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

Research output: Contribution to journalArticle

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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 - Jan 1 1995
Externally publishedYes

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Interleukin-12
Genetic Therapy
Neoplasms
Sarcoma
Kanamycin Kinase
Cell Line
Natural Killer Cells
Genes
Immunity
Fibroblasts
T-Lymphocytes
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Tahara, H., Zitvogel, L., Storkus, W. J., Zeh, H. J., McKinney, T. G., Schreiber, R. 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.

Effective eradication of established murine tumors with IL-12 gene therapy using a polycistronic retroviral vector. / Tahara, H.; Zitvogel, L.; Storkus, W. J.; Zeh, H. J.; McKinney, T. G.; Schreiber, R. D.; Gubler, U.; Robbins, P. D.; Lotze, M. T.

In: Journal of Immunology, Vol. 154, No. 12, 01.01.1995, p. 6466-6474.

Research output: Contribution to journalArticle

Tahara, H, Zitvogel, L, Storkus, WJ, Zeh, HJ, McKinney, TG, Schreiber, RD, Gubler, U, Robbins, PD & Lotze, MT 1995, 'Effective eradication of established murine tumors with IL-12 gene therapy using a polycistronic retroviral vector', Journal of Immunology, vol. 154, no. 12, pp. 6466-6474.
Tahara H, Zitvogel L, Storkus WJ, Zeh HJ, McKinney TG, Schreiber RD et al. Effective eradication of established murine tumors with IL-12 gene therapy using a polycistronic retroviral vector. Journal of Immunology. 1995 Jan 1;154(12):6466-6474.
Tahara, H. ; Zitvogel, L. ; Storkus, W. J. ; Zeh, H. J. ; McKinney, T. G. ; Schreiber, R. D. ; Gubler, U. ; Robbins, P. D. ; Lotze, M. T. / Effective eradication of established murine tumors with IL-12 gene therapy using a polycistronic retroviral vector. In: Journal of Immunology. 1995 ; Vol. 154, No. 12. pp. 6466-6474.
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AU - Storkus, W. J.

AU - Zeh, H. J.

AU - McKinney, T. G.

AU - Schreiber, R. D.

AU - Gubler, U.

AU - Robbins, P. D.

AU - Lotze, M. T.

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N2 - 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.

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