title: Human Leukocyte Antigen (HLA) A*1101-Restricted Epstein-Barr Virus-Specific T-cell Receptor Gene Transfer to Target Nasopharyngeal Carcinoma.
abstract: 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.
authors.affiliation: School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Greg
authors.initials: G
authors.lastname: Parsonage
authors.affiliation: School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: School of Health, University of Northampton, Boughton Green Road, Northampton, United Kingdom.
authors.forename: Lee R
authors.initials: LR
authors.lastname: Machado
authors.affiliation: School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Christine H
authors.initials: CH
authors.lastname: James
authors.affiliation: School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Asmaa
authors.initials: A
authors.lastname: Salman
authors.affiliation: School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Searle
authors.affiliation: 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.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Hui
authors.affiliation: 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.
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.affiliation: School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom. s.p.lee@bham.ac.uk.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Lee
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002277:Carcinoma; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015234:HLA-A Antigens / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008969:Molecular Sequence Data; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000209:etiology* / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D014161:Transduction, Genetic; D047368:Tumor Burden; D014763:Viral Matrix Proteins / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D011948:Receptors, Antigen, T-Cell; D014763:Viral Matrix Proteins; D007371:Interferon-gamma