Hsu, Meng-Tung and Willimsky, Gerald and Hansmann, Leo and Blankenstein, Thomas (2025) T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapy. FRONTIERS IN IMMUNOLOGY, 16: 1518691. ISSN 1664-3224,
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; BCR-ABL1 COMPOUND MUTATIONS; ENHANCED ANTITUMOR-ACTIVITY; CLINICAL RESISTANCE; NEURAL-NETWORKS; EXPRESSION; MECHANISMS; INHIBITOR; DISEASE; chronic myeloid leukemia; imatinib; resistance; neoantigen; T cell receptor |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Jul 2026 11:30 |
| Last Modified: | 28 Jul 2026 11:30 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67289 |
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