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Nat Biomed Eng ; 6(11): 1284-1297, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35941192

RESUMO

The production of autologous T cells expressing a chimaeric antigen receptor (CAR) is time-consuming, costly and occasionally unsuccessful. T-cell-derived induced pluripotent stem cells (TiPS) are a promising source for the generation of 'off-the-shelf' CAR T cells, but the in vitro differentiation of TiPS often yields T cells with suboptimal features. Here we show that the premature expression of the T-cell receptor (TCR) or a constitutively expressed CAR in TiPS promotes the acquisition of an innate phenotype, which can be averted by disabling the TCR and relying on the CAR to drive differentiation. Delaying CAR expression and calibrating its signalling strength in TiPS enabled the generation of human TCR- CD8αß+ CAR T cells that perform similarly to CD8αß+ CAR T cells from peripheral blood, achieving effective tumour control on systemic administration in a mouse model of leukaemia and without causing graft-versus-host disease. Driving T-cell maturation in TiPS in the absence of a TCR by taking advantage of a CAR may facilitate the large-scale development of potent allogeneic CD8αß+ T cells for a broad range of immunotherapies.


Assuntos
Células-Tronco Pluripotentes Induzidas , Receptores de Antígenos Quiméricos , Camundongos , Animais , Humanos , Linfócitos T , Células-Tronco Pluripotentes Induzidas/metabolismo , Receptores de Antígenos de Linfócitos T , Antígenos CD8/metabolismo , Receptores de Antígenos Quiméricos/metabolismo
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