A vaccinia virus armed with interleukin-10 Is a promising therapeutic agent for treatment of murine pancreatic cancer

Louisa S. Chard, Eleni Maniati, Pengju Wang, Zhongxian Zhang, Dongling Gao, Jiwei Wang, Fengyu Cao, Jahangir Ahmed, Margueritte El Khouri, Jonathan Hughes, Shengdian Wang, Xiaozhu Li, Bela Denes, Istvan Fodor, Thorsten Hagemann, Nicholas R. Lemoine, Yaohe Wang

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36 Citations (Scopus)

Abstract

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 (VVLDTK-IL10) and control VVDTK 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 VVLDTK, VVLDTK-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 cancermodel and a K-ras-p53 mutant-transgenic pancreatic cancer model after systemic delivery, with induction of long-term antitumor immunity. The antitumor efficacy of VVLDTK-IL10 was dependent on CD4 and CD8, but not NK cells. Clearance of VVLDTK-IL10 was reduced at early time points compared with the control virus. Treatment with VVLDTK-IL10 resulted in a reduction in virus-specific, but not tumor-specific CD8 cells compared with VVLDTK. Conclusions: These results suggest that VVLDTK-IL10 has strong potential as an antitumor therapeutic for pancreatic cancer.

Original languageEnglish
Pages (from-to)405-416
Number of pages12
JournalClinical Cancer Research
Volume21
Issue number2
DOIs
Publication statusPublished - Jan 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Chard, L. S., Maniati, E., Wang, P., Zhang, Z., Gao, D., Wang, J., Cao, F., Ahmed, J., El Khouri, M., Hughes, J., Wang, S., Li, X., Denes, B., Fodor, I., Hagemann, T., Lemoine, N. R., & Wang, Y. (2015). A vaccinia virus armed with interleukin-10 Is a promising therapeutic agent for treatment of murine pancreatic cancer. Clinical Cancer Research, 21(2), 405-416. https://doi.org/10.1158/1078-0432.CCR-14-0464