gms | German Medical Science

63. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie (JNS)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

13. - 16. Juni 2012, Leipzig

Targeting EGFRvIII-positive glioma cells using a novel natural killer cell chimeric antigen receptor type consisting of DAP12 and the single chain antibody variable fragment MR1-1

Meeting Abstract

  • N. Müller - Sektion Experimentelle Neurochirurgie/Tumor Immunologie, Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus, TU Dresden
  • K. Töpfer - Sektion Experimentelle Neurochirurgie/Tumor Immunologie, Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus, TU Dresden
  • M. Cartellieri - Institute für Immunologie, Medizinische Fakultät Carl Gustav Carus, TU Dresden
  • G. Schackert - Sektion Experimentelle Neurochirurgie/Tumor Immunologie, Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus, TU Dresden
  • A. Temme - Sektion Experimentelle Neurochirurgie/Tumor Immunologie, Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus, TU Dresden

Deutsche Gesellschaft für Neurochirurgie. Japanische Gesellschaft für Neurochirurgie. 63. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie (JNS). Leipzig, 13.-16.06.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. DocP 088

DOI: 10.3205/12dgnc475, URN: urn:nbn:de:0183-12dgnc4758

Veröffentlicht: 4. Juni 2012

© 2012 Müller et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Objective: Natural killer cells (NK) are able to recognize and kill tumor cells with loss of HLA class I expression and concomitant decrease of HLA-E on their surface. However, most gliomas still express HLA class I, and NK cell reactivity against HLA I-negative solid tumors is blocked by inhibitory non classical HLA and by the lack of activating ligands on the surface of the tumor cells. To overcome this problem we sought to generate and evaluate a novel chimeric antigen receptor consisting of an anti-Epidermal Growth Factor Receptor Variant III (EGFRvIII) single chain antibody scFv(MR1-1) and the DNAX activation protein of 12kDa (DAP12), a signaling adaptor protein of NK cells containing an immunoreceptor tyrosine-based activation motif.

Methods: Using recombinant DNA technology we generated a lentiviral vector encoding the scFv-(MR1-1)-DAP12 NK cell receptor. This vector and control vectors were used to transduce the human NK cell line YTS. The expression and the effector function of scFv-(MR1-1)-DAP12 in YTS cells were tested in flow cytometry, chromium release assay and western blot analysis using U87-MG-EGFRvIII glioma target cells.

Results: The NK cell line YTS engrafted with the chimeric scFv(MR1-1)-DAP12 receptor conferred a selective cytotoxicity against EGFRvIII-positive glioma cells, whereas control effector cells only expressing DAP12 showed no effect. Co-incubation of YTS engrafted with scFv(MR1-1)-DAP12 with EGFRvIII-positive target cells was associated with the appearance of phosphorylated ZAP70 confirming functional signaling via the DAP12-proportion of the chimeric receptor.

Conclusions: Our results suggest that this new receptor type might be suitable for NK-cell based immunotherapy of gliomas. Further studies in xenograft models and using primary NK cells are warranted to further pursue NK cell-based immunotherapy of gliomas.