TY  - JOUR
AU  - Hsu, Meng-Tung
AU  - Willimsky, Gerald
AU  - Hansmann, Leo Alexander
AU  - Blankenstein, Thomas
TI  - T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapy.
JO  - Frontiers in immunology
VL  - 16
SN  - 1664-3224
CY  - Lausanne
PB  - Frontiers Media
M1  - DKFZ-2025-00332
SP  - 1518691
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Humans
KW  - Imatinib Mesylate: pharmacology
KW  - Fusion Proteins, bcr-abl: genetics
KW  - Fusion Proteins, bcr-abl: immunology
KW  - Immunotherapy, Adoptive: methods
KW  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive: therapy
KW  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive: immunology
KW  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive: genetics
KW  - Mice
KW  - Receptors, Antigen, T-Cell: genetics
KW  - Receptors, Antigen, T-Cell: immunology
KW  - Receptors, Antigen, T-Cell: metabolism
KW  - Mutation
KW  - Mice, Transgenic
KW  - CD8-Positive T-Lymphocytes: immunology
KW  - HLA-A2 Antigen: immunology
KW  - HLA-A2 Antigen: genetics
KW  - HLA-A2 Antigen: metabolism
KW  - Epitopes, T-Lymphocyte: immunology
KW  - Protein Kinase Inhibitors: pharmacology
KW  - Protein Kinase Inhibitors: therapeutic use
KW  - T cell receptor (Other)
KW  - chronic myeloid leukemia (Other)
KW  - imatinib (Other)
KW  - neoantigen (Other)
KW  - resistance (Other)
KW  - Imatinib Mesylate (NLM Chemicals)
KW  - Fusion Proteins, bcr-abl (NLM Chemicals)
KW  - Receptors, Antigen, T-Cell (NLM Chemicals)
KW  - HLA-A2 Antigen (NLM Chemicals)
KW  - Epitopes, T-Lymphocyte (NLM Chemicals)
KW  - Protein Kinase Inhibitors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39931057
C2  - pmc:PMC11807957
DO  - DOI:10.3389/fimmu.2025.1518691
UR  - https://inrepo02.dkfz.de/record/298887
ER  -