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Antitumor efficacy of a human interleukin-12 expression plasmid demonstrated in a human peripheral blood leukocyte/human lung tumor xenograft SCID mouse model

Cancer Gene Therapy volume 8, pages 371–377 (2001)Cite this article

Abstract

Genes encoding the p35 and p40 subunits of human interleukin-12 (IL-12) and the bacterial aminoglycoside phosphotransferase were cloned into a mammalian expression plasmid. The resultant plasmid, pCMVIL-12neo, was used to transfect human lung tumor cell linesin vitro. Stably transfected subclones were generated and found to secrete human IL-12 for at least 10 days following a lethal dose of γ-radiation. The ability of the IL-12–producing tumor cells to promote an antitumor responsein vivo was evaluated in SCID mice co-engrafted subcutaneously with human peripheral blood lymphocytes (PBLs) and viable human lung tumor cells (SCID-Winn assay). Using this model system, it was established that IL-12 released locally into tumors by irradiated IL-12–transfected cells activated the human PBL and promoted their ability to suppress tumor development in a dose-dependent fashion. PBL subset depletion studies revealed that the antitumor effect promoted by the IL-12–modified cells was dependent on the presence of human CD8+ T cells and, to a lesser extent, human CD56+ natural killer cells within the xenograft. We conclude that (a) irradiated human lung tumor cells genetically modified with pCMVIL-12neo secrete bioactive human IL-12 at concentrations sufficient to promote a human lymphocyte-mediated antitumor response in the microenvironment of the xenograft, and (b) that the SCID-Winn assay provides a useful model for the preclinical evaluation of cytokine-based human immunotherapy protocols. Cancer Gene Therapy (2001) 8, 371–377

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Acknowledgements

We are grateful to Stanley Wolf (Genetics Institute, Andover, MA) for generously supplying the cDNA for the p35 and p40 subunits of human IL-12.

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  1. Nejat K Egilmez: These authors contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Immunology, Roswell Park Cancer Institute, Buffalo, 14263, NY

    Stephen D Hess, Nejat K Egilmez & Richard B Bankert

  2. Department of Internal Medicine, Takayama Red Cross Hospital, Gifu, Japan

    Junko Shiroko

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  1. Stephen D Hess
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  2. Nejat K Egilmez
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  3. Junko Shiroko
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  4. Richard B Bankert
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Correspondence to Nejat K Egilmez.

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Hess, S., Egilmez, N., Shiroko, J. et al. Antitumor efficacy of a human interleukin-12 expression plasmid demonstrated in a human peripheral blood leukocyte/human lung tumor xenograft SCID mouse model. Cancer Gene Ther 8, 371–377 (2001). https://doi.org/10.1038/sj.cgt.7700314

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