Department of Anesthesiology, Washington University School of Medicine, St Louis, MO.
Department of Anesthesiology, Innovative Medicines Development, Bristol-Myers Squibb, Princeton, NJ.
Crit Care Med. 2019 May;47(5):632-642. doi: 10.1097/CCM.0000000000003685.
To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559; Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression.
Randomized, placebo-controlled, dose-escalation.
Seven U.S. hospital ICUs.
Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/μL.
Participants received single-dose BMS-936559 (10-900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels.
The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose: 2/4; 30 mg: 2/4; 100 mg: 1/4; 300 mg: 1/4; 900 mg: 0/4; placebo: 0/4). All participants had adverse events (75% grade 1-2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1-2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days.
In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with sepsis.
首次评估抗程序化细胞死亡配体 1 免疫检查点抑制剂（BMS-936559；百时美施贵宝，普林斯顿，新泽西州）在伴有脓毒症相关免疫抑制的参与者中的安全性和药代动力学，并评估其对免疫生物标志物的影响。
随机、安慰剂对照、剂量递增。
美国 7 家医院 ICU。
24 名患有脓毒症、器官功能障碍（低血压、急性呼吸衰竭和/或急性肾损伤）和绝对淋巴细胞计数≤1100 个细胞/μL 的参与者。
参与者接受单次 BMS-936559（10-900mg；n=20）或安慰剂（n=4）输注。主要终点是死亡和不良事件；关键次要终点包括受体占有率和单核细胞人类白细胞抗原-DR 水平。
治疗组年龄较大（接受治疗的中位年龄为 62 岁，接受治疗的中位年龄为 62 岁，接受治疗的中位年龄为 62 岁，接受治疗的中位年龄为 62 岁，接受治疗的中位年龄为 62 岁），有更多器官功能障碍的比例更高（55%接受治疗的患者）；其他基线特征无差异。总死亡率为 25%（10mg 剂量：2/4；30mg：2/4；100mg：1/4；300mg：1/4；900mg：0/4；安慰剂：0/4）。所有参与者均出现不良事件（75%为 1-2 级）。17%发生严重不良事件（3/20 治疗组，1/4 安慰剂），均与药物无关。54%的参与者发生了潜在的免疫相关不良事件；大多数为 1-2 级，均无需使用皮质类固醇，且均与药物无关。未观察到细胞因子水平的显著变化。在 BMS-936559（900mg）给药后 28 天达到完全受体占有率。在两个最高剂量下，观察到单核细胞人类白细胞抗原-DR 表达（>5000 个单克隆抗体/细胞）明显增加，并持续超过 28 天。
在这项针对脓毒症中程序性细胞死亡蛋白 1/程序性细胞死亡配体 1 通路抑制的首次临床评估中，BMS-936559耐受性良好，无药物引起的细胞因子过度释放或细胞因子风暴的证据，在较高剂量下，28 天内恢复免疫状态的迹象。需要进一步的随机临床试验来评估程序性细胞死亡蛋白 1/程序性细胞死亡配体 1 通路抑制剂在脓毒症患者中的临床安全性和疗效。
