title: Large-scale production and characterization of novel CD4+ cytotoxic T cells with broad tumor specificity for immunotherapy.
abstract: Immune-cell-based approaches using cytotoxic and dendritic cells are under constant scrutiny to design novel therapies for the treatment of tumors. These strategies are hampered by the lack of efficient and economical large-scale production methods for effector cells. Here we describe the propagation of large amounts of a unique population of CD4(+) cytotoxic T cells, which we termed tumor killer T cells (TKTC), because of their potent and broad antitumor cell activity. With this cultivation strategy, TKTCs from peripheral blood mononuclear cells are generated within a short period of time using a pulse with a stimulating cell line followed by continuous growth in serum-free medium supplemented with a mixture of interleukin-2 and cyclosporin A. Expression and functional profiling did not allow a classification of TKTCs to any thus far defined subtype of T cells. Cytotoxic assays showed that TKTCs kill a panel of tumor targets of diverse tissue origin while leaving normal cells unaffected. Blocking experiments revealed that TKTC killing was, to a significant extent, mediated by tumor necrosis factor-related apoptosis-inducing ligand and was independent of MHC restriction. These results suggest that TKTCs have a high potential as a novel tool in the adoptive immunotherapy of cancer.
authors.affiliation: Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Vienna, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Jursik
authors.forename: Michaela
authors.initials: M
authors.lastname: Prchal
authors.forename: Regina
authors.initials: R
authors.lastname: Grillari-Voglauer
authors.forename: Karel
authors.initials: K
authors.lastname: Drbal
authors.forename: Elke
authors.initials: E
authors.lastname: Fuertbauer
authors.forename: Herbert
authors.initials: H
authors.lastname: Jungfer
authors.forename: Winfried H
authors.initials: WH
authors.lastname: Albert
authors.forename: Eva
authors.initials: E
authors.lastname: Steinhuber
authors.forename: Thomas
authors.initials: T
authors.lastname: Hemetsberger
authors.forename: Johannes
authors.initials: J
authors.lastname: Grillari
authors.forename: Hannes
authors.initials: H
authors.lastname: Stockinger
authors.forename: Hermann
authors.initials: H
authors.lastname: Katinger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta