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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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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DOI: https://doi.org/10.1038/sj.gt.3301034
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