THERAPEUTIC TARGETING OF NATURALLY PRESENTED MYELOPEROXIDASE-DERIVED HLA PEPTIDE LIGANDS ON MYELOID LEUKEMIA CELLS BY TCR-TRANSGENIC T CELLS
R. Klar, S. Schober, M.. Rami, S. Mall, J. Merl, S.M. Hauck, M. Uefﬁng, A. Admon, J. Slotta-Huspenina, M. Schwaiger, S. Stevanovic, R.A.J. Oostendorp, D.H. Busch, C. Peschel and A.M. Krackhardt. (13-05-2014).Leukemia, 2014, 1-12, doi:10.1038/leu.2014.131
Research Area C
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 (TCRs), 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 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.