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Modified tumour antigen-encoding mRNA facilitates the analysis of naturally occurring and vaccine-induced CD4 and CD8 T cells in cancer patients

Knights, Ashley ; Nuber, Natko ; Thomson, Christopher ; de la Rosa, Olga ; Jäger, Elke ; Tiercy, Jean-Marie ; van den Broek, Maries ; Pascolo, Steve ; Knuth, Alexander ; Zippelius, Alfred

In: Cancer Immunology, Immunotherapy, 2009, vol. 58, no. 3, p. 325-338

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    Titre
    • Modified tumour antigen-encoding mRNA facilitates the analysis of naturally occurring and vaccine-induced CD4 and CD8 T cells in cancer patients
    Auteur
    • Knights, Ashley. Medical Oncology, Department of Internal Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Nuber, Natko. Medical Oncology, Department of Internal Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Thomson, Christopher. Medical Oncology, Department of Internal Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • de la Rosa, Olga. Medical Oncology, Department of Internal Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Jäger, Elke. Krankenhaus Nordwest, Frankfurt, Germany
    • Tiercy, Jean-Marie. University Hospital, Geneva, Switzerland
    • van den Broek, Maries. Medical Oncology, Department of Internal Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Pascolo, Steve. Medical Oncology, Department of Internal Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Knuth, Alexander. Medical Oncology, Department of Internal Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Zippelius, Alfred. Medical Oncology, Department of Internal Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Cancer Immunology, Immunotherapy, 2009, vol. 58, no. 3, p. 325-338. Springer-Verlag
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:314048
    Summary
    The development of effective anti-cancer vaccines requires precise assessment of vaccine-induced immunity. This is often hampered by low ex vivo frequencies of antigen-specific T cells and limited defined epitopes. This study investigates the applicability of modified, in vitro-transcribed mRNA encoding a therapeutically relevant tumour antigen to analyse T cell responses in cancer patients. In this study transfection of antigen presenting cells, by mRNA encoding the tumour antigen NY-ESO-1, was optimised and applied to address spontaneous and vaccine-induced T cell responses in cancer patients. Memory CD8+ T cells from lung cancer patients having detectable humoral immune responses directed towards NY-ESO-1 could be efficiently detected in peripheral blood. Specific T cells utilised a range of different T cell receptors, indicating a polyclonal response. Specific killing of a panel of NY-ESO-1 expressing tumour cell lines indicates recognition restricted to several HLA allelic variants, including a novel HLA-B49 epitope. Using a modified mRNA construct targeting the translated antigen to the secretory pathway, detection of NY-ESO-1-specific CD4+ T cells in patients could be enhanced, which allowed the in-depth characterisation of established T cell clones. Moreover, broad CD8+ and CD4+ T cell responses covering multiple epitopes were detected following mRNA stimulation of patients treated with a recombinant vaccinia/fowlpox NY-ESO-1 vaccine. This approach allows for a precise monitoring of responses to tumour antigens in a setting that addresses the breadth and magnitude of antigen-specific T cell responses, and that is not limited to a particular combination of known epitopes and HLA-restrictions