α1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease
α1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease
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DOI：
10.1182/blood-2017-11-815746
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发表时间：
2018-03-22
期刊：
影响因子：
20.3
通讯作者：
Reddy, Pavan
中科院分区：
文献类型：
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作者：
Magenau, John M.;Goldstein, Steven C.;Reddy, Pavan
急性移植物抗宿主病（acute graft-versus-host disease，SR-aGVHD）后的皮质类固醇抵抗导致异基因造血细胞移植后的高发病率和死亡率。目前用于SR-aGVHD的免疫抑制疗法提供边际有效性，因为反应差或过度毒性，主要来自感染。α（1）-抗胰蛋白酶（AAT）是一种天然丰富的丝氨酸蛋白酶抑制剂，能够通过下调炎症和增加调节性T细胞（T-reg）与效应性T细胞（T（eff）s）的比率来抑制实验性GVHD。在这项前瞻性多中心临床研究中，我们试图确定AAT给药在SR-aGVHD中的安全性和应答率。40名中位年龄为59岁的患者接受静脉内AAT每周两次持续4周作为SR-aGVHD的一线治疗。主要终点是总体反应率（ORR），即在不添加进一步免疫抑制剂的情况下，到第28天完全（CR）或部分反应的SR-aGVHD患者的比例。治疗耐受性良好，无药物相关不良事件。治疗后观察到血清AAT水平显著升高。第28天的ORR和CR率分别为65%和35%，包括所有aGVHD靶器官的缓解。在第60天，在没有干预免疫抑制的情况下，73%的患者持续应答。感染性死亡率在6个月时为10%，在末次AAT输注后30天内为2.5%。与临床前数据一致，相关样本显示AAT治疗后活化T（reg）s与T（eff）s的比值增加。这些数据表明，AAT是安全的，并且可能在治疗SR-aGVHD中潜在有效。
Corticosteroid resistance after acute graft-versus-host disease (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation. Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness because of poor response or excessive toxicity, primarily from infection. alpha(1)-Antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by downmodulating inflammation and increasing ratios of regulatory (T-reg) to effector T cells (T(eff)s). In this prospective multicenter clinical study, we sought to determine the safety and response rate of AAT administration in SR-aGVHD. Forty patients with a median age of 59 years received intravenous AAT twice weekly for 4 weeks as first-line treatment of SR-aGVHD. The primary end point was overall response rate (ORR), the proportion of patients with SR-aGVHD in complete (CR) or partial response by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug-related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rates by day 28 were 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with preclinical data, correlative samples showed an increase in ratio of activated T(reg)s to T(eff)s after AAT treatment. These data suggest that AAT is safe and may be potentially efficacious in treating SR-aGVHD.