%0 Journal Article
%A Hsu, Meng-Tung
%A Willimsky, Gerald
%A Hansmann, Leo Alexander
%A Blankenstein, Thomas
%T T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapy.
%J Frontiers in immunology
%V 16
%@ 1664-3224
%C Lausanne
%I Frontiers Media
%M DKFZ-2025-00332
%P 1518691
%D 2025
%X BCR-ABL kinase is the major oncogenic driver of chronic myeloid leukemia (CML). Tyrosine kinase inhibitors (TKIs), which are highly potent in targeting BCR-ABL, are currently used as first-line treatment. Although TKIs are effective, drug resistance caused by the emergence of drug-selected secondary mutations in BCR-ABL remains a major problem for relapse, especially in patients with compound mutations. In this study, we aimed to investigate potential neoepitopes derived from mutated BCR-ABL and to generate neoepitope-specific TCRs for adoptive T cell therapy. Two candidate peptides derived from the E255V and the T315I mutation (designated ABL-E255V and ABL-T315I) were selected for study based on their in silico predicted binding affinity to HLA-A2. By immunizing transgenic mice that express a diverse human T cell receptor (TCR) repertoire restricted to HLA-A2, we detected CD8+ T cell responses against the ABL-E255V, but not the ABL-T315I peptide. From immune responding mice, two E255V-specific TCRs were isolated. Human CD8+ T cells were engineered to express the specific TCRs for characterization, in which one TCR was identified as a therapeutic candidate due to its superior avidity and lack of detectable off-target reactivity. Importantly, we demonstrated that the ABL-E255V neoepitope was naturally processed and presented. In summary, our results demonstrate that HLA-A2+ CML cells harboring the E255V mutation can be targeted by specific TCRs, which may benefit patients who are highly resistant to available TKIs due to compound mutations.
%K Animals
%K Humans
%K Imatinib Mesylate: pharmacology
%K Fusion Proteins, bcr-abl: genetics
%K Fusion Proteins, bcr-abl: immunology
%K Immunotherapy, Adoptive: methods
%K Leukemia, Myelogenous, Chronic, BCR-ABL Positive: therapy
%K Leukemia, Myelogenous, Chronic, BCR-ABL Positive: immunology
%K Leukemia, Myelogenous, Chronic, BCR-ABL Positive: genetics
%K Mice
%K Receptors, Antigen, T-Cell: genetics
%K Receptors, Antigen, T-Cell: immunology
%K Receptors, Antigen, T-Cell: metabolism
%K Mutation
%K Mice, Transgenic
%K CD8-Positive T-Lymphocytes: immunology
%K HLA-A2 Antigen: immunology
%K HLA-A2 Antigen: genetics
%K HLA-A2 Antigen: metabolism
%K Epitopes, T-Lymphocyte: immunology
%K Protein Kinase Inhibitors: pharmacology
%K Protein Kinase Inhibitors: therapeutic use
%K T cell receptor (Other)
%K chronic myeloid leukemia (Other)
%K imatinib (Other)
%K neoantigen (Other)
%K resistance (Other)
%K Imatinib Mesylate (NLM Chemicals)
%K Fusion Proteins, bcr-abl (NLM Chemicals)
%K Receptors, Antigen, T-Cell (NLM Chemicals)
%K HLA-A2 Antigen (NLM Chemicals)
%K Epitopes, T-Lymphocyte (NLM Chemicals)
%K Protein Kinase Inhibitors (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39931057
%2 pmc:PMC11807957
%R 10.3389/fimmu.2025.1518691
%U https://inrepo02.dkfz.de/record/298887