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Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF

Gene Therapy volume 19, pages 711–723 (2012)Cite this article

Abstract

Interleukin (IL)-12 and granulocyte-monocyte colony-stimulating factor (GM-CSF) have recently been used as immunotherapeutic agents in cancer gene therapy. IL-12 and GM-CSF have differential roles in the antitumor immune response, as IL-12 targets T, NK and natural killer T (NKT) cells and GM-CSF principally targets antigen-presenting cells (APCs). To strengthen the therapeutic efficacy of these two cytokines, we generated an oncolytic adenovirus (Ad), Ad-ΔB7/IL12/GMCSF, coexpressing IL-12 and GM-CSF. Using a murine B16-F10 syngeneic tumor model, we show that Ad-ΔB7/IL12/GMCSF promoted antitumor responses and increased survival compared with an oncolytic Ad expressing IL-12 or GM-CSF alone (Ad-ΔB7/IL12 or Ad-ΔB7/GMCSF, respectively). By measuring cytotoxic T lymphocyte activity and interferon-γ production, we show that the enhanced therapeutic effect was mediated by the induction of immune cell cytotoxicity. In situ delivery of Ad-ΔB7/IL12/GMCSF resulted in massive infiltration of CD4+ T cells, CD8+ T cells, NK cells and CD86+ APCs into the tissue surrounding the necrotic area of the tumor. Moreover, GM-CSF effectively promoted antitumor immune memory, which was significantly augmented by IL-12. Lastly, IL12-expressing oncolytic Ads prevented tumor-induced thymic atrophy and was associated with reduced apoptosis and increased proliferation in the thymus. Taken together, these data demonstrate that an oncolytic Ad coexpressing IL-12 and GM-CSF is a potential therapeutic tool for the treatment of cancer.

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Acknowledgements

This work was supported by Grants from the Ministry of Knowledge Economy (10030051, Dr C-O Yun), the Korea Science and Engineering Foundation (R15-2004-024-02001-0, 2009K001644, 2010-0029220, Dr C-O. Yun), the Korea Food and Drug Administration (KFDA-10172-332 to Dr C-O Yun), and Yonsei University College of Medicine faculty research Grant (6-2010-0052, Dr C-O Yun). Kyung-Ju Choi, Song-Nan Zhang and Ji-Seong Kim are graduate students sponsored by the Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea. Il-Kyu Choi is a graduate student sponsored by KOSEF through National Core Research Center for Nanomedical Technology, Seoul, South Korea.

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Author notes

  1. K-J Choi, S-N Zhang and I-K Choi: These authors contributed equally to the work.

Authors and Affiliations

  1. Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea

    K-J Choi, S-N Zhang & J-S Kim

  2. Department of Oncology, Affiliated Hospital of Yanbian University, Yanji, China

    S-N Zhang

  3. Graduate Program for Nanomedical Science, Yonsei University, Seoul, South Korea

    I-K Choi

  4. Department of Bioengineering, College of Engineering, Hanyang University, Seoul, South Korea

    C-O Yun

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  1. K-J Choi
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Correspondence to C-O Yun.

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Choi, KJ., Zhang, SN., Choi, IK. et al. Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF. Gene Ther 19, 711–723 (2012). https://doi.org/10.1038/gt.2011.125

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