%0 Journal Article
%A Foldvari, Zsofia
%A Knetter, Cathrine
%A Yang, Weiwen
%A Gjerdingen, Thea Johanne
%A Bollineni, Ravi Chand
%A Tran, Trung The
%A Lund-Johansen, Fridtjof
%A Kolstad, Arne
%A Drousch, Kimberley
%A Klopfleisch, Robert
%A Leisegang, Matthias
%A Olweus, Johanna
%T A systematic safety pipeline for selection of T-cell receptors to enter clinical use.
%J npj vaccines
%V 8
%N 1
%@ 2059-0105
%C [London]
%I Nature Publishing Group
%M DKFZ-2023-01703
%P 126
%D 2023
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37607971
%R 10.1038/s41541-023-00713-y
%U https://inrepo02.dkfz.de/record/278732