T cell re-targeting to EBV antigens following TCR gene transfer: CD28-containing receptors mediate enhanced antigen-specific IFNgamma production.

Journal article

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.

Authors: Schaft, N; Lankiewicz, B; Drexhage, J; Berrevoets, C; Moss, D

• Publication status: Published
• Journal: International immunology
• Volume: 18
• Issue: 4
• Pages: 591-601
• Publication date: 2006-04-01
• DOI: 10.1093/intimm/dxh401
• EISSN: 1460-2377
• ISSN: 0953-8178
• Language: English
• Keywords: Genetic Therapy; Antigens, CD28; T-Lymphocytes; Enzyme-Linked Immunosorbent Assay; Jurkat Cells; Epstein-Barr Virus Nuclear Antigens; Transduction, Genetic; Flow Cytometry; Genes, T-Cell Receptor; Humans; Gene Transfer Techniques; Receptors, Antigen, T-Cell; Interferon-gamma