Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis.
Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis.
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DOI：
10.1186/s12916-015-0455-8
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发表时间：
2015-09-04
期刊：
影响因子：
9.3
通讯作者：
Schaeverbeke T
中科院分区：
文献类型：
--
作者：
Bertrand A;Kostine M;Barnetche T;Truchetet ME;Schaeverbeke T
靶向CTLA-4是癌症控制的最新策略：阻断CTLA-4通过促进t细胞活化和细胞毒性t淋巴细胞增殖来增强抗肿瘤免疫。这种诱导对肿瘤的耐受性破坏可能是免疫相关不良事件（irAEs）的原因。我们的目的是评估接受抗ctla -4抗体（ipilimumab和tremelimumab）治疗的肿瘤患者中irae的发生率和性质。在MEDLINE、EMBASE和Cochrane数据库中系统检索截至2014年2月的文献，以确定相关文章。配对审稿人独立选择纳入的文章和提取的数据。合并发病率采用R©，package meta计算。总的来说，81篇文章被纳入了这项研究，来自22项临床试验的1265名患者被纳入了meta分析。所描述的irae包括皮肤病变（皮疹、瘙痒和白癜风）、结肠炎、不常见的肝炎、垂体炎、甲状腺炎和一些罕见的事件，如结节病、葡萄膜炎、格林-巴勒综合征、免疫介导的细胞减少症和风湿病/霍顿多肌痛。所有级别irae的总发生率为72% （95% CI, 65 - 79%）。高级别irae的总发生率为24% （95% CI, 18 - 30%）。发生irae的风险依赖于剂量，依匹单抗3mg /kg的所有级别irae的发生率评估为61% (95% CI, 56 - 66%)，依匹单抗10mg /kg的发生率为79% （95% CI, 69 - 89%）。0.6%的患者死于irae。irAEs发作的中位时间为治疗开始后约10周（IQR, 6-12），与前三个周期相对应，但因受累器官系统而异。这种免疫激活也可以指示肿瘤特异性t细胞激活，并且在60%的患者中，irAE的发生与CTLA-4阻断的临床反应相关。转移性肿瘤的潜在长期生存代价是一种非典型免疫毒性，反映了抗ctla -4抗体的作用机制。更好地了解这些恶性肿瘤及其多学科管理方法将有助于减少发病率和治疗中断。本文的在线版本（doi:10.1186/s12916-015-0455-8）包含补充材料，可供授权用户使用。
Targeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an antitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a tolerance break against the tumor may be responsible for immune-related adverse events (irAEs). Our objective was to assess the incidence and nature of irAEs in oncologic patients receiving anti-CTLA-4 antibodies (ipilimumab and tremelimumab). A systematic search of literature up to February 2014 was performed in MEDLINE, EMBASE, and Cochrane databases to identify relevant articles. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using R©, package meta. Overall, 81 articles were included in the study, with a total of 1265 patients from 22 clinical trials included in the meta-analysis. Described irAEs consisted of skin lesions (rash, pruritus, and vitiligo), colitis, and less frequently hepatitis, hypophysitis, thyroiditis, and some rare events such as sarcoidosis, uveitis, Guillain-Barré syndrome, immune-mediated cytopenia and polymyalgia rheumatic/Horton. The overall incidence of all-grade irAEs was 72 % (95 % CI, 65–79 %). The overall incidence of high-grade irAEs was 24 % (95 % CI, 18–30 %). The risk of developing irAEs was dependent of dosage, with incidence of all-grade irAEs being evaluated to 61 % (95 % CI, 56–66 %) for ipilimumab 3 mg/kg and 79 % (95 % CI, 69–89 %) for ipilimumab 10 mg/kg. Death due to irAEs occurred in 0.86 % of patients. The median time of onset of irAEs was about 10 weeks (IQR, 6–12) after the onset of treatment, corresponding with the first three cycles but varied according to the organ system involved. Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60 % of patients. The price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies. A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions. The online version of this article (doi:10.1186/s12916-015-0455-8) contains supplementary material, which is available to authorized users.