title: Novel adoptive T-cell immunotherapy using a WT1-specific TCR vector encoding silencers for endogenous TCRs shows marked antileukemia reactivity and safety.
abstract: Adoptive T-cell therapy for malignancies using redirected T cells genetically engineered by tumor antigen-specific T-cell receptor (TCR) gene transfer is associated with mispairing between introduced and endogenous TCR chains with unknown specificity. Therefore, deterioration of antitumor reactivity and serious autoimmune reactivity are major concerns. To address this problem, we have recently established a novel retroviral vector system encoding siRNAs for endogenous TCR genes (siTCR vector). In this study, to test the clinical application of siTCR gene therapy for human leukemia, we examined in detail the efficacy and safety of WT1-siTCR-transduced T cells. Compared with conventional WT1-TCR (WT1-coTCR) gene-transduced T cells, these cells showed significant enhancement of antileukemia reactivity resulting from stronger expression of the introduced WT1-specific TCR with inhibition of endogenous TCRs. Notably, WT1-siTCR gene-transduced T cells were remarkably expandable after repetitive stimulation with WT1 peptide in vitro, without any deterioration of antigen specificity. WT1-siTCR gene-transduced T cells from leukemia patients successfully lysed autologous leukemia cells, but not normal hematopoietic progenitor cells. In a mouse xenograft model, adoptively transferred WT1-siTCR gene-transduced T cells exerted distinct antileukemia efficacy but did not inhibit human hematopoiesis. Our results suggest that gene-immunotherapy for leukemia using this WT1-siTCR system holds considerable promise.
authors.affiliation: Department of Bioregulatory Medicine, Ehime University Graduate School of Medicine, Ehime University Proteo-Medicine Research Center, Ehime, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Ochi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Sachiko
authors.initials: S
authors.lastname: Okamoto
authors.forename: Jun
authors.initials: J
authors.lastname: An
authors.forename: Kozo
authors.initials: K
authors.lastname: Nagai
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shirakata
authors.forename: Junichi
authors.initials: J
authors.lastname: Mineno
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kuzushima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D019169:Jurkat Cells; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics* / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D025721:WT1 Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D053631:Interleukin Receptor Common gamma Subunit; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D016693:Receptors, Antigen, T-Cell, alpha-beta; D025721:WT1 Proteins