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Interferon-alpha gene therapy in combination with CD80 transduction reduces tumorigenicity and growth of established tumor in poorly immunogenic tumor models

Gene Therapy volume 6, pages 1988–1994 (1999)Cite this article

Abstract

Interferon-alpha (IFN-α) or CD80 transduction of tumor cells individually reduces tumorigenicity and enhances antitumor responses. Here, we report that the combination of IFN-α and CD80 cancer gene therapy in poorly immunogenic murine tumor models, the colorectal adenocarcinoma cell line MC38, and the methylcholanthrene-induced fibrosarcoma cell line MCA205 reduces tumor growth more efficiently without affecting in vitro growth. Wild-type (WT), neomycin-resistance (Neo) gene-, or CD80-transduced tumor cells grew progressively in all immunocompetent mice. In contrast, IFN-α-transduced MC38 or MCA205 cells were rejected in 13 of 15 and seven of 15 mice, respectively. Synergistic effects were observed when IFN-α- and CD80-transduced tumor cells were mixed and inoculated. These admixed cells were rejected by 14 of 15 (MC38) or seven of 15 mice (MCA205), whereas, a mixture of IFN-α and Neo cells or CD80 and Neo cells led to tumors associated with progressive growth. Induction of long-lasting tumor immunity against WT tumor cells was demonstrated by rejection of a subsequent rechallenge in 10 of 13 (MC38) and six of seven (MCA205) tumor-free mice. The therapeutic efficacy with established WT MC38 tumors was shown when mice were treated with a vaccine consisting of repetitive injections of IFN-α- and CD80-transduced MC38 cells into the contralateral flank (P < 0.01). this treatment was associated with accumulation of cd4+, CD8+ cells and dendritic cells within the established tumor, demonstrating induction of antitumor immune responses. Combination gene therapy using IFN-α and CD80 is an effective immune therapy of cancer and could be considered for clinical trials.

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Acknowledgements

We thank Prof Keiji Mitamura (Showa University, Tokyo, Japan) for his encouragement and support, and appreciate Drs Joseph Baar, Hiromune Shimamura, Galina V Shurin, Ronna L Campbell, Quan Cai, Yasuhiko Nishioka, Takashi Iwazawa, Christine Odoux (University of Pittsburgh, PA) for helpful discussion. We also thank Mr Robbie B Mailliard, Mr Alexander Ducruet and Ms Madeline A Wahl (University of Pittsburgh, PA) for their outstanding technical assistance. This study was supported in part by grants from Schering-Plough Institute, PO1CA68067-01, and PO1CA73743-01 to Michael T Lotze.

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  1. Department of Surgery, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    K Hiroishi, T Tüting, H Tahara & M T Lotze

  2. Department of Dermatology, J Gutenberg-University, Mainz, Germany

    T Tüting

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Hiroishi, K., Tüting, T., Tahara, H. et al. Interferon-alpha gene therapy in combination with CD80 transduction reduces tumorigenicity and growth of established tumor in poorly immunogenic tumor models. Gene Ther 6, 1988–1994 (1999). https://doi.org/10.1038/sj.gt.3301034

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