PMID- 25711537 OWN - NLM STAT- MEDLINE DCOM- 20160719 LR - 20240210 IS - 2326-6074 (Electronic) IS - 2326-6066 (Print) IS - 2326-6066 (Linking) VI - 3 IP - 10 DP - 2015 Oct TI - Human Leukocyte Antigen (HLA) A*1101-Restricted Epstein-Barr Virus-Specific T-cell Receptor Gene Transfer to Target Nasopharyngeal Carcinoma. PG - 1138-47 LID - 10.1158/2326-6066.CIR-14-0203-T [doi] AB - Infusing virus-specific T cells is effective treatment for rare Epstein-Barr virus (EBV)-associated posttransplant lymphomas, and more limited success has been reported using this approach to treat a far more common EBV-associated malignancy, nasopharyngeal carcinoma (NPC). However, current approaches using EBV-transformed lymphoblastoid cell lines to reactivate EBV-specific T cells for infusion take 2 to 3 months of in vitro culture and favor outgrowth of T cells targeting viral antigens expressed within EBV(+) lymphomas, but not in NPC. Here, we explore T-cell receptor (TCR) gene transfer to rapidly and reliably generate T cells specific for the NPC-associated viral protein LMP2. We cloned a human leukocyte antigen (HLA) A*1101-restricted TCR, which would be widely applicable because 40% of NPC patients carry this HLA allele. Studying both the wild-type and modified forms, we have optimized expression of the TCR and demonstrated high-avidity antigen-specific function (proliferation, cytotoxicity, and cytokine release) in both CD8(+) and CD4(+) T cells. The engineered T cells also inhibited LMP2(+) epithelial tumor growth in a mouse model. Furthermore, transduced T cells from patients with advanced NPC lysed LMP2-expressing NPC cell lines. Using this approach, within a few days large numbers of high-avidity LMP2-specific T cells can be generated reliably to treat NPC, thus providing an ideal clinical setting to test TCR gene transfer without the risk of autoimmunity through targeting self-antigens. CI - (c)2015 American Association for Cancer Research. FAU - Zheng, Yong AU - Zheng Y AD - School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom. FAU - Parsonage, Greg AU - Parsonage G AD - School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom. FAU - Zhuang, Xiaodong AU - Zhuang X AD - School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom. FAU - Machado, Lee R AU - Machado LR AD - School of Health, University of Northampton, Boughton Green Road, Northampton, United Kingdom. FAU - James, Christine H AU - James CH AD - School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom. FAU - Salman, Asmaa AU - Salman A AD - School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom. FAU - Searle, Peter F AU - Searle PF AD - School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom. FAU - Hui, Edwin P AU - Hui EP AD - Partner State Key Laboratory of Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, PR China. FAU - Chan, Anthony T C AU - Chan AT AD - Partner State Key Laboratory of Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, PR China. FAU - Lee, Steven P AU - Lee SP AD - School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom. s.p.lee@bham.ac.uk. LA - eng SI - GENBANK/KU163590 GR - 15152/CRUK_/Cancer Research UK/United Kingdom GR - A5798/CRUK_/Cancer Research UK/United Kingdom GR - C489/A5798/CRUK_/Cancer Research UK/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150224 PL - United States TA - Cancer Immunol Res JT - Cancer immunology research JID - 101614637 RN - 0 (Cytokines) RN - 0 (EBV-associated membrane antigen, Epstein-Barr virus) RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA-A Antigens) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (Viral Matrix Proteins) RN - 82115-62-6 (Interferon-gamma) SB - IM EIN - Cancer Immunol Res. 2016 Feb;4(2):173-4. PMID: 26839310 MH - Animals MH - CD4-Positive T-Lymphocytes/immunology/metabolism MH - CD8-Positive T-Lymphocytes/immunology/metabolism MH - Carcinoma MH - Cell Line, Tumor MH - Cytokines/biosynthesis MH - Cytotoxicity, Immunologic MH - Disease Models, Animal MH - Epitopes, T-Lymphocyte/immunology MH - Epstein-Barr Virus Infections/*complications/*immunology MH - Female MH - Gene Expression MH - Gene Transfer Techniques MH - HLA-A Antigens/*immunology MH - Herpesvirus 4, Human/*immunology MH - Humans MH - Immunotherapy MH - Interferon-gamma/biosynthesis MH - Mice MH - Molecular Sequence Data MH - Nasopharyngeal Carcinoma MH - Nasopharyngeal Neoplasms/*etiology/therapy MH - Receptors, Antigen, T-Cell/*genetics MH - Transduction, Genetic MH - Tumor Burden MH - Viral Matrix Proteins/immunology MH - Xenograft Model Antitumor Assays PMC - PMC4456157 MID - EMS62383 OID - NLM: EMS62383 EDAT- 2015/02/26 06:00 MHDA- 2016/07/20 06:00 PMCR- 2016/04/01 CRDT- 2015/02/26 06:00 PHST- 2014/10/30 00:00 [received] PHST- 2015/02/12 00:00 [accepted] PHST- 2015/02/26 06:00 [entrez] PHST- 2015/02/26 06:00 [pubmed] PHST- 2016/07/20 06:00 [medline] PHST- 2016/04/01 00:00 [pmc-release] AID - 2326-6066.CIR-14-0203-T [pii] AID - 10.1158/2326-6066.CIR-14-0203-T [doi] PST - ppublish SO - Cancer Immunol Res. 2015 Oct;3(10):1138-47. doi: 10.1158/2326-6066.CIR-14-0203-T. Epub 2015 Feb 24.