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Cancer Immunology, Immunotherapy

, Volume 58, Issue 3, pp 325–338 | Cite as

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

  • Ashley J. KnightsEmail author
  • Natko Nuber
  • Christopher W. Thomson
  • Olga de la Rosa
  • Elke Jäger
  • Jean-Marie Tiercy
  • Maries van den Broek
  • Steve Pascolo
  • Alexander Knuth
  • Alfred ZippeliusEmail author
Original Article

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

T cells Tumour immunity Vaccination Antigens/peptides/epitopes 

Notes

Acknowledgments

We are grateful to Heidi Mattlin, Conny Schneider, Bruno Schmid and Claudia Matter for excellent technical assistance. Dr I. Davis & Dr W. Chen, Melbourne Ludwig Institute, for providing NY-ESO-1 peptides, and Dr D. Rimoldi and Dr V. Cesson, Lausanne Ludwig Institute, for the MHC class II blocking antibodies. This work was supported in part by the Cancer Research Institute/Ludwig Institute for Cancer Research & Cancer Vaccine Collaborative, The Atlantic Philanthropies, Swiss National Science Foundation and UBS Wealth Management. A.Z. was supported in part by the Emmy-Noether Program (Zi685-2/3) of the Deutsche Forschungsgemeinschaft.

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Ashley J. Knights
    • 1
    Email author
  • Natko Nuber
    • 1
  • Christopher W. Thomson
    • 1
  • Olga de la Rosa
    • 1
  • Elke Jäger
    • 2
  • Jean-Marie Tiercy
    • 3
  • Maries van den Broek
    • 1
  • Steve Pascolo
    • 1
  • Alexander Knuth
    • 1
  • Alfred Zippelius
    • 1
    • 4
    Email author
  1. 1.Medical Oncology, Department of Internal MedicineUniversity Hospital ZurichZurichSwitzerland
  2. 2.Krankenhaus NordwestFrankfurtGermany
  3. 3.University HospitalGenevaSwitzerland
  4. 4.University Hospital BaselBaselSwitzerland

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