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. Stevanović, R. A.J. Oostendorp, D. H. Busch, C. Peschel, A. M. Krackhardt

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

20 Zitate (Scopus)

Abstract

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.

OriginalspracheEnglisch
Seiten (von - bis)2355-2366
Seitenumfang12
FachzeitschriftLeukemia
Jahrgang28
Ausgabenummer12
DOIs
PublikationsstatusVeröffentlicht - 11 Dez. 2014
Extern publiziertJa

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