分类： 生物学 >> 生物物理学 >> 肿瘤学 提交时间： 2016-05-12
Chard, Louisa S.
Ahmed, Jahangir
El Khouri, Margueritte
Hughes, Jonathan
Lemoine, Nicholas R.
Wang, Yaohe
Maniati, Eleni
Hagemann, Thorsten
Wang, Pengju
Zhang, Zhongxian
Gao, Dongling
Wang, Jiwei
Cao, Fengyu
Lemoine, Nicholas R.
Wang, Yaohe
Wang, Shengdian
Li, Xiaozhu
Denes, Bela
Fodor, Istvan
摘要： Purpose: Vaccinia virus has strong potential as a novel therapeutic agent for treatment of pancreatic cancer. We investigated whether arming vaccinia virus with interleukin-10 (IL10) could enhance the antitumor efficacy with the view that IL10 might dampen the host immunity to the virus, increasing viral persistence, thus maximizing the oncolytic effect and antitumor immunity associated with vaccinia virus. Experimental Design: The antitumor efficacy of IL10-armed vaccinia virus (VVL Delta TK-IL10) and control VV Delta TK was assessed in pancreatic cancer cell lines, mice bearing subcutaneous pancreatic cancer tumors and a pancreatic cancer transgenic mouse model. Viral persistence within the tumors was examined and immune depletion experiments as well as immunophenotyping of splenocytes were carried out to dissect the functional mechanisms associated with the viral efficacy. Results: Compared with unarmed VVL Delta TK, VVL Delta TK-IL10 had a similar level of cytotoxicity and replication in vitro in murine pancreatic cancer cell lines, but rendered a superior antitumor efficacy in the subcutaneous pancreatic cancer model and a K-ras-p53 mutant-transgenic pancreatic cancer model after systemic delivery, with induction of long-term antitumor immunity. The antitumor efficacy of VVL Delta TK-IL10 was dependent on CD4(+) and CD8(+), but not NK cells. Clearance of VVL Delta TK-IL10 was reduced at early time points compared with the control virus. Treatment with VVL Delta TK-IL10 resulted in a reduction in virus-specific, but not tumor-specific CD8+ cells compared with VVL Delta TK. Conclusions: These results suggest that VVL Delta TK-IL10 has strong potential as an antitumor therapeutic for pancreatic cancer. (C) 2014 AACR.
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