Interactions Between Pseudomonas Immunotoxins and the Plasma Membrane: Implications for CAT-8015 Immunotoxin Therapy
Interactions Between Pseudomonas Immunotoxins and the Plasma Membrane: Implications for CAT-8015 Immunotoxin Therapy
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DOI：
10.3389/fonc.2018.00553
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发表时间：
2018-11-27
影响因子：
4.7
通讯作者：
Winlove, C. Peter
中科院分区：
文献类型：
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作者：
Bokori-Brown, Monika;Metz, Jeremy;Winlove, C. Peter
急性淋巴细胞白血病（ALL）仍然是儿童癌症相关死亡的最常见原因，需要新的治疗方法来治疗复发性/难治性儿童ALL。一种方法是用假单胞菌免疫毒素CAT-8015靶向ALL母细胞。尽管CAT-8015具有强效抗白血病活性，在儿童ALL的I期研究中客观缓解率为32%，但溶血性尿毒症综合征（HUS）和血管渗漏综合征（VLS）（主要剂量限制性毒性）限制了这种治疗方法在儿童中的使用。CAT-8015诱导的HUS/VLS的发病机制的研究受到缺乏复制临床表现的适当模型系统的阻碍，但对血管内皮细胞（EC）和血细胞的损伤被认为是两种综合征的主要起始因素。由于几乎没有证据表明鼠模型复制人HUS/VLS，CAT-8015诱导的HUS/VLS主要影响儿童，我们开发了人类模型，并使用新的方法来研究CAT-8015与来自儿科ALL患者的红细胞（RBC）和切除的人肠系膜动脉的EC的相互作用。我们提供的证据表明，CAT-8015直接与红细胞相互作用，介导的假单胞菌毒素。我们还显示了红细胞膜的电特性和红细胞对CAT-8015诱导的溶解的敏感性之间的相关性，这可能具有临床意义。最后，我们提供了CAT-8015对离体人肠系膜动脉的EC具有直接细胞毒性的证据。总之，我们开发的人类模型构成了理解免疫毒素治疗中HUS/VLS起源的第一步，也是非常重要的一步，并将允许进一步研究HUS/VLS发病机制。
Acute Lymphoblastic Leukemia (ALL) remains the most frequent cause of cancer-related mortality in children and novel therapies are needed for the treatment of relapsed/refractory childhood ALL. One approach is the targeting of ALL blasts with the Pseudomonas immunotoxin CAT-8015. Although CAT-8015 has potent anti-leukemia activity, with a 32% objective response rate in a phase 1 study of childhood ALL, haemolytic-uremic syndrome (HUS) and vascular leak syndrome (VLS), major dose-limiting toxicities, have limited the use of this therapeutic approach in children. Investigations into the pathogenesis of CAT-8015-induced HUS/VLS are hindered by the lack of an adequate model system that replicates clinical manifestations, but damage to vascular endothelial cells (ECs) and blood cells are believed to be major initiating factors in both syndromes. Since there is little evidence that murine models replicate human HUS/VLS, and CAT-8015-induced HUS/VLS predominantly affects children, we developed human models and used novel methodologies to investigate CAT-8015 interactions with red blood cells (RBCs) from pediatric ALL patients and ECs of excised human mesenteric arteries. We provide evidence that CAT-8015 directly interacts with RBCs, mediated by Pseudomonas toxin. We also show correlation between the electrical properties of the RBC membrane and RBC susceptibility to CAT-8015-induced lysis, which may have clinical implication. Finally, we provide evidence that CAT-8015 is directly cytototoxic to ECs of excised human mesenteric arteries. In conclusion, the human models we developed constitutes the first, and very important, step in understanding the origins of HUS/VLS in immunotoxin therapy and will allow further investigations of HUS/VLS pathogenesis.