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

International Immunology
Niels SchaftReno Debets

Abstract

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 dev...Continue Reading

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Citations

May 13, 2008·Human Gene Therapy·Duane A MitchellJohn H Sampson
Feb 12, 2010·Expert Opinion on Biological Therapy·Miriam CoccorisReno Debets
Apr 17, 2009·Expert Opinion on Biological Therapy·Victoria Marcu-MalinaJürgen Kuball
Mar 8, 2011·Expert Opinion on Biological Therapy·Dario SangioloWanda Piacibello
Sep 12, 2008·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Ralph WillemsenReno Debets
Oct 17, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Coen GoversReno Debets
Jul 16, 2014·International Journal of Molecular Medicine·Changli TaoShulin Huang
May 21, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Zsolt SebestyénReno Debets
Sep 13, 2020·Cancers·Yonggang PeiErle S Robertson
Mar 7, 2021·Cancers·Aleksei TitovEmil Bulatov
Jun 3, 2015·Disease Models & Mechanisms·Michaela Sharpe, Natalie Mount

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