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Wild-type and modified gp100 peptide-pulsed dendritic cell vaccination of advanced melanoma patients can lead to long-term clinical responses independent of the peptide used

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Abstract

Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients. Several strategies have been employed to load DC with antigen, including peptide loading. To increase immunogenicity of peptides, major histocompatibility complex (MHC) class I binding affinity and stability of peptide–MHC complexes at the cell surface may be improved by modification of the amino acid sequence. In this study, we compared the capacity of DC loaded with wild-type versus modified gp100 peptides with higher binding affinities to induce an immune and clinical response in advanced melanoma patients. Metastatic HLA-A2.1+ melanoma patients were vaccinated intravenously (on average 25 × 106 DC) and intradermally (on average 11 × 106 DC) with mature DC loaded with keyhole limpet hemocyanin (KLH) together with tyrosinase peptide and either wild-type (15 patients) or modified (12 patients) gp100 peptides. All vaccinated patients showed a pronounced proliferative T cell or humoral response against KLH. Gp100-specific T cell responses were monitored in post-treatment delayed type hypersensitivity (DTH) skin biopsies by tetramer and functional analysis. Antigen-specific T cells were found in 2 of 15 patients vaccinated with wild-type gp100-loaded DC, versus 1 of 12 patients vaccinated with modified peptide-loaded DC. These three patients also had the best clinical response, with long-term (>8 years) complete responses in two patients, one in each group. We conclude that vaccination with peptide-loaded DC can result in long-term clinical responses in a minority of metastatic melanoma patients, and that the use of modified as compared to wild-type gp100 peptides for DC loading does not result in a relevant enhanced immune responses.

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Acknowledgments

This work was supported by grants from the Netherlands Organization for Scientific Research (920-03-250), the Dutch Cancer Society (AZN/KUN 95/910 and 99/1950), the EU (Cancer immunotherapy LSHC-CT-2006-518234 and DC-THERA LSHB-CT-2004-512074), and the TIL-foundation.

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Authors and Affiliations

  1. Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    W. Joost Lesterhuis & Cornelis J. A. Punt

  2. Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Gerty Schreibelt, Nicole M. Scharenborg, H. Mary-lène H. Brouwer, Ruurd Torensma, Gosse J. Adema, Carl G. Figdor & I. Jolanda M. de Vries

  3. Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Marie-Jeanne P. Gerritsen

  4. Department of Hematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Sandra Croockewit

  5. de Duve Institute, Université Catholique de Louvain, Brussels, Belgium

    Pierre G. Coulie

Authors
  1. W. Joost Lesterhuis
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  2. Gerty Schreibelt
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  3. Nicole M. Scharenborg
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  4. H. Mary-lène H. Brouwer
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  11. I. Jolanda M. de Vries
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  12. Cornelis J. A. Punt
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Corresponding author

Correspondence to I. Jolanda M. de Vries.

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Lesterhuis, W.J., Schreibelt, G., Scharenborg, N.M. et al. Wild-type and modified gp100 peptide-pulsed dendritic cell vaccination of advanced melanoma patients can lead to long-term clinical responses independent of the peptide used. Cancer Immunol Immunother 60, 249–260 (2011). https://doi.org/10.1007/s00262-010-0942-x

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  • DOI: https://doi.org/10.1007/s00262-010-0942-x

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