Aurora A kinase inhibition enhances oncolytic herpes virotherapy through cytotoxic synergy and innate cellular immune modulation.
Aurora A kinase inhibition enhances oncolytic herpes virotherapy through cytotoxic synergy and innate cellular immune modulation.
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DOI：
10.18632/oncotarget.14885
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发表时间：
2017-03-14
期刊：
影响因子：
--
通讯作者：
Cripe TP
中科院分区：
文献类型：
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作者：
Currier MA;Sprague L;Rizvi TA;Nartker B;Chen CY;Wang PY;Hutzen BJ;Franczek MR;Patel AV;Chaney KE;Streby KA;Ecsedy JA;Conner J;Ratner N;Cripe TP
恶性外周神经鞘瘤（MPNST）和神经母细胞瘤模型对试验用小分子Aurora A激酶抑制剂alisertib有反应。我们以前报道过MPNST和神经母细胞瘤也对溶瘤性疱疹病毒（oHSV）治疗敏感。在本文中，我们发现，与任一单药治疗相比，alisertib和HSV 1716（一种来源于HSV-1并通过缺失RL 1减毒的病毒）的联合治疗显示出显著增加的抗肿瘤疗效。在MPNST和神经母细胞瘤的两种异种移植模型中，Alisertib和HSV 1716减少了肿瘤生长并增加了存活率。我们发现增强的抗肿瘤作用是由于多种机制，可能每种机制都有助于联合作用。首先，溶瘤性疱疹病毒增加了未感染细胞对alisertib细胞毒性的敏感性，这一过程我们称之为病毒诱导的治疗性佐剂（VITA）。其次，alisertib增加了病毒产生的峰值，并减缓了病毒从肿瘤中的清除，这两者都可能是其阻止病毒介导的肿瘤内NK细胞增加的结果。我们还发现alisertib抑制病毒诱导的瘤内髓源性抑制细胞的蓄积，这些细胞通常是促肿瘤发生的。我们的数据表明，需要在神经母细胞瘤或MPNST患者中开展oHSV和alisertib联合治疗的临床试验。
Malignant peripheral nerve sheath tumor (MPNST) and neuroblastoma models respond to the investigational small molecule Aurora A kinase inhibitor, alisertib. We previously reported that MPNST and neuroblastomas are also susceptible to oncolytic herpes virus (oHSV) therapy. Herein, we show that combination of alisertib and HSV1716, a virus derived from HSV-1 and attenuated by deletion of RL1, exhibits significantly increased antitumor efficacy compared to either monotherapy. Alisertib and HSV1716 reduced tumor growth and increased survival in two xenograft models of MPNST and neuroblastoma. We found the enhanced antitumor effect was due to multiple mechanisms that likely each contribute to the combination effect. First, oncolytic herpes virus increased the sensitivity of uninfected cells to alisertib cytotoxicity, a process we term virus-induced therapeutic adjuvant (VITA). Second, alisertib increased peak virus production and slowed virus clearance from tumors, both likely a consequence of it preventing virus-mediated increase of intratumoral NK cells. We also found that alisertib inhibited virus-induced accumulation of intratumoral myeloid derived suppressor cells, which normally are protumorigenic. Our data suggest that clinical trials of the combination of oHSV and alisertib are warranted in patients with neuroblastoma or MPNST.