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Effective eradication of established murine tumors with IL-12 gene-therapy using a polycistronic retroviral vector

Academic Article
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Overview

authors

  • Tahara, H.
  • Zitvogel, L.
  • Storkus, W. J.
  • Zeh, H. J.
  • McKinney, T. G.
  • Schreiber, R. D.
  • Gubler, U.
  • Robbins, Paul D.
  • Lotze, M. T.

publication date

  • June 1995

journal

  • Journal of Immunology  Journal

abstract

  • Our recent studies using IL-12 protein or fibroblasts genetically engineered to secrete IL-12 have demonstrated profound antitumor effects of IL-12 in murine models. The antitumor effects of local, high level IL-12 expression were examined using a retroviral vector, which can express both IL-12 subunits (p35 and p40) and the neomycin phosphotransferase (Neo)-marker gene from a polycistronic message utilizing internal ribosome entry site sequences. All animals intradermally (i.d.) receiving MCA207 murine sarcoma cell line nontransfected or Neo-transfected had progressively growing tumor, whereas all animals injected with MCA207 transfected with IL-12 were tumor free and were subsequently determined to be immune to a rechallenge of nontransfected MCA207 i.d. Similar results were obtained in experiments using the poorly immunogenic MCA102 murine sarcoma cell line. The inoculation of live MCA207-IL-12 tumor cells also caused the regression of contralateral nontransfected MCA207 inoculated either at the same time (80% protection) or up to 3 days before (33% protection) to the therapeutic tumor inoculation. In vivo depletion studies suggest that NK cells and IFN-gamma play important roles in the development of the early phase of the antitumor response, but that T cells (both CD4+ and CD8+) play the major role in the subsequent events, leading to long-term immunity. The potent antitumor effects observed for paracrine gene-delivered administration of IL-12 have thus been confirmed for multiple tumor cell types and in multiple murine strains. We believe that these results support the feasibility of IL-12 gene therapy for the treatment of human cancer.

subject areas

  • Animals
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Female
  • Gene Expression
  • Genetic Therapy
  • Genetic Vectors
  • Interleukin-12
  • Killer Cells, Natural
  • Lymphocyte Depletion
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental
  • Neutralization Tests
  • Retroviridae
  • Sarcoma, Experimental
  • Transfection
  • Tumor Necrosis Factor-alpha
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Identity

International Standard Serial Number (ISSN)

  • 0022-1767

PubMed ID

  • 7759882
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Additional Document Info

start page

  • 6466

end page

  • 6474

volume

  • 154

issue

  • 12

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