Alpha-1 Antitrypsin-Expressing Mesenchymal Stromal Cells Confer a Long-Term Survival Benefit in a Mouse Model of Lethal GvHD
Alpha-1 Antitrypsin-Expressing Mesenchymal Stromal Cells Confer a Long-Term Survival Benefit in a Mouse Model of Lethal GvHD
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DOI：
10.1016/j.ymthe.2019.05.007
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发表时间：
2019-08-07
影响因子：
12.4
通讯作者：
Minter, Lisa M.
中科院分区：
文献类型：
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作者：
Geiger, Sabine;Ozay, Emrah I.;Minter, Lisa M.
急性移植物抗宿主病是异基因造血干细胞移植相关的常见并发症。对初始类固醇治疗耐药的患者预后较差。 apceth-201 由人同种异体间充质基质细胞组成，通过慢病毒转导工程改造，表达蛋白酶抑制剂 α-1 抗胰蛋白酶，以增强间充质基质细胞的抗炎潜力。我们在体外证明 apceth-201 间充质基质细胞可有效抑制 T 细胞增殖并将巨噬细胞极化为抗炎 M2 型。为了评估 apceth-201 的体内功效，在两种不同的急性移植物抗宿主病小鼠模型中进行了测试。人源化模型中的对照动物很快死于疾病，而接受 apceth-201 治疗的动物的中位生存期增加了一倍。该产品还在移植物抗宿主疾病模型系统中进行了测试，该模型非常模仿单倍相合造血干细胞移植，目前正在评估这种方法在临床中的使用。对照动物很快死于疾病，而 apceth-201 治疗使 57% 的动物长期存活。第二次注射后 25 天内，有反应的动物的临床评分恢复到基线，表明移植物抗宿主病已完全消退。这些有希望的数据促使我们计划使用 apceth-201 进行 I 期研究。
Acute graft-versus-host disease is a frequent complication associated with allogeneic hematopoietic stem cell transplantation. Patients that become refractory to initial steroid treatment have a poor prognosis. apceth-201 consists of human allogeneic mesenchymal stromal cells, engineered by lentiviral transduction to express the protease inhibitor alpha-1 antitrypsin, to augment the anti-inflammatory potential of the mesenchymal stromal cells. We show that apceth-201 mesenchymal stromal cells efficiently suppress T cell proliferation and polarize macrophages to an anti-inflammatory M2 type, in vitro. To assess the in vivo efficacy of apceth-201, it was tested in two different mouse models of acute graft-versus-host disease. Control animals in a humanized model succumbed quickly to disease, whereas median survival was doubled in apceth-201-treated animals. The product was also tested in a graft-versus-host disease model system that closely mimics haploidentical hematopoietic stem cell transplantation, an approach that is now being evaluated for use in the clinic. Control animals succumbed quickly to disease, whereas treatment with apceth-201 resulted in long-term survival of 57% of the animals. Within 25 days after the second injection, clinical scores returned to baseline in responding animals, indicating complete resolution of graft-versus-host disease. These promising data have led to planning of a phase I study using apceth-201.