T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.
Nat Biotechnol
; 40(4): 488-498, 2022 04.
Article
de En
| MEDLINE
| ID: mdl-34873326
ABSTRACT
Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*0201, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Lymphocytes T
/
DNA nucleotidylexotransferase
Limites:
Animals
Langue:
En
Journal:
Nat Biotechnol
Sujet du journal:
BIOTECNOLOGIA
Année:
2022
Type de document:
Article
Pays d'affiliation:
Norvège