Dendritic cells pulsed with RNA encoding allogeneic MHC and antigen induce T cells with superior antitumor activity and higher TCR functional avidity.
Adoptive transfer of T cells expressing transgenic T-cell receptors (TCRs) with antitumor function is a hopeful new therapy for patients with advanced tumors; however, there is a critical bottleneck in identifying high-affinity TCR specificities needed to treat different malignancies. We have developed a strategy using autologous dendritic cells cotransfected with RNA encoding an allogeneic major histocompatibility complex molecule and a tumor-associated antigen to obtain allo-restricted peptide-specific T cells having superior capacity to recognize tumor cells and higher functional avidity. This approach provides maximum flexibility because any major histocompatibility complex molecule and any tumor-associated antigen can be combined in the dendritic cells used for priming of autologous T cells. TCRs of allo-restricted T cells, when expressed as transgenes in activated peripheral blood lymphocytes, transferred superior function compared with self-restricted TCR. This approach allows high-avidity T cells and TCR specific for tumor-associated self-peptides to be easily obtained for direct adoptive T-cell therapy or for isolation of therapeutic transgenic TCR sequences.
Wilde
Susanne
S
Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health, Marchioninistrasse 25, Munich, Germany.
Sommermeyer
Daniel
D
Frankenberger
Bernhard
B
Schiemann
Matthias
M
Milosevic
Slavoljub
S
Spranger
Stefani
S
Pohla
Heike
H
Uckert
Wolfgang
W
Busch
Dirk H
DH
Schendel
Dolores J
DJ
D019264:Adoptive Transfer; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007519:Isoantigens / Q000235:genetics / Q000276:immunology*; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D012313:RNA / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D000951:Antigens, Neoplasm; D006680:HLA Antigens; D007519:Isoantigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D012313:RNA