Individual myeloma-specific T-cell clones eliminate tumour cells and correlate with clinical outcomes in patients with multiple myeloma.
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.
Michalek
Jaroslav
J
University Cell Immunotherapy Centre, Masaryk University, Kamenice 5, Brno, Czech Republic. jmichalek@fnbrno.cz
Ocadlikova
Darina
D
Matejkova
Eva
E
Foltankova
Veronika
V
Dudová
Silvie
S
Slaby
Ondrej
O
Horvath
Radek
R
Pour
Ludek
L
Hajek
Roman
R
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
D000951:Antigens, Neoplasm; D022801:Complementarity Determining Regions; D016056:Immunodominant Epitopes