Amplification of Oncolytic Vaccinia Virus Widespread Tumor Cell Killing by Sunitinib through Multiple Mechanisms

被引:54
作者
Kim, Minah [1 ,2 ]
Nitschke, Maximilian [1 ,2 ]
Sennino, Barbara [1 ,2 ]
Murer, Patrizia [1 ,2 ]
Schriver, Brian J. [1 ,2 ]
Bell, Alexander [1 ,2 ]
Subramanian, Aishwarya [1 ,2 ]
McDonald, Corry E. [1 ,2 ]
Wang, Jiahu [3 ]
Cha, Howard [1 ,2 ]
Bourgeois-Daigneault, Marie-Claude [3 ]
Kirn, David H. [4 ]
Bell, John C. [3 ]
De Silva, Naomi [4 ]
Breitbach, Caroline J. [4 ]
McDonald, Donald M. [1 ,2 ]
机构
[1] Univ Calif San Francisco, Cardiovasc Res Inst, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA
[3] Ottawa Hosp Res Inst, Ctr Innovat Canc Therapeut, Ottawa, ON, Canada
[4] SillaJen Biotherapeut Inc, San Francisco, CA USA
基金
美国国家卫生研究院;
关键词
PANCREATIC NEUROENDOCRINE TUMORS; ANTIVIRAL INNATE IMMUNITY; COLONY-STIMULATING FACTOR; PEXA-VEC JX-594; COLORECTAL-CANCER; DENDRITIC CELLS; CLINICAL-TRIAL; LIVER-CANCER; GM-CSF; POXVIRUS;
D O I
10.1158/0008-5472.CAN-15-3308
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 that developed spontaneously and progressed 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 multitargeted receptor tyrosine kinase inhibitor. These effects were not mimicked by selective inhibition of VEGFR2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells 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(+) cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by coadministration of sunitinib. Significance: These findings reveal multiple unrecognized features of the antitumor properties of oncolytic vaccinia viruses, all of which can be amplified by the multitargeted kinase inhibitor sunitinib. (C) 2018 AACR.
引用
收藏
页码:922 / 937
页数:16
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