Journal Article

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

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

2014

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/106 / 13/51 / 38 / 38/77 / 631/67/1059/2325 / 64/60 / 82 / 82/58 / Animals / Antigen Presentation - immunology / Antigens / Avidity / Biocompatibility / Cancer Research / Care and treatment / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Line / Cell Survival - genetics / Cell Survival - immunology / Cells / Critical Care Medicine / Disease Models, Animal / Environmental health / Epitope Mapping / Epitopes / Epitopes, T-Lymphocyte - chemistry / Epitopes, T-Lymphocyte - immunology / Genetic aspects / Graft versus host disease / Hematology / Hematopoietic system / Heterografts / Histocompatibility antigen HLA / Histocompatibility antigens / Histocompatibility Antigens Class I - immunology / Histocompatibility Antigens Class I - metabolism / HLA Antigens - immunology / HLA Antigens - metabolism / HLA histocompatibility antigens / HLA-B7 Antigen - immunology / HLA-B7 Antigen - metabolism / Humans / Immunotherapy / Intensive / Internal Medicine / Leukemia / Leukemia, Myeloid - genetics / Leukemia, Myeloid - immunology / Leukemia, Myeloid - metabolism / Leukemia, Myeloid - mortality / Leukocytes / Ligands / Lymphocytes / Lymphocytes T / Medicine / Medicine & Public Health / Methods / Mice / Myelocytic leukemia / Myeloid leukemia / Nonlymphoid leukemia / Oncology / original-article / Peptides / Peptides - immunology / Peptides - metabolism / Peroxidase / Peroxidase - chemistry / Peroxidase - genetics / Peroxidase - immunology / Properties / Receptors, Antigen, T-Cell - genetics / Receptors, Antigen, T-Cell - metabolism / T cell receptors / T-Cell Antigen Receptor Specificity - immunology / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Therapeutic targets / Toxicity / Transduction, Genetic / Transplants & implants