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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 CD3zeta or Fc(epsilon)RIgamma. 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 IFNgamma 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.

Original publication

DOI

10.1093/intimm/dxh401

Type

Journal article

Journal

Int Immunol

Publication Date

04/2006

Volume

18

Pages

591 - 601

Keywords

CD28 Antigens, Enzyme-Linked Immunosorbent Assay, Epstein-Barr Virus Nuclear Antigens, Flow Cytometry, Gene Transfer Techniques, Genes, T-Cell Receptor, Genetic Therapy, Humans, Interferon-gamma, Jurkat Cells, Receptors, Antigen, T-Cell, T-Lymphocytes, Transduction, Genetic