title: [Development of Tax-redirected T-cell immunotherapy using TCR gene transduction in patients with ATL].
abstract: ATL is an aggressive T-cell malignancy caused by HTLV-1 virus infection. Tax, which is the most important regulatory protein of HTLV-1, is associated with aggressive proliferation of host cells and is also a major target antigen for CD8⁺ cytotoxic T-cells (CTLs). Recently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has proven effective for ATL, and donor-derived Tax-specific CTL might contribute to graft-versus-ATL effects in some recipients who maintained complete remission after allo-HSCT. We, for the first time, analyzed the Tax-specific T-cell receptor (TCR) repertoire, phenotypes and functions of Tax-specific CTLs at single-cell levels in HLA-A24⁺ ATL patients who underwent allo-HSCT. We found that 1) a particular amino acid sequence motif (PDR) in the CDR3 region of TCR-β was conserved in different patients and also within the same patient before and after allo-HSCT, and 2) the PDR⁺ Tax-specific CTL clone selectively expanded in ATL long-term survivors as less-differentiated effector memory CTLs. Actually, the PDR⁺ CTL showed not only strong binding activity for the Tax-tetramer but also strong killing activity against patients' HTLV-1-infected T-cells without any reaction against normal cells. We are presently evaluating the killing activities of PDR⁺ TCR-transduced T-cells against Tax in immunodeficient mice, with the aim of developing a new immunotherapy for ATL.
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kanda
mesh_terms: D064591:Allografts; D000818:Animals; D016355:Genes, pX; D015490:HTLV-I Infections; D018380:Hematopoietic Stem Cell Transplantation; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D006801:Humans; D007167:Immunotherapy; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell