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Cytokine gene therapy of gliomas: effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells

Gene Therapy volume 8, pages 1157–1166 (2001)Cite this article

Abstract

To provide a means for comparing strategies for cytokine gene therapy against intracranial (i.c.) tumors, we generated rat gliosarcoma 9L cells transfected with interleukin-4 (9L-IL4), interleukin-12 (9L-IL12), granulocyte–macrophage colony-stimulating factor (9L-GMCSF) or interferon-α (9L-IFNα). To simulate direct and highly efficient cytokine gene delivery, cytokine transfected 9L tumors were implanted i.c. into syngeneic rats. i.c. injection led to tumor-outgrowth in the brain and killed most animals, whereas these cell lines were rejected following intradermal (i.d.) injection. Cytokine-expressing i.c. 9L tumors, however, had a greater degree of infiltration by immune cells compared with control, mock-transfected 9L-neo, but to a lesser degree than i.d. cytokine-expressing tumors. Tumor angiogenesis was suppressed in cytokine-transfected tumors. In a prophylaxis model, i.d. vaccination with 9L-IL4 resulted in long-term survival of 90% of rats challenged i.c. with parental 9L; whereas 40% of 9L-GM-CSF, 40% of 9L-IFNα and 0% of 9L-IL12-immunized rats were protected. In a therapy model (day 3 i.c. 9L tumors), only i.d. immunization with 9L-IL4 had long-term therapeutic benefits as 43% of rats survived >100 days. These data indicate that peripheral immunization with 9L-IL4 had the most potent therapeutic benefit among various cytokines and approaches tested against established, i.c. 9L tumors.

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Acknowledgements

This work was supported by Grants CA68550, CA68067, and NS01810, a grant from the Copeland Fund of The Pittsburgh Foundation, and a grant from the CMRF of the University of Pittsburgh. The authors would like to express their appreciation to Drs Hideaki Tahara, Kazumasa Hiroishi and Tadamichi Suzuki who provided the DFG-retroviral vectors used in this study.

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Authors and Affiliations

  1. University of Pittsburgh Cancer Institute and Department of Neurological Surgery, Brain Tumor Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    H Okada, J Attanucci, M Erff, WK Fellows & IF Pollack

  2. University of Pittsburgh Cancer Institute and Department of Pathology, Brain Tumor Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    L Villa & WH Chambers

  3. University of Pittsburgh Cancer Institute and Department of Surgery, Brain Tumor Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    MT Lotze

  4. University of Pittsburgh Cancer Institute and Department of Molecular Genetics and Biochemistry, Brain Tumor Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    MT Lotze

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  1. H Okada
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Okada, H., Villa, L., Attanucci, J. et al. Cytokine gene therapy of gliomas: effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells. Gene Ther 8, 1157–1166 (2001). https://doi.org/10.1038/sj.gt.3301496

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