Human Leukocyte Antigen (HLA) A*1101-restricted Epstein-Barr virus-specific T-cell receptor gene transfer to target Nasopharyngeal carcinoma

Zheng, Y., Parsonage, G., Zhuang, X., Machado, L., James, C., Salman, A., Searle, P., Hui, E. P., Chan, A. T. C. and Lee, S. P. (2015) Human Leukocyte Antigen (HLA) A*1101-restricted Epstein-Barr virus-specific T-cell receptor gene transfer to target Nasopharyngeal carcinoma. Cancer Immunology Research. 3(10) 2326-6066.

Zheng_etal_AACR_2015_Human_Leukocyte_Antigen_HLA_A_1101_restricted_Epstein_Barr_virus_specific_T_cell_rece ... (1MB)

Item Type:	Article
Abstract:	Infusing virus-specific T-cells is effective treatment for rare Epstein-Barr virus (EBV)-associated post-transplant 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 2-3 months of in vitro culture and favour outgrowth of T-cells targeting viral antigens expressed within EBV+ lymphomas but not 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 HLA A*1101-restricted TCR, which would be widely applicable since 40% of NPC patients carry this HLA allele. Studying both wild-type and modified forms we have optimised expression of the TCR and demonstrated high avidity antigen-specific function (proliferation, cytotoxicity, cytokine release) in both CD8+ and CD4+ T-cells. The engineered T-cells also inhibited LMP2+ epithelial tumour growth in a mouse model. Furthermore, transduced T-cells from patients with advanced NPC lysed LMP2-expressing NPC cell lines. Therefore, using this approach, within a few days large numbers of high avidity LMP2-specific T-cells can be reliably generated to treat NPC, providing an ideal clinical setting to test TCR gene transfer without the risk of autoimmunity through targeting self-antigens.
Creators:	Zheng, Yong, Parsonage, Greg, Zhuang, Xiaodong, Machado, Lee, James, Christine, Salman, Asmaa, Searle, Peter, Hui, Edwin Pun, Chan, Anthony T C and Lee, S P
Faculties, Divisions and Institutes:	Research Centres > Centre for Health Sciences and Services Research Centres > Centre for Physical Activity and Life Sciences
Date:	1 October 2015
Date Type:	Publication
Journal or Publication Title:	Cancer Immunology Research
Volume:	3
Number:	10
Language:	English
DOI:	https://doi.org/10.1158/2326-6066.CIR-14-0203-T
ISSN:	2326-6066
Status:	Published / Disseminated
Refereed:	Yes
URI:	http://nectar.northampton.ac.uk/id/eprint/11115

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