A novel Epstein–Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy
| Autor: | A-Ri Shin, Un-Hee Kim, Hyun-Il Cho, Ji-Na Won, Hyun-Jung Sohn, Hyun-Joo Lee, Tai-Gyu Kim |
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| Rok vydání: | 2018 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine Herpesvirus 4 Human Cancer Research Adoptive cell transfer T-Lymphocytes Transgene Genetic enhancement Receptors Antigen T-Cell chemical and pharmacologic phenomena Mice Transgenic CD8-Positive T-Lymphocytes Jurkat cells Epstein–Barr virus Viral Matrix Proteins Jurkat Cells Mice 03 medical and health sciences latent membrane protein-1 Cell Line Tumor hemic and lymphatic diseases HLA-A2 Antigen Animals Humans T-cell receptor Receptor adoptive cell transfer cancer immunotherapy Chemistry Genetic Therapy Epstein–Barr virus latent membrane protein 1 Adoptive Transfer Molecular biology 030104 developmental biology Oncology Immunization Translational Therapeutics K562 Cells K562 cells |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/bjc.2017.475 |
| Popis: | Background: Adoptive transfer of genetically engineered T-cells to express antigen-specific T-cell receptor (TCR) is a feasible and effective therapeutic approach for numerous types of cancers, including Epstein–Barr virus (EBV)-associated malignancies. Here, we describe a TCR gene transfer regimen to rapidly and reliably generate T-cells specific to EBV-encoded latent membrane protein-1 (LMP1), which is a potential target for T-cell-based immunotherapy. Methods: A novel TCR specific to LMP1 (LMP1-TCR) was isolated from HLA-A*0201 transgenic mice that were immunised with the minimal epitope LMP1166 (TLLVDLLWL), and LMP1-TCR-transduced peripheral blood lymphocytes were evaluated for functional specificities. Results: Both human CD8 and CD4 T-cells expressing the LMP1-TCR provoked high levels of cytokine secretion and cytolytic activity towards peptide-pulsed and LMP1-expressing tumour cells. Notably, recognition of these T-cells to peptide-pulsed cells was maintained at low concentration of peptide, implying that the LMP1-TCR has high avidity. Infusion of these engineered T-cells revealed remarkable therapeutic effects and inhibition of tumour growth in a preclinical xenogeneic model. We observed explosive ex vivo proliferation of functional TCR-transduced T-cells with artificial antigen-presenting cells that express co-stimulatory molecules CD80 and 4-1BBL. Conclusions: These data suggest that the novel TCR-targeting LMP1 might allow the potential design of T-cell-based immunotherapeutic strategies against EBV-positive malignancies. |
| Databáze: | OpenAIRE |
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