PMID- 24736212 OWN - NLM STAT- MEDLINE DCOM- 20150311 LR - 20211021 IS - 1476-5551 (Electronic) IS - 0887-6924 (Linking) VI - 28 IP - 12 DP - 2014 Dec TI - Therapeutic targeting of naturally presented myeloperoxidase-derived HLA peptide ligands on myeloid leukemia cells by TCR-transgenic T cells. PG - 2355-66 LID - 10.1038/leu.2014.131 [doi] AB - 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. FAU - Klar, R AU - Klar R AD - Medizinische Klinik III, Klinikum rechts der Isar, Technische Universitat Munchen, Munchen, Germany. FAU - Schober, S AU - Schober S AD - Medizinische Klinik III, Klinikum rechts der Isar, Technische Universitat Munchen, Munchen, Germany. FAU - Rami, M AU - Rami M AD - Medizinische Klinik III, Klinikum rechts der Isar, Technische Universitat Munchen, Munchen, Germany. FAU - Mall, S AU - Mall S AD - Medizinische Klinik III, Klinikum rechts der Isar, Technische Universitat Munchen, Munchen, Germany. FAU - Merl, J AU - Merl J AD - Research Unit Protein Science, Helmholtz Zentrum Munchen (GmbH), German Research Center for Environmental Health, Neuherberg, Germany. FAU - Hauck, S M AU - Hauck SM AD - Research Unit Protein Science, Helmholtz Zentrum Munchen (GmbH), German Research Center for Environmental Health, Neuherberg, Germany. FAU - Ueffing, M AU - Ueffing M AD - Research Unit Protein Science, Helmholtz Zentrum Munchen (GmbH), German Research Center for Environmental Health, Neuherberg, Germany. FAU - Admon, A AU - Admon A AD - Department of Biology, Technion Israel Institute of Technology, Haifa, Israel. FAU - Slotta-Huspenina, J AU - Slotta-Huspenina J AD - Institut fur Allgemeine Pathologie und Pathologische Anatomie, Klinikum rechts der Isar, Technische Universitat Munchen, Munchen, Germany. FAU - Schwaiger, M AU - Schwaiger M AD - Nuklearmedizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, Munchen, Germany. FAU - Stevanovic, S AU - Stevanovic S AD - Department of Immunology, University of Tubingen, Tubingen, Germany. FAU - Oostendorp, R A J AU - Oostendorp RA AD - Medizinische Klinik III, Klinikum rechts der Isar, Technische Universitat Munchen, Munchen, Germany. FAU - Busch, D H AU - Busch DH AD - 1] Institut fur Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universitat Munchen, Munchen, Germany [2] Clinical Cooperation Group, Antigen Specific T Cell Therapy, Helmholtz Zentrum Munchen (GmbH), German Center for Environmental Health, Munchen, Germany. FAU - Peschel, C AU - Peschel C AD - 1] Medizinische Klinik III, Klinikum rechts der Isar, Technische Universitat Munchen, Munchen, Germany [2] German Cancer Consortium (DKTK), Munich, Germany. FAU - Krackhardt, A M AU - Krackhardt AM AD - 1] Medizinische Klinik III, Klinikum rechts der Isar, Technische Universitat Munchen, Munchen, Germany [2] Clinical Cooperation Group, Antigen Specific T Cell Therapy, Helmholtz Zentrum Munchen (GmbH), German Center for Environmental Health, Munchen, Germany [3] German Cancer Consortium (DKTK), Munich, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140416 PL - England TA - Leukemia JT - Leukemia JID - 8704895 RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA Antigens) RN - 0 (HLA-B*07 antigen) RN - 0 (HLA-B7 Antigen) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Ligands) RN - 0 (Peptides) RN - 0 (Receptors, Antigen, T-Cell) RN - EC 1.11.1.7 (Peroxidase) SB - IM MH - Animals MH - Antigen Presentation/immunology MH - CD8-Positive T-Lymphocytes/immunology/metabolism MH - Cell Line MH - Cell Survival/genetics/immunology MH - Disease Models, Animal MH - Epitope Mapping MH - Epitopes, T-Lymphocyte/chemistry/immunology MH - HLA Antigens/*immunology/metabolism MH - HLA-B7 Antigen/immunology/metabolism MH - Heterografts MH - Histocompatibility Antigens Class I/immunology/metabolism MH - Humans MH - Leukemia, Myeloid/*genetics/*immunology/metabolism/mortality MH - Ligands MH - Mice MH - Peptides/*immunology/metabolism MH - Peroxidase/chemistry/genetics/*immunology MH - Receptors, Antigen, T-Cell/*genetics/metabolism MH - T-Cell Antigen Receptor Specificity/immunology MH - T-Lymphocytes/*immunology/*metabolism MH - Transduction, Genetic EDAT- 2014/04/17 06:00 MHDA- 2015/03/12 06:00 CRDT- 2014/04/17 06:00 PHST- 2013/10/22 00:00 [received] PHST- 2014/04/01 00:00 [revised] PHST- 2014/04/03 00:00 [accepted] PHST- 2014/04/17 06:00 [entrez] PHST- 2014/04/17 06:00 [pubmed] PHST- 2015/03/12 06:00 [medline] AID - leu2014131 [pii] AID - 10.1038/leu.2014.131 [doi] PST - ppublish SO - Leukemia. 2014 Dec;28(12):2355-66. doi: 10.1038/leu.2014.131. Epub 2014 Apr 16.