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Enhancing antimelanoma immune responses through apoptosis

Cancer Gene Therapy volume 10, pages 726–736 (2003)Cite this article

Abstract

We examined the feasibility of using tumor apoptosis at accessible sites to enhance antimelanoma immune responses in a model of spontaneous canine melanoma. We show that priming peripheral blood mononuclear cells with apoptotic melanoma cells significantly enhanced autologous and allogeneic lymphokine-activated killing of tumor cells. Since various pathways required for intrinsic apoptosis are often inactivated in melanoma, we used Fas ligand (FasL) overexpression to promote extrinsic apoptosis. FasL induced apoptosis in five of six cell lines. Each of the susceptible lines, but not the resistant one, expressed Fas mRNA. In addition, direct intratumoral administration of FasL DNA to tumor-bearing dogs was safe, with no adverse events reported over 7 days of observation. A reduction of tumor burden was seen in three of five dogs treated. The reduction of tumor volume was correlated with Fas expression by the tumors, although one dog with a Fas-negative tumor survived for 82 weeks after treatment. Our data show that overexpression of FasL is suitable to promote apoptosis of Fas+ melanomas, and support the notion that priming immune responder cells with apoptotic tumor cells may enhance antitumor responses. The results also suggest that intratumoral administration of FasL offers a safe route for therapeutic gene delivery.

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Acknowledgements

We thank the technical and nursing staffs of the Animal Cancer Center of Colorado State University and Animal Hospital Center for assistance with care and handling of dogs in this study and Drs Erin Dickerson and Valerie Fadok for critical review of the manuscript. This work was supported in part by Grant 1626 from the AKC Canine Health Foundation and Grant 98CA-36 from the Morris Animal Foundation. SRB was supported in part by a fellowship from the University of Colorado Cancer Center.

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Author notes

  1. Gary R Cutter

    Present address: Center for Research Design and Statistical Methods, University of Nevada, Reno, NV, 89557, USA

Authors and Affiliations

  1. Center for Cancer Causation and Prevention, AMC Cancer Research Center and Donald Monk Cancer Research Foundation, Denver, Colorado, USA

    Stacie R Bianco, Juan Sun, Susan P Fosmire, Gary R Cutter & Jaime F Modiano

  2. GlobeImmune Pharmaceuticals, Denver, Colorado, USA

    Juan Sun, Kenneth Hance, Richard C Duke & Donald Bellgrau

  3. Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, USA

    Marcia L Padilla & Stuart C Helfand

  4. Animal Hospital Center, Highlands Ranch, Colorado, USA

    Michelle G Ritt & David T Matthiesen

  5. Idexx Veterinary Services, Broomfield, Colorado, USA

    David M Getzy

  6. Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado, USA

    Richard C Duke, Donald Bellgrau & Jaime F Modiano

  7. University of Colorado Cancer Center, Denver, Colorado, USA

    Richard C Duke, Donald Bellgrau, Gary R Cutter & Jaime F Modiano

  8. Animal Cancer Center, Colorado State University, Fort Collins, Colorado, USA

    Stephen J Withrow, Susan Lana & Steven W Dow

  9. University of Wisconsin Comprehensive Cancer Center, Wisconsin, USA

    Stuart C Helfand

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  1. Stacie R Bianco
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Correspondence to Jaime F Modiano.

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Bianco, S., Sun, J., Fosmire, S. et al. Enhancing antimelanoma immune responses through apoptosis. Cancer Gene Ther 10, 726–736 (2003). https://doi.org/10.1038/sj.cgt.7700625

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