Gopalakrishnan Bhavani, Cheney Carolyn, Mani Rajeswaran, Mo Xiaokui, Bucci Donna, Walker Alison, Klisovic Rebecca, Bhatnagar Bhavana, Walsh Katherine, Rueter Bjoern, Waizenegger Irene C, Heider Karl-Heinz, Blum William, Vasu Sumithira, Muthusamy Natarajan
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
Oncotarget. 2018 Jan 3;9(11):9706-9713. doi: 10.18632/oncotarget.23880. eCollection 2018 Feb 9.
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.
急性髓系白血病（AML）是成人中第二常见的白血病类型。AML的发病率随年龄增长而增加，在67岁时达到峰值。60岁以上的患者由于对传统化疗耐药，预后不佳。沃拉替尼（BI 6727）是一种靶向波罗样激酶的细胞周期调节剂，已在AML的临床试验中进行了评估。我们评估了沃拉替尼在原发性患者样本和自然杀伤（NK）细胞中的作用。在等效剂量下，沃拉替尼对AML原始细胞具有细胞毒性，但在很大程度上使健康的NK细胞免受影响。然后，我们使用抗体依赖性细胞毒性（ADCC）试验评估了沃拉替尼与BI 836858联合治疗对原发性AML原始细胞样本的影响。沃拉替尼处理的NK细胞的功能未受损，这在沃拉替尼处理的NK细胞和对照处理的NK细胞中BI 836858介导的ADCC水平相当中得到证明。总之，沃拉替尼对AML原始细胞具有细胞毒性，同时保留NK细胞的活力和功能。在用沃拉替尼预处理的患者样本中观察到更高的BI 836858介导的ADCC。这些发现为在AML中测试BI 836858和沃拉替尼的联合用药提供了有力的理论依据。
