PuSH - Publikationsserver des Helmholtz Zentrums München: Therapeutic targeting of naturally presented myeloperoxidase-derived HLA peptide ligands in myeloid leukemia cells by TCR-transgenic T cells.

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Klar, R.* ; Schober, S.* ; Rami, M.* ; Mall, S.* ; Merl, J. ; Hauck, S.M. ; Ueffing, M. ; Admon, A.* ; Slotta-Huspenina, J.* ; Schwaiger, M.* ; Stevanovic, S.* ; Oostendorp, R.A.* ; Busch, D.H. ; Peschel, C.* ; Krackhardt, A.M.

Therapeutic targeting of naturally presented myeloperoxidase-derived HLA peptide ligands in myeloid leukemia cells by TCR-transgenic T cells.

Leukemia 28, 2355-2366 (2014)

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T cells have been proven to be therapeutically effective in patients with relapsed leukemias, although target antigens on leukemic cells as well as T-cell receptors (TCR), potentially recognizing those antigens, are mostly unknown. We have applied an immunopeptidomic approach and isolated human leukocyte antigen (HLA) ligands from primary leukemia cells. We identified a number of ligands derived from different genes that are restrictedly expressed in the hematopoietic system. We exemplarily selected myeloperoxidase (MPO) as a potential target and isolated a high avidity TCR with specificity for a HLA-B*07:02-(HLA-B7)-restricted epitope of MPO in the single HLA-mismatched setting. T cells transgenic for this TCR demonstrated high peptide and antigen specificity as well as leukemia reactivity of TCR-transgenic T cells in vitro and in vivo. In contrast, no significant on- and off-target toxicity could be observed. In conclusion, we here demonstrate exemplarily for MPO that leukemia-derived HLA ligands can be selected for specific effector tool development to redirect T cells to be used for graft manipulation or adoptive T-cell therapies in diverse transplant settings. This approach can be extended to other HLA ligands and HLA molecules in order to provide better treatment options for this life-threatening disease.

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