L., et al. (2019) Pulmonary Complications of Immune Checkpoint Inhibitors in Patients with Non Small Cell Lung Cancer. European Respiratory Review: An Official Journal of the European Respiratory Society, 28, Article 190058. https://doi.org/10.1183/16000617.0058-2019 |
| [32] | Espi, M., Teuma, C., Novel-Catin, E., Maillet, D., Souquet, P.J., Dalle, S., et al. (2021) Renal Adverse Effects of Immune Checkpoints Inhibitors in Clinical Practice: Immunotox Study. European Journal of Cancer, 147, 29-39. https://doi.org/10.1016/j.ejca.2021.01.005 |
| [33] | Hu, R., Chen, M., Xu, Y., Wang, M., Zheng, K. and Li, X. (2020) Renal Immune‐Related Adverse Events of Immune Checkpoint Inhibitor. Asia-Pacific Journal of Clinical Oncology, 16, 305-311. https://doi.org/10.1111/ajco.13387 |
| [34] | Kostine, M., Finckh, A., Bingham, C.O., Visser, K., Leipe, J., Schulze-Koops, H., et al. (2021) EULAR Points to Consider for the Diagnosis and Management of Rheumatic Immune-Related Adverse Events Due to Cancer Immunotherapy with Checkpoint Inhibitors. Annals of the Rheumatic Diseases, 80, 36-48. https://doi.org/10.1136/annrheumdis-2020-217139 |
| [35] | Suarez-Almazor, M.E., Pundole, X., Abdel-Wahab, N., Johnson, D.B., Gupta, D., Glezerman, I., et al. (2020) Multinational Association of Supportive Care in Cancer (MASCC) 2020 Clinical Practice Recommendations for the Management of Immune-Mediated Cardiovascular, Rheumatic, and Renal Toxicities from Checkpoint Inhibitors. Supportive Care in Cancer, 28, 6159-6173. https://doi.org/10.1007/s00520-020-05710-8 |
