Amplification of Oncolytic Vaccinia Virus Widespread Tumor Cell Killing by Sunitinib through Multiple Mechanisms.
Amplification of Oncolytic Vaccinia Virus Widespread Tumor Cell Killing by Sunitinib through Multiple Mechanisms.
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通过多种机制通过多种机制扩增了溶瘤疫苗病毒广泛杀死肿瘤细胞。
DOI：
10.1158/0008-5472.can-15-3308
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发表时间：
2018-02-15
期刊：
影响因子：
11.2
通讯作者：
McDonald DM
中科院分区：
文献类型：
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作者：
Kim M;Nitschké M;Sennino B;Murer P;Schriver BJ;Bell A;Subramanian A;McDonald CE;Wang J;Cha H;Bourgeois-Daigneault MC;Kirn DH;Bell JC;De Silva N;Breitbach CJ;McDonald DM
溶瘤病毒在癌症治疗中的应用提出了许多问题。在这项研究中，我们评估了mpJX-594（小鼠原型JX-594），一种通过静脉注射给药的可复制牛痘病毒，靶向肿瘤血管系统，产生比感染更广泛的免疫激活和肿瘤细胞杀伤，并抑制侵袭和转移的潜力。在患有胰腺神经内分泌肿瘤（PNET）的RIP-Tag 2转基因小鼠中检查了这些作用，这些肿瘤自发发展并与人类一样进展。mpJX-594最初感染肿瘤血管内皮细胞，导致肿瘤中的血管修剪和延长的渗漏，但在正常器官中没有;在U87胶质瘤中观察到平行效应。病毒感染扩散到肿瘤细胞，肿瘤细胞的杀伤比感染更广泛。在第5天，广泛的肿瘤细胞杀伤通过CD 8 + T淋巴细胞的消耗而被阻止，并且不需要GM-CSF，因为表达人、小鼠或不表达GM-CSF的mpJX-594变体产生等量的杀伤。mpJX-594的抗血管、抗肿瘤和抗转移作用通过同时或序贯给予舒尼替尼（一种多靶向受体酪氨酸激酶抑制剂（TKI））而增强。尽管进行了等效的血管修剪，但这些作用并没有通过选择性抑制VEGFR-2来模拟，而是伴随着调节性T细胞（TcR）的抑制和活化的CD 8 + T细胞的更大流入。总之，我们的结果表明，mpJX-594靶向肿瘤血管，继发性扩散到肿瘤细胞，并在原发性肿瘤和转移瘤中产生广泛的CD 8 + T细胞依赖性肿瘤细胞杀伤，并且这些作用可以通过共同施用舒尼替尼来放大。
Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors (PNET) that developed spontaneously and progress as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8+ T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multi-targeted receptor tyrosine kinase inhibitor (TKI). These effects were not mimicked by selective inhibition of VEGFR-2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells (Tregs) and greater influx of activated CD8+ T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8+ T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by co-administration of sunitinib.