International Immunology Advance Access published online on February 28, 2006
International Immunology, doi:10.1093/intimm/dxh401
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1 Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; Present address: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
* To whom correspondence should be addressed. EBV is associated with a broad range of malignancies. Adoptive immunotherapy of these tumors with EBV-specific CTL proved useful. We generated a panel of primary human T cells specific to various EBV antigens (i.e. Epstein-Barr nuclear antigen 3A, 3B and BamHI-M leftward reading frame) via transfer of modified TCR genes that are either coupled to CD3
Received April 16, 2005
Accepted January 23, 2006
Article
T cell re-targeting to EBV antigens following TCR gene transfer: CD28-containing receptors mediate enhanced antigen-specific IFN
Niels Schaft 1,
Birgit Lankiewicz 2,
Joost Drexhage 2,
Cor Berrevoets 2,
Denis J. Moss 3,
Victor Levitsky 4,
Marc Bonneville 5,
Steven P. Lee 6,
Andrew J. McMichael 7,
Jan-Willem Gratama 2,
Reinier L. H. Bolhuis 8,
Ralph Willemsen 2,
and
Reno Debets 2 *
production
2 Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands
3 Tumor Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, University of Queensland, Brisbane, Australia
4 Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden
5 INSERM U463, Institut de Biologie, Nantes, France
6 Cancer Research UK, Institute for Cancer Studies, University of Birmingham, Birmingham, UK
7 MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, UK
8 Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; Present address: Archifact, Meerewijck 79, 2451 XC Leimuiden, the Netherlands
Reno Debets, E-mail: j.debets{at}erasmusmc.nl
Abstract 
or Fc(
)RI
. TCR-transduced T cells from 20-60% of donors (total number of 25) demonstrated specific lysis of EBV peptide-loaded target cells, whereas lymphoblastoid cell lines expressing native EBV antigens were not killed by any of the EBV-specific T cell populations. This non-responsiveness, confirmed at the level of nuclear factor of activated T cells activation, is not due to receptor configuration since identical receptor formats specific for melanoma antigens successfully re-targeted T cells to native melanoma cells. In an effort to generate a more potent receptor, we introduced a CD28 domain into one of the EBV-specific TCR. This TCR did not affect the cytotoxic response of re-targeted T cells, but dramatically enhanced antigen-specific IFN production. We therefore conclude that these novel CD28-containing EBV-specific TCRs provide a basis for further development of TCR gene transfer to treat EBV-induced diseases.
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