A novel Epstein–Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy

• Published in: British journal of cancer 2018-02, Vol.118 (4), p.534-545
• Main Authors: Cho, Hyun-Il, Kim, Un-Hee, Shin, A-Ri, Won, Ji-Na, Lee, Hyun-Joo, Sohn, Hyun-Jung, Kim, Tai-Gyu
• Format: Article
• Language: English
• Subjects: 631/250/251; 692/4028/67/1059; Adoptive Transfer; Animals; Antigen-presenting cells; Antigens; Avidity; Biomedical and Life Sciences; Biomedicine; Cancer Research; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - transplantation; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; CD80 antigen; Cell Line, Tumor; Cell proliferation; Cytolytic activity; Drug Resistance; Epidemiology; Epitopes; Epstein-Barr virus; Gene therapy; Genetic engineering; Genetic Therapy; Herpesvirus 4, Human - immunology; Histocompatibility antigen HLA; HLA-A2 Antigen - genetics; Humans; Immunization; Immunotherapy; Jurkat Cells; K562 Cells; Lymphocytes; Lymphocytes T; Membrane proteins; Mice; Mice, Transgenic; Molecular Medicine; Oncology; Peptides; Peripheral blood; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Transgenic mice; Translational Therapeutics; Tumors; Viral Matrix Proteins - immunology
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2017.475

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 LMP1 166 (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.