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

• Published in: Gene therapy Vol. 19; no. 7; pp. 711 - 723
• Main Authors: Choi, K-J, Zhang, S-N, Choi, I-K, Kim, J-S, Yun, C-O
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2012; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Adenovirus; Adenoviruses; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Animals; Antigen-presenting cells; Antigen-Presenting Cells - immunology; Antitumor activity; Apoptosis; Applied cell therapy and gene therapy; Atrophy; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer; Cancer cells; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD86 antigen; Cell Biology; Cell Line, Tumor; Colony-stimulating factor; Cytokines; Cytotoxicity; Data processing; Fundamental and applied biological sciences. Psychology; gamma -Interferon; Gene Expression; Gene Therapy; Genetic Therapy - methods; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Health. Pharmaceutical industry; Human Genetics; Immune response; Immune system; Immunologic Memory; Immunological memory; Immunotherapy; Industrial applications and implications. Economical aspects; Interleukin 1; Interleukin 12; Interleukin-12 - genetics; Interleukins; Killer Cells, Natural - immunology; Leukocytes (granulocytic); Lymphocytes T; Male; Medical sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Metastases; Mice; Mice, Inbred C57BL; Monocytes; Nanotechnology; Natural killer cells; Oncolysis; Oncolytic Viruses - genetics; original-article; Physiological aspects; Prevention; T-Lymphocytes, Cytotoxic - immunology; Thymus; Thymus Gland - immunology; Thymus Gland - pathology; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tumors; γ-Interferon; IL-12; GM-CSF; oncolytic adenovirus; Antineoplastic agent; Adenovirus 12; Adenoviridae; Thymus gland; Memory; Cytokine; Interleukin 12; Virus; Atrophy; Prevention; Human adenovirus; Mastadenovirus; Gene therapy; Vector
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2011.125

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.