Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
NEJM Evid. 2022 Jan;1(1):EVIDoa2100009. doi: 10.1056/EVIDoa2100009. Epub 2021 Nov 22.
Atherosclerosis is a chronic inflammatory disease of the artery wall. Regulatory T cells (Tregs) limit inflammation and promote tissue healing. Low doses of interleukin (IL)-2 have the potential to increase Tregs, but its use is contraindicated for patients with ischemic heart disease. METHODS: In this randomized, double-blind, placebo-controlled, dose-escalation trial, we tested low-dose subcutaneous aldesleukin (recombinant IL-2), given once daily for 5 consecutive days. In study part A, the primary end point was safety, and patients with stable ischemic heart disease were randomly assigned to receive placebo or to one of five dose groups (range, 0.3 to 3.0 × 106 IU daily). In study part B, patients with acute non-ST elevation myocardial infarction or unstable angina were randomly assigned to receive placebo or to one of two dose groups (1.5 and 2.5 × 106 IU daily). The coprimary end points were safety and the dose required to increase circulating Tregs by 75%. Single-cell RNA-sequencing of circulating immune cells was used to provide a mechanistic assessment of the effects of aldesleukin. RESULTS: Forty-four patients were randomly assigned to either study part A (n=26) or part B (n=18). In total, 3 patients withdrew before dosing, 27 received active treatment, and 14 received placebo. The majority of adverse events were mild. Two serious adverse events occurred, with one occurring after drug administration. In parts A and B, there was a dose-dependent increase in Tregs. In part B, the estimated dose to achieve a 75% increase in Tregs was 1.46 × 106 IU (95% confidence interval, 1.06 to 1.87). Single-cell RNA-sequencing demonstrated the engagement of distinct pathways and cell–cell interactions. CONCLUSIONS: In this phase 1b/2a study, low-dose IL-2 expanded Tregs without adverse events of major concern. Larger trials are needed to confirm the safety and to further evaluate the efficacy of low-dose IL-2 as an anti-inflammatory therapy for patients with ischemic heart disease. (Funded by the Medical Research Council, the British Heart Foundation, and others; ClinicalTrials.gov number, NCT03113773)
动脉粥样硬化是动脉壁的一种慢性炎症性疾病。调节性 T 细胞（Tregs）可限制炎症并促进组织愈合。低剂量白细胞介素（IL）-2 具有增加 Tregs 的潜力，但因其会诱发缺血性心脏病，故其应用受到限制。
在这项随机、双盲、安慰剂对照、剂量递增的试验中，我们测试了低剂量皮下注射白细胞介素（重组 IL-2），连续 5 天每天一次。在研究 A 部分中，主要终点是安全性，稳定型缺血性心脏病患者被随机分配至接受安慰剂或 5 个剂量组（范围，每天 0.3 至 3.0×106 IU）之一。在研究 B 部分中，急性非 ST 段抬高型心肌梗死或不稳定型心绞痛患者被随机分配至接受安慰剂或 2 个剂量组（每天 1.5 和 2.5×106 IU）之一。共同的主要终点是安全性和增加循环 Tregs 所需的剂量（增加 75%）。使用循环免疫细胞的单细胞 RNA 测序来提供对白细胞介素作用机制的评估。
44 名患者被随机分配至研究 A（n=26）或研究 B（n=18）。总共 3 名患者在给药前退出，27 名患者接受了活性治疗，14 名患者接受了安慰剂。大多数不良事件为轻度。发生了 2 例严重不良事件，其中 1 例发生在药物治疗后。在 A 部分和 B 部分中，Tregs 呈剂量依赖性增加。在 B 部分中，达到 Tregs 增加 75%的估计剂量为 1.46×106 IU（95%置信区间，1.06 至 1.87）。单细胞 RNA 测序显示，独特的通路和细胞-细胞相互作用被激活。
在这项 1b/2a 期研究中，低剂量 IL-2 扩展了 Tregs，且无主要关注的不良事件。需要更大规模的试验来确认安全性，并进一步评估低剂量 IL-2 作为缺血性心脏病患者抗炎治疗的疗效。（由英国医学研究理事会、英国心脏基金会等资助；ClinicalTrials.gov 编号，NCT03113773）
