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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.

Original publication

DOI

10.1158/2326-6066.cir-14-0203-t

Type

Journal article

Journal

Cancer immunology research

Publication Date

10/2015

Volume

3

Pages

1138 - 1147

Addresses

School of Cancer Sciences, Cancer Immunology & Immunotherapy Centre (CIIC), University of Birmingham, Edgbaston, Birmingham, United Kingdom.

Keywords

CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Animals, Humans, Mice, Herpesvirus 4, Human, Epstein-Barr Virus Infections, Carcinoma, Nasopharyngeal Neoplasms, Disease Models, Animal, Receptors, Antigen, T-Cell, Viral Matrix Proteins, HLA-A Antigens, Epitopes, T-Lymphocyte, Cytokines, Immunotherapy, Tumor Burden, Xenograft Model Antitumor Assays, Gene Transfer Techniques, Transduction, Genetic, Cytotoxicity, Immunologic, Gene Expression, Molecular Sequence Data, Female, Interferon-gamma, Nasopharyngeal Carcinoma