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- Title
A systematic safety pipeline for selection of T-cell receptors to enter clinical use.
- Authors
Foldvari, Zsofia; Knetter, Cathrine; Yang, Weiwen; Gjerdingen, Thea Johanne; Bollineni, Ravi Chand; Tran, Trung The; Lund-Johansen, Fridtjof; Kolstad, Arne; Drousch, Kimberley; Klopfleisch, Robert; Leisegang, Matthias; Olweus, Johanna
- 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.
- Subjects
AMINO acids; PATIENT selection; T cells; LABORATORY mice; PEPTIDES; ANIMAL disease models; ALLELES
- Publication
NPJ Vaccines, 2023, Vol 8, Issue 1, p1
- ISSN
2059-0105
- Publication type
Article
- DOI
10.1038/s41541-023-00713-y