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| Item Type: | Article |
|---|---|
| Title: | High-affinity T-cell receptor specific for MyD88 L265P mutation for adoptive T-cell therapy of B-cell malignancies |
| Creators Name: | Çınar, Ö., Brzezicha, B., Grunert, C., Kloetzel, P.M., Beier, C., Peuker, C.A., Keller, U., Pezzutto, A. and Busse, A. |
| Abstract: | BACKGROUND: Adoptive transfer of engineered T cells has shown remarkable success in B-cell malignancies. However, the most common strategy of targeting lineage-specific antigens can lead to undesirable side effects. Also, a substantial fraction of patients have refractory disease. Novel treatment approaches with more precise targeting may be an appealing alternative. Oncogenic somatic mutations represent ideal targets because of tumor specificity. Mutation-derived neoantigens can be recognized by T-cell receptors (TCRs) in the context of MHC-peptide presentation. METHODS: Here we have generated T-cell lines from healthy donors by autologous in vitro priming, targeting a missense mutation on the adaptor protein MyD88, changing leucine at position 265 to proline (MyD88 L265P), which is one of the most common driver mutations found in B-cell lymphomas. RESULTS: Generated T-cell lines were selectively reactive against the mutant HLA-B*07:02-restricted epitope but not against the corresponding wild-type peptide. Cloned TCRs from these cell lines led to mutation-specific and HLA-restricted reactivity with varying functional avidity. T cells engineered with a mutation-specific TCR (TCR-T cells) recognized and killed B-cell lymphoma cell lines characterized by intrinsic MyD88 L265P mutation. Furthermore, TCR-T cells showed promising therapeutic efficacy in xenograft mouse models. In addition, initial safety screening did not indicate any sign of off-target reactivity. CONCLUSION: Taken together, our data suggest that mutation-specific TCRs can be used to target the MyD88 L265P mutation, and hold promise for precision therapy in a significant subgroup of B-cell malignancies, possibly achieving the goal of absolute tumor specificity, a long sought-after dream of immunotherapy. |
| Keywords: | B-Cell Lymphoma, Cell- and Tissue-Based Therapy, Mutation, Myeloid Differentiation Factor 88, T-Cell Antigen Receptors |
| Source: | Journal for ImmunoTherapy of Cancer |
| ISSN: | 2051-1426 |
| Publisher: | BMJ Publishing Group |
| Volume: | 9 |
| Number: | 7 |
| Page Range: | e002410 |
| Date: | 30 July 2021 |
| Official Publication: | https://doi.org/10.1136/jitc-2021-002410 |
| PubMed: | View item in PubMed |
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