Loss of p53 impairs death receptor expression and confers resistance to CD19 CAR T-cell therapy in BCP-ALL

• Loss of p53 confers resistance to CAR T therapy by impairing death receptor expression. • Modulation of death receptor expression may improve CAR T–mediated killing of TP53 WT and TP53 Mut BCP-ALL. 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 ( TP53 Mut ) compared with TP53 –wild-type ( TP53 WT ) 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 TP53 Mut BCP-ALL, they may also provide opportunities to enhance the efficacy of CAR T treatment both in patients with TP53 Mut and TP53 WT BCP-ALL. Furthermore, these data underscore the need for alternative curative therapies for this very high-risk patient group.