Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region.
Donor-derived T lymphocytes directed against minor histocompatibility antigens (mHags) exclusively expressed on cells of the hematopoietic lineages can eliminate hematologic malignancies. Transfer of T-cell receptors (TCRs) directed against these mHags into T lymphocytes may provide a strategy to generate antileukemic T cells. To investigate the feasibility of this strategy the TCR usage of mHag HA-2-specific T-cell clones was characterized. Thirteen different types of HA-2-specific T-cell clones were detected, expressing TCRs with diversity in TCR alpha- and beta-chain usage, however, containing in the TCR alpha chain a single conserved gene segment J alpha 42, indicating that J alpha 42 is involved in HA-2-specific recognition. We transferred various HA-2 TCRs into T lymphocytes from HLA-A2-positive HA-2-negative individuals resulting in T cells with redirected cytolytic activity against HA-2-expressing target cells. Transfer of chimeric TCRs demonstrated that the HA-2 specificity is not only determined by the J alpha 42 region but also by the N-region of the alpha chain and the CDR3 region of the beta chain. Finally, when HA-2 TCRs were transferred into T cells from HLA-A2-negative donors, the HA-2 TCR-modified T cells exerted potent antileukemic reactivity without signs of anti-HLA-A2 alloreactivity. These results indicate that HA-2 TCR transfer may be used as an alternative strategy to generate HA-2-specific T cells to treat hematologic malignancies of HLA-A2-positive, HA-2-expressing patients that received transplants from HLA-A2-matched or -mismatched donors.
Heemskerk
Mirjam H M
MH
Department of Hematology, Leiden University Medical Center, C2-R, PO Box 9600, 2300 RC Leiden, The Netherlands. m.h.m.heemskerk@lumc.nl
Hoogeboom
Manja
M
de Paus
Roelof A
RA
Kester
Michel G D
MG
van der Hoorn
Menno A W G
MA
Goulmy
Els
E
Willemze
Roel
R
Falkenburg
J H Frederik
JH
D000595:Amino Acid Sequence; D001773:Blood Cells / Q000276:immunology; D017124:Conserved Sequence; D003601:Cytotoxicity Tests, Immunologic; D019673:Genes, T-Cell Receptor alpha; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007133:Immunoglobulin Joining Region / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology* / Q000473:pathology; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D014161:Transduction, Genetic
C080145:HA-2 antigen; D015789:HLA-A2 Antigen; D007133:Immunoglobulin Joining Region; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta