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

Knights, Ashley J.; Nuber, Natko; Thomson, Christopher W.; de la Rosa, O.; Jager, E.; Tiercy, Jean-Marie; van den Broek, M.; Pascolo, S.; Knuth, A.; Zippelius, A.

doi:10.1007/s00262-008-0556-8

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Title		Modified tumour antigen-encoding mRNA facilitates the analysis of naturally occurring and vaccine-induced CD4 and CD8 T cells in cancer patients
Authors		Knights, Ashley J. Nuber, Natko Thomson, Christopher W. de la Rosa, O. Jager, E. Tiercy, Jean-Marie van den Broek, M. Pascolo, S. Knuth, A. Zippelius, A. show all authors [1 - 10]
Published in		Cancer Immunology, Immunotherapy. 2009, vol. 58, no. 3, p. 325-338
Abstract		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.
Keywords		Antibodies, Monoclonal/chemistry — Antigens, Neoplasm/chemistry/metabolism — CD4-Positive T-Lymphocytes/metabolism — CD8-Positive T-Lymphocytes/metabolism — Cancer Vaccines — Carcinoma, Non-Small-Cell Lung/metabolism — Cell Line, Tumor — Epitopes/chemistry — Humans — Interferon-gamma/metabolism — Lung Neoplasms/metabolism — Models, Genetic — Neoplasms/blood/metabolism — Peptides/chemistry — RNA, Messenger/metabolism
Identifiers		DOI: 10.1007/s00262-008-0556-8 PMID: 18663444
Full text		Article - Limited access to UNIGE Other version: http://www.springerlink.com/content/p7524415qv3832w6/fulltext.pdf
Structures		Faculté de médecine / Section de médecine clinique / Département de médecine
Research group		Compatibilité tissulaire et transplantation clinique (562)
Citation (ISO format)		KNIGHTS, Ashley J. et al. Modified tumour antigen-encoding mRNA facilitates the analysis of naturally occurring and vaccine-induced CD4 and CD8 T cells in cancer patients. In: Cancer Immunology, Immunotherapy, 2009, vol. 58, n° 3, p. 325-338. doi: 10.1007/s00262-008-0556-8 https://archive-ouverte.unige.ch/unige:19892