title: T-cell receptor gene therapy targeting melanoma-associated antigen-A4 inhibits human tumor growth in non-obese diabetic/SCID/γcnull mice.
abstract: Adoptive cell therapy with lymphocytes that have been genetically engineered to express tumor-reactive T-cell receptors (TCR) is a promising approach for cancer immunotherapy. We have been exploring the development of TCR gene therapy targeting cancer/testis antigens, including melanoma-associated antigen (MAGE) family antigens, that are ideal targets for adoptive T-cell therapy. The efficacy of TCR gene therapy targeting MAGE family antigens, however, has not yet been evaluated in vivo. Here, we demonstrate the in vivo antitumor activity in immunodeficient non-obese diabetic/SCID/γc(null) (NOG) mice of human lymphocytes genetically engineered to express TCR specific for the MAGE-A4 antigen. Polyclonal T cells derived from human peripheral blood mononuclear cells were transduced with the αβ TCR genes specific for MAGE-A4, then adoptively transferred into NOG mice inoculated with MAGE-A4 expressing human tumor cell lines. The transferred T cells maintained their effector function in vivo, infiltrated into tumors, and inhibited tumor growth in an antigen-specific manner. The combination of adoptive cell therapy with antigen peptide vaccination enhanced antitumor activity, with improved multifunctionality of the transferred cells. These data suggest that TCR gene therapy with MAGE-A4-specific TCR is a promising strategy to treat patients with MAGE-A4-expressing tumors; in addition, the acquisition of multifunctionality in vivo is an important factor to predict the quality of the T-cell response during adoptive therapy with human lymphocytes.
authors.affiliation: Department of Cancer Vaccine, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Shirakura
authors.forename: Yukari
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Linan
authors.initials: L
authors.lastname: Wang
authors.forename: Naoko
authors.initials: N
authors.lastname: Imai
authors.forename: Chisaki
authors.initials: C
authors.lastname: Amaike
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sato
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.forename: Ikuei
authors.initials: I
authors.lastname: Nukaya
authors.forename: Junichi
authors.initials: J
authors.lastname: Mineno
authors.forename: Kazutoh
authors.initials: K
authors.lastname: Takesako
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ikeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004938:Esophageal Neoplasms / Q000276:immunology / Q000628:therapy*; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007124:Immunoenzyme Techniques; D016219:Immunotherapy, Adoptive; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D012190:Retroviridae; D014161:Transduction, Genetic; D022223:Vaccines, Subunit / Q000627:therapeutic use
chemical_list: D000951:Antigens, Neoplasm; D015234:HLA-A Antigens; C095204:MAGEA4 protein, human; D009363:Neoplasm Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D022223:Vaccines, Subunit