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), pp. 1138-1147. 2326-6066.
| 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. |
| Additional Information: | A pre-publication version of this article was made available electronically by the publisher on 24 February 2015 |
| Subjects: |
R Medicine > RM Therapeutics. Pharmacology > RM270 Immunotherapy. Serotherapy R Medicine > RC Internal medicine > RC254 Neoplasms. Tumors. Oncology Q Science > QR Microbiology > QR180 Immunology |
| 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 |
| Publisher: | American Association for Cancer Research |
| Faculties, Divisions and Institutes: |
University Faculties, Divisions and Research Centres - OLD > Research Centre > Institute of Health and Wellbeing > Ageing Research Centre Research Centres > Centre for Health Sciences and Services Research Centres > Centre for Physical Activity and Life Sciences |
| Date: | 1 October 2015 |
| Date Type: | Publication |
| Page Range: | pp. 1138-1147 |
| 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 |
| URI: | http://nectar.northampton.ac.uk/id/eprint/7426 |
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