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

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

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280 Scopus citations

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-γ 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.

Original languageEnglish (US)
Pages (from-to)6466-6474
Number of pages9
JournalJournal of Immunology
Volume154
Issue number12
StatePublished - 1995

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Tahara, H., Zitvogel, L., Storkus, W. J., Zeh, H. J., McKinney, T. G., Schreiber, R. D., Gubler, U., Robbins, P. D., & Lotze, M. T. (1995). Effective eradication of established murine tumors with IL-12 gene therapy using a polycistronic retroviral vector. Journal of Immunology, 154(12), 6466-6474.