Polo-like kinase inhibitor volasertib marginally enhances the efficacy of the novel Fc-engineered anti-CD33 antibody BI 836858 in acute myeloid leukemia.
Polo-like kinase inhibitor volasertib marginally enhances the efficacy of the novel Fc-engineered anti-CD33 antibody BI 836858 in acute myeloid leukemia.
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DOI：
10.18632/oncotarget.23880
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发表时间：
2018-02-09
期刊：
影响因子：
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通讯作者：
Muthusamy N
中科院分区：
文献类型：
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作者：
Gopalakrishnan B;Cheney C;Mani R;Mo X;Bucci D;Walker A;Klisovic R;Bhatnagar B;Walsh K;Rueter B;Waizenegger IC;Heider KH;Blum W;Vasu S;Muthusamy N
急性髓性白血病（AML）是成人中第二常见的白血病类型。AML的发病率随着年龄的增长而增加，在67岁时达到高峰。60岁以上的患者由于对常规化疗耐药而预后不良。Volasertib（BI 6727）是一种靶向polo样激酶的细胞周期调节剂，已在AML临床试验中进行了评价。我们评价了volasertib在原代患者样本和NK细胞中的作用。在同等剂量下，volasertib对AML原始细胞具有细胞毒性，但在很大程度上不影响健康的NK细胞。然后，我们使用抗体依赖性细胞毒性（ADCC）试验评价了volasertib联合BI 836858治疗对原代AML原始细胞样本的影响。Volasertib处理的NK细胞与对照处理的NK细胞中BI 836858介导的ADCC水平相当，证明Volasertib处理的NK细胞未损害NK功能。总之，volasertib对AML原始细胞具有细胞毒性，同时保留NK细胞活力和功能。在接受volasertib预处理的患者样本中观察到BI 836858介导的ADCC较高。这些结果为BI 836858和volasertib联合治疗AML提供了强有力的依据。
Acute myeloid leukemia (AML) is the second most common type of leukemia in adults. Incidence of AML increases with age with a peak incidence at 67 years. Patients older than 60 years have an unfavorable prognosis due to resistance to conventional chemotherapy. Volasertib (BI 6727) is a cell-cycle regulator targeting polo-like kinase which has been evaluated in clinical trials in AML. We evaluated effects of volasertib in primary patient samples and NK cells. At equivalent doses, volasertib is cytotoxic to AML blasts but largely spares healthy NK cells. We then evaluated the effect of volasertib treatment in combination with BI 836858 on primary AML blast samples using antibody-dependent cellular cytotoxicity (ADCC) assays. Volasertib treatment of NK cells did not impair NK function as evidenced by comparable levels of BI 836858 mediated ADCC in both volasertib-treated and control-treated NK cells. In summary, volasertib is cytotoxic to AML blasts while sparing NK cell viability and function. Higher BI 836858 mediated ADCC was observed in patient samples pretreated with volasertib. These findings provide a strong rationale to test combination of BI 836858 and volasertib in AML.