title: Antileukemia multifunctionality of CD4(+) T cells genetically engineered by HLA class I-restricted and WT1-specific T-cell receptor gene transfer.
abstract: To develop gene-modified T-cell-based antileukemia adoptive immunotherapy, concomitant administration of CD4(+) and CD8(+) T cells that have been gene modified using identical HLA class I-restricted leukemia antigen-specific T-cell receptor (TCR) gene transfer has not yet been fully investigated. Here, using CD4(+) and CD8(+) T cells that had been gene modified with a retroviral vector expressing HLA-A*24:02-restricted and Wilms' tumor 1 (WT1)-specific TCR-α/β genes and siRNAs for endogenous TCRs (WT1-siTCR/CD4(+) T cells and WT1-siTCR/CD8(+) T cells), we examined the utility of this strategy. WT1-siTCR/CD4(+) T cells sufficiently recognized leukemia cells in an HLA class I-restricted manner and provided target-specific Th1 help for WT1-siTCR/CD8(+) T cells. By using a xenografted mouse model, we found that WT1-siTCR/CD4(+) T cells migrated to leukemia sites and subsequently attracted WT1-siTCR/CD8(+) T cells via chemotaxis. Therapy-oriented experiments revealed effective enhancement of leukemia suppression mediated by concomitant administration of WT1-siTCR/CD4(+) T cells and WT1-siTCR/CD8(+) T cells. Importantly, this augmented efficacy in the presence of WT1-siTCR/CD4(+) T cells was correlated with longer survival and enhanced formation of memory T cells by WT1-siTCR/CD8(+) T cells. Collectively, our experimental findings strongly suggest that this strategy would be clinically advantageous for the treatment of human leukemia.
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.|Princess Margaret Cancer Center, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Ochi
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.|Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Ochi
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Asai
authors.affiliation: Laboratory of Hematology and Oncology, Graduate School of Health Science, Niigata University, Niigata, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Narita
authors.affiliation: Center for Cell and Gene Therapy, Takara Bio Inc., Otsu, Shiga, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Center for Cell and Gene Therapy, Takara Bio Inc., Otsu, Shiga, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Mineno
authors.affiliation: Division of Immunology, Aichi Cancer Center, Nagoya, Aichi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kuzushima
authors.affiliation: Department of Cancer Vaccine and Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shiku
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yasukawa
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement; D005260:Female; D019672:Genes, T-Cell Receptor; D005818:Genetic Engineering; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D051379:Mice; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D025721:WT1 Proteins / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D025721:WT1 Proteins; C583751:WT1 protein, human