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Checkpoint inhibitor therapy in preclinical sepsis models: a systematic review and meta-analysis
Intensive Care Medicine Experimental Pub Date : 2020-02-04 , DOI: 10.1186/s40635-019-0290-x
Lindsay M Busch 1 , Junfeng Sun 1 , Xizhong Cui 1 , Peter Q Eichacker 1 , Parizad Torabi-Parizi 1
Affiliation  

Background Animal studies reporting immune checkpoint inhibitors (CPIs) improved host defense and survival during bacterial sepsis provided one basis for phase I CPI sepsis trials. We performed a systematic review and meta-analysis examining the benefit of CPI therapy in preclinical studies, and whether variables potentially altering this clinical benefit were investigated. Studies were analyzed that compared survival following bacteria or lipopolysaccharide challenge in animals treated with inhibitors to programmed death-1 (PD-1), PD-ligand1 (PD-L1), cytotoxic T lymphocyte-associated protein-4 (CTLA-4), or B- and T-lymphocyte attenuator (BTLA) versus control. Results Nineteen experiments from 11 studies ( n = 709) were included. All experiments were in mice, and 10 of the 19 were published from a single research group. Sample size calculations and randomization were not reported in any studies, and blinding procedures were reported in just 1. Across all 19 experiments, CPIs increased the odds ratio for survival (OR, 95% CI) [3.37(1. 55, 7.31)] but with heterogeneity ( I 2 = 59%, p < 0.01). After stratification by checkpoint molecule targeted, challenge site or type, or concurrent antibacterial treatment, CPIs had consistent effects over most experiments in the 9 that included antibacterial treatment [OR = 2.82 (1.60, 4.98), I 2 = 6%, p = 0.39 with versus 4.01 (0.89, 18.05), I 2 = 74%, p < 0.01 without]. All 9 antibiotic experiments employed cecal-ligation and puncture (CLP) bacterial challenge while 6 also included a Candida albicans challenge 3–4 days after CLP. In these six experiments ( n = 322), CPIs were directed at the fungal challenge when CLP lethality had resolved, and were consistently beneficial [2.91 (2.41, 3.50), I 2 = 0%, p = 0.99]. In the three experiments ( n = 66) providing antibiotics without fungal challenge, CPIs were administered within 1 day of CLP and had variable and non-significant effects [0.05 (0.00, 1.03); 7.86 (0.28, 217.11); and 8.50 (0.90, 80.03)]. No experiment examined pneumonia. Conclusions Preclinical studies showing that CPIs add benefit to antibiotic therapy for the common bacterial infections causing sepsis clinically are needed to support this therapeutic approach. Studies should be reproducible across multiple laboratories and include procedures to reduce the risk of bias.

中文翻译:

临床前脓毒症模型中的检查点抑制剂治疗:系统评价和荟萃分析

背景 动物研究报告免疫检查点抑制剂 (CPI) 在细菌性脓毒症期间改善宿主防御和存活,为 I 期 CPI 脓毒症试验提供了一个基础。我们进行了一项系统回顾和荟萃分析,检查 CPI 治疗在临床前研究中的益处,以及是否研究了可能改变这种临床益处的变量。研究分析了在接受程序性死亡 1 (PD-1)、PD-配体 1 (PD-L1)、细胞毒性 T 淋巴细胞相关蛋白-4 (CTLA-4) 抑制剂治疗的动物中,比较细菌或脂多糖攻击后的存活率,或 B 和 T 淋巴细胞衰减器 (BTLA) 与对照。结果 包括来自 11 项研究 (n = 709) 的 19 项实验。所有的实验都是在老鼠身上进行的,19 个中有 10 个来自一个研究小组。任何研究都没有报告样本量计算和随机化,只有 1 个报告了盲法程序。在所有 19 项实验中,CPI 增加了生存的优势比 (OR, 95% CI) [3.37(1. 55, 7.31)]但具有异质性(I 2 = 59%,p < 0.01)。在按检查点分子靶向、攻击部位或类型或同时抗菌治疗分层后,CPI 在包括抗菌治疗的 9 项实验中的大多数实验中具有一致的效果 [OR = 2.82 (1.60, 4.98), I 2 = 6%, p = 0.39与 4.01 (0.89, 18.05), I 2 = 74%, p < 0.01 无]。所有 9 项抗生素实验均采用盲肠结扎和穿刺 (CLP) 细菌攻击,而 6 项还包括 CLP 后 3-4 天的白色念珠菌攻击。在这六个实验中 (n = 322),当 CLP 致死率解决时,CPI 针对真菌攻击,并且始终有益 [2.91 (2.41, 3.50), I 2 = 0%, p = 0.99]。在没有真菌攻击的情况下提供抗生素的三个实验 (n = 66) 中,在 CLP 的 1 天内施用 CPI 并且具有可变和非显着影响 [0.05 (0.00, 1.03); 7.86 (0.28, 217.11); 和 8.50 (0.90, 80.03)]。没有实验检查肺炎。结论 需要临床前研究表明 CPI 为临床上引起败血症的常见细菌感染的抗生素治疗增加益处,以支持这种治疗方法。研究应该在多个实验室中可重复,并包括降低偏倚风险的程序。在没有真菌攻击的情况下提供抗生素的三个实验 (n = 66) 中,在 CLP 的 1 天内施用 CPI 并且具有可变和非显着影响 [0.05 (0.00, 1.03); 7.86 (0.28, 217.11); 和 8.50 (0.90, 80.03)]。没有实验检查肺炎。结论 需要临床前研究表明 CPI 为临床上引起败血症的常见细菌感染的抗生素治疗增加益处,以支持这种治疗方法。研究应该在多个实验室中可重复,并包括降低偏倚风险的程序。在没有真菌攻击的情况下提供抗生素的三个实验 (n = 66) 中,在 CLP 的 1 天内施用 CPI 并且具有可变和非显着影响 [0.05 (0.00, 1.03); 7.86 (0.28, 217.11); 和 8.50 (0.90, 80.03)]。没有实验检查肺炎。结论 需要临床前研究表明 CPI 为临床上引起败血症的常见细菌感染的抗生素治疗增加益处,以支持这种治疗方法。研究应该在多个实验室中可重复,并包括降低偏倚风险的程序。结论 需要临床前研究表明 CPI 为临床上引起败血症的常见细菌感染的抗生素治疗增加益处,以支持这种治疗方法。研究应该在多个实验室中可重复,并包括降低偏倚风险的程序。结论 需要临床前研究表明 CPI 为临床上引起败血症的常见细菌感染的抗生素治疗增加益处,以支持这种治疗方法。研究应在多个实验室中可重复,并包括降低偏倚风险的程序。
更新日期:2020-02-04
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