High-affinity T-cell receptor specific for MyD88 L265P mutation for adoptive T-cell therapy of B-cell malignancies

被引:9
作者
Cinar, Oezcan [1 ,2 ,3 ,4 ,5 ]
Brzezicha, Bernadette [6 ]
Grunert, Corinna [1 ,2 ,3 ,4 ,5 ]
Kloetzel, Peter Michael [2 ,3 ,4 ,7 ]
Beier, Christin [2 ,3 ,4 ,7 ]
Peuker, Caroline Anna [1 ,2 ,3 ,4 ]
Keller, Ulrich [1 ,2 ,3 ,4 ,5 ]
Pezzutto, Antonio [1 ,2 ,3 ,4 ,5 ]
Busse, Antonia [1 ,2 ,3 ,4 ,5 ]
机构
[1] Charite Univ Med Berlin, Dept Hematol Oncol & Tumor Immunol, Berlin, Germany
[2] Free Univ Berlin, Berlin, Germany
[3] Humboldt Univ, Berlin, Germany
[4] Berlin Inst Hlth, Berlin, Germany
[5] Helmholtz Assoc, Max Delbruck Ctr Mol Med, Berlin, Germany
[6] Expt Pharmacol & Oncol Berlin Buch GmbH EPO, Berlin, Germany
[7] Charite Univ Med Berlin, Inst Biochem, Berlin, Germany
关键词
immunotherapy; adoptive; hematological neoplasms; receptors; antigen; cell engineering; T lymphocytes; RECOGNITION; EXPRESSION; RESISTANCE; LYMPHOMA; NAIVE;
D O I
10.1136/jitc-2021-002410
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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页数:12
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