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Immunotherapy for murine K1735 melanoma: Combinatorial use of recombinant adenovirus expressing CD40L and other immunomodulators

Cancer Gene Therapy volume 9, pages 597–605 (2002)Cite this article

Abstract

We have constructed and tested five recombinant adenoviruses (Ads) that express a variety of immunomodulators, including CD40 ligand (CD40L), a potent costimulator of several components of the immune system. We demonstrate that CD40L expressed from Ad in K1735 mouse melanoma cells leads to a strong reduction in tumorigenicity and to efficient protective immunity in a vaccination setting. Subsequently, using a therapeutic approach, we found that local, intratumoral coinjection of CD40L- and IL-2–expressing Ads was superior to any other agents tested and resulted in an at least 1.9-fold increase in mean survival time, in contrast to systemic application of recombinant CD40L or GM-CSF proteins, which had no significant effects. When using vaccination as a therapeutic approach, the combinations of CD40L plus IL-2 or GM-CSF plus IL-2 from Ad gave rise to an extended (2.8-fold) increase in mean survival time. A detailed analysis of immune cells present within regressing tumors indicated that mainly CD4+ and CD8+ T cells, and to a lesser extent dendritic cells, infiltrated the tumor mass, but not NK cells, macrophages, or granulocytes. These results propose that a combination of CD40L plus IL-2 has an improved efficacy over the use of single agents when applied for direct in situ therapy or vaccination therapy.

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Acknowledgements

This work was supported by the Kanton Zürich and by a grant from the Krebsliga of the Kanton Zürich (to SH). We thank E Horvath for excellent technical assistance and F Ochsenbein for graphic designs. Statistical analysis was performed with the help of W Blanckenhorn, Museum of Zoology, University of Zürich. We further thank R Dummer, Department of Dermatology, University Hospital Zürich, and L Martin, Molecular Biology, for careful reading of the manuscript.

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  1. Isabelle Peter and Michael Nawrath: Both authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular Biology, University of Zürich, Winterthurerstrasse 190, Zürich, CH-8057, Switzerland

    Isabelle Peter, Anna Mezzacasa & Silvio Hemmi

  2. Institute of Medical Virology, University of Zürich, Gloriastrasse 30, Zürich, CH-8028, Switzerland

    Michael Nawrath

  3. Department of Dermatology, University Hospital, Gloriastrasse 31, Zürich, CH-8091, Switzerland

    Jivko Kamarashev

  4. Department of Experimental Immunology, University Hospital, Gloriastrasse 31, Zürich, CH-8091, Switzerland

    Bernhard Odermatt

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  1. Isabelle Peter
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Correspondence to Silvio Hemmi.

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Peter, I., Nawrath, M., Kamarashev, J. et al. Immunotherapy for murine K1735 melanoma: Combinatorial use of recombinant adenovirus expressing CD40L and other immunomodulators. Cancer Gene Ther 9, 597–605 (2002). https://doi.org/10.1038/sj.cgt.7700475

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