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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 3rd, T G McKinney, R D Schreiber, U Gubler, P D Robbins and M T Lotze
J Immunol June 15, 1995, 154 (12) 6466-6474;
H Tahara
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L Zitvogel
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W J Storkus
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H J Zeh 3rd
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T G McKinney
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R D Schreiber
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U Gubler
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P D Robbins
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M T Lotze
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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-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.

  • Copyright © 1995 by American Association of Immunologists

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The Journal of Immunology
Vol. 154, Issue 12
15 Jun 1995
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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
The Journal of Immunology June 15, 1995, 154 (12) 6466-6474;

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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
The Journal of Immunology June 15, 1995, 154 (12) 6466-6474;
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Print ISSN 0022-1767        Online ISSN 1550-6606