Generation of T-cell-receptor-negative CD8αβ-positive CAR T cells from T-cell-derived induced pluripotent stem cells Journal Article


Authors: van der Stegen, S. J. C.; Lindenbergh, P. L.; Petrovic, R. M.; Xie, H.; Diop, M. P.; Alexeeva, V.; Shi, Y.; Mansilla-Soto, J.; Hamieh, M.; Eyquem, J.; Cabriolu, A.; Wang, X.; Abujarour, R.; Lee, T.; Clarke, R.; Valamehr, B.; Themeli, M.; Riviere, I.; Sadelain, M.
Article Title: Generation of T-cell-receptor-negative CD8αβ-positive CAR T cells from T-cell-derived induced pluripotent stem cells
Abstract: 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– CD8αβ+ CAR T cells that perform similarly to CD8αβ+ 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 CD8αβ+ T cells for a broad range of immunotherapies. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
Keywords: cd8 antigen; t lymphocyte; t-lymphocytes; mouse; animal; cytology; metabolism; animals; mice; receptors, antigen, t-cell; cell membranes; stem cells; disease control; in-vitro; lymphocyte antigen receptor; induced pluripotent stem cells; t-cells; receptor expression; cell signaling; peripheral blood; antigen receptors; induced pluripotent stem cell; humans; human; human t cells; receptors, chimeric antigen; cd8 antigens; cell-be; cell/b.e; cell/be; t cells receptors; cd8alphabeta antigen
Journal Title: Nature Biomedical Engineering
Volume: 6
Issue: 11
ISSN: 2157-846X
Publisher: Nature Publishing Group  
Date Published: 2022-11-01
Start Page: 1284
End Page: 1297
Language: English
DOI: 10.1038/s41551-022-00915-0
PUBMED: 35941192
PROVIDER: scopus
PMCID: PMC9669107
DOI/URL:
Notes: Erratum issued, see DOI: [10.1038/s41551-024-01181-y] -- Source: Scopus
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