title: Individual myeloma-specific T-cell clones eliminate tumour cells and correlate with clinical outcomes in patients with multiple myeloma.
abstract: Despite novel treatment strategies, multiple myeloma (MM) remains an incurable disease with low immunogenicity and multiple immune defects. We developed an ex vivo strategy for inducing myeloma-specific cytotoxic T lymphocytes (CTLs) and demonstrate the possibility of identification and long-term in vivo monitoring of individual myeloma-specific T-cell clones using the most sensitive clonotypic assay that is able to detect low frequencies of T-cell clones (1 clonotypic cell in 10(6) cells). Ten patients with MM were examined for the presence of tumour-reactive T cells using dendritic cells loaded with autologous tumour cells. All patients had detectable myeloma-reactive T cells in vitro. Expanded myeloma-reactive T cells demonstrated specific cytotoxic effects against autologous tumour cells in vitro (median 39.6% at an effector:target ratio of 40:1). The clonality of myeloma-specific T cells was studied with a clonotypic assay, which demonstrated both oligoclonal and monoclonal populations of myeloma-specific T cells. CD8(+) CTLs were the most immunodominant myeloma-specific T-cell clones and clinical responses were closely associated with the in vivo expansion and long-term persistence of individual CD8(+) T-cell clones, usually at very low frequencies (10(-3)-10(-6)). We conclude that the clonotypic assay is the most sensitive tool for immunomonitoring of low-frequency T cells.
authors.affiliation: University Cell Immunotherapy Centre, Masaryk University, Kamenice 5, Brno, Czech Republic. jmichalek@fnbrno.cz
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Michalek
authors.forename: Darina
authors.initials: D
authors.lastname: Ocadlikova
authors.forename: Eva
authors.initials: E
authors.lastname: Matejkova
authors.forename: Veronika
authors.initials: V
authors.lastname: Foltankova
authors.forename: Silvie
authors.initials: S
authors.lastname: Dudová
authors.forename: Ondrej
authors.initials: O
authors.lastname: Slaby
authors.forename: Radek
authors.initials: R
authors.lastname: Horvath
authors.forename: Ludek
authors.initials: L
authors.lastname: Pour
authors.forename: Roman
authors.initials: R
authors.lastname: Hajek
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002999:Clone Cells / Q000276:immunology; D022801:Complementarity Determining Regions / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D018189:Immunomagnetic Separation / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015166:Monitoring, Immunologic / Q000379:methods; D009101:Multiple Myeloma / Q000276:immunology* / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D022801:Complementarity Determining Regions; D016056:Immunodominant Epitopes