1. Loss of p53 impairs death receptor expression and confers resistance to CD19 CAR T-cell therapy in BCP-ALL
- Author
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Willem P. J. Cox, Noël M. M. Dautzenberg, Linde Dekker, Tesa Klenovsek, Annelisa M. Cornel, Marliek van Hoesel, Dorette S. van Ingen Schenau, Reno S. Bladergroen, Roland P. Kuiper, Laurens T. van der Meer, Friso G. Calkoen, Stefan Nierkens, and Frank N. van Leeuwen
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract: Loss of p53 function predicts a dismal outcome in relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Chimeric antigen receptor T-cell (CAR T) therapy was recently approved to salvage relapsed/refractory BCP-ALL. We observed a significantly worse overall survival after CD19-targeting CAR T therapy in children with TP53-mutated (TP53Mut) compared with TP53–wild-type (TP53WT) BCP-ALL. To investigate the effect of p53 loss on CAR T therapy response, we modeled TP53 mutations in 2 BCP-ALL cell lines and observed resistance to CAR T upon p53 loss. Moreover, expression analysis in cell lines and xenografts demonstrated that loss of p53 abrogates the expression of the death receptors Fas and death receptor 5 (DR5), both implicated in CAR T cytotoxicity. Conversely, ectopic expression of Fas improved CAR T cytotoxicity. Furthermore, p53 stabilization induced expression of both Fas and DR5, accompanied by increased CAR T–mediated killing. Although these findings provide mechanistic insight into why CAR T therapy fails against TP53Mut BCP-ALL, they may also provide opportunities to enhance the efficacy of CAR T treatment both in patients with TP53Mut and TP53WT BCP-ALL. Furthermore, these data underscore the need for alternative curative therapies for this very high-risk patient group.
- Published
- 2025
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