RT Journal Article
SR Electronic
T1 High-affinity T-cell receptor specific for MyD88 L265P mutation for adoptive T-cell therapy of B-cell malignancies
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e002410
DO 10.1136/jitc-2021-002410
VO 9
IS 7
A1 Çınar, Özcan
A1 Brzezicha, Bernadette
A1 Grunert, Corinna
A1 Kloetzel, Peter Michael
A1 Beier, Christin
A1 Peuker, Caroline Anna
A1 Keller, Ulrich
A1 Pezzutto, Antonio
A1 Busse, Antonia
YR 2021
UL http://jitc.bmj.com/content/9/7/e002410.abstract
AB 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.Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. For further information, please contact oezcan.cinar@charite.de. Supplementary files can be found in the online version of this article. Complete length nucleic acid and amino acid sequences of T-cell receptors can be found in the published patent application: WO 2020/152161 A1.