A systematic safety pipeline for selection of T-cell receptors to enter clinical use.
Journal
NPJ vaccines
ISSN: 2059-0105
Titre abrégé: NPJ Vaccines
Pays: England
ID NLM: 101699863
Informations de publication
Date de publication:
22 Aug 2023
22 Aug 2023
Historique:
received:
19
10
2022
accepted:
31
07
2023
medline:
23
8
2023
pubmed:
23
8
2023
entrez:
22
8
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37607971
doi: 10.1038/s41541-023-00713-y
pii: 10.1038/s41541-023-00713-y
pmc: PMC10444760
doi:
Types de publication
Journal Article
Langues
eng
Pagination
126Subventions
Organisme : NCI NIH HHS
ID : R01 CA022677
Pays : United States
Informations de copyright
© 2023. Springer Nature Limited.
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