T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapy
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...
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Frontiers Media S.A.
2025-01-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1518691/full |
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| author | Meng-Tung Hsu Gerald Willimsky Gerald Willimsky Gerald Willimsky Leo Hansmann Leo Hansmann Leo Hansmann Leo Hansmann Thomas Blankenstein |
| author_facet | Meng-Tung Hsu Gerald Willimsky Gerald Willimsky Gerald Willimsky Leo Hansmann Leo Hansmann Leo Hansmann Leo Hansmann Thomas Blankenstein |
| author_sort | Meng-Tung Hsu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c1059c7ae207426b886eb86bda404d0b |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-c1059c7ae207426b886eb86bda404d0b2025-01-27T06:40:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011610.3389/fimmu.2025.15186911518691T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapyMeng-Tung Hsu0Gerald Willimsky1Gerald Willimsky2Gerald Willimsky3Leo Hansmann4Leo Hansmann5Leo Hansmann6Leo Hansmann7Thomas Blankenstein8Molecular Immunology and Gene Therapy, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, GermanyCharité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyGerman Cancer Research Center, Heidelberg, GermanyGerman Cancer Consortium, partner site Berlin, Berlin, GermanyCharité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyGerman Cancer Research Center, Heidelberg, GermanyGerman Cancer Consortium, partner site Berlin, Berlin, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyMolecular Immunology and Gene Therapy, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, GermanyBCR-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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1518691/fullchronic myeloid leukemiaimatinibresistanceneoantigenT cell receptor |
| spellingShingle | Meng-Tung Hsu Gerald Willimsky Gerald Willimsky Gerald Willimsky Leo Hansmann Leo Hansmann Leo Hansmann Leo Hansmann Thomas Blankenstein T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapy Frontiers in Immunology chronic myeloid leukemia imatinib resistance neoantigen T cell receptor |
| title | T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapy |
| title_full | T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapy |
| title_fullStr | T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapy |
| title_full_unstemmed | T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapy |
| title_short | T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapy |
| title_sort | t cell receptors specific for an imatinib induced mutation in bcr abl for adoptive t cell therapy |
| topic | chronic myeloid leukemia imatinib resistance neoantigen T cell receptor |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1518691/full |
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