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-wildtype and TP53-mutated 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 to TP53-wildtype (TP53^WT) BCP-ALL. To investigate the effect of p53 loss on CAR T therapy response, we modelled TP53 mutations in two 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 expression of the death receptors Fas and 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. While these findings provide mechanistic insight as to 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 of alternative curative therapies for this very high-risk patient group.