Transduction of Primary Lymphocytes with Epstein-Barr Virus (EBV) Latent Membrane Protein-Specific T-Cell Receptor Induces Lysis of Virus-Infected Cells: A Novel Strategy for the Treatment of Hodgkin's Disease and Nasopharyngeal Carcinoma |
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Authors: | Lisa A. Jurgens Rajiv Khanna James Weber Rimas J. Orentas |
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Affiliation: | (1) Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin;(2) Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin;(3) Queensland Institute for Medical Research, Brisbane, Australia;(4) Department of Pediatrics, Section of Hematology-Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226 |
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Abstract: | Adoptive immunotherapy with in vitro expanded cytotoxic T lymphocytes specific for Epstein-Barr virus (EBV) can successfully treat post-transplant lymphoproliferative disease (PTLD). However, extension of a similar strategy to Hodgkin's disease (HD) and nasopharyngeal carcinoma (NPC) is limited by the poor immunogenicity of the limited set of EBV latency antigens expressed in these malignancies, making T-cell expansion difficult. Retroviral transduction of LMP-specific T-cell receptors (TCR) into activated T lymphocytes may provide a universal, MHC-restricted, means to generate effector cells without the need for tissue culture based methods of CTL expansion. We report the transfer of two LMP2-specific TCRs from human T-cell clones (HLA-A2 and HLA-A23,24 restricted) that confer the ability to lyse EBV-immortalized B-lymphoblastoid cell lines (B-LCL). B-LCL are the best model for native expression of LMP2. We also demonstrate the rapid transfer of the TCR by nucleofection of primary T cells using a simple plasmid-based vector. The ability to detect nucleofected TCRVβ chain by antibody, fully assembled TCR by tetramer, and peptide-MHC-specific lytic activity indicates that nucleofection can serve as a tool for rapid screening of TCR specificity. |
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Keywords: | Immunotherapy adoptive Epstein-Barr virus T-cell receptor retroviral transduction gene therapy |
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