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@ARTICLE{Foldvari:278732,
author = {Z. Foldvari and C. Knetter and W. Yang and T. J. Gjerdingen
and R. C. Bollineni and T. T. Tran and F. Lund-Johansen and
A. Kolstad and K. Drousch and R. Klopfleisch and M.
Leisegang$^*$ and J. Olweus},
title = {{A} systematic safety pipeline for selection of {T}-cell
receptors to enter clinical use.},
journal = {npj vaccines},
volume = {8},
number = {1},
issn = {2059-0105},
address = {[London]},
publisher = {Nature Publishing Group},
reportid = {DKFZ-2023-01703},
pages = {126},
year = {2023},
abstract = {Cancer immunotherapy using T cell receptor-engineered T
cells (TCR-Ts) represents a promising treatment option.
However, technologies for pre-clinical safety assessment are
incomplete or inaccessible to most laboratories. Here, TCR-T
off-target reactivity was assessed in five steps: (1)
Mapping target amino acids necessary for TCR-T recognition,
followed by (2) a computational search for, and (3)
reactivity screening against, candidate cross-reactive
peptides in the human proteome. Natural processing and
presentation of recognized peptides was evaluated using (4)
short mRNAs, and (5) full-length proteins. TCR-Ts were
screened for recognition of unintended HLA alleles, and as
proxy for off-target reactivity in vivo, a syngeneic,
HLA-A*02:01-transgenic mouse model was used. Validation
demonstrated importance of studying recognition of
full-length candidate off-targets, and that the clinically
applied 1G4 TCR has a hitherto unknown reactivity to
unintended HLA alleles, relevant for patient selection. This
widely applicable strategy should facilitate evaluation of
candidate therapeutic TCRs and inform clinical
decision-making.},
cin = {BE01},
ddc = {610},
cid = {I:(DE-He78)BE01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37607971},
doi = {10.1038/s41541-023-00713-y},
url = {https://inrepo02.dkfz.de/record/278732},
}