TY - JOUR
T1 - Loss of p53 impairs death receptor expression and confers resistance to CD19 CAR T-cell therapy in BCP-ALL
AU - Cox, Willem
AU - Dautzenberg, Noël
AU - Dekker, Linde
AU - Klenovsek, Tesa
AU - Cornel, Annelisa
AU - van Hoesel, Marliek
AU - van Ingen Schenau, Dorette S.
AU - Bladergroen, Reno
AU - Kuiper, RP
AU - van der Meer, Laurens
AU - Calkoen, Friso G
AU - van Leeuwen, Frank
N1 - © 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
PY - 2025/2
Y1 - 2025/2
N2 - 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.
AB - 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.
UR - https://www.mendeley.com/catalogue/2a153ac4-225f-322c-8625-08126b770384/
U2 - 10.1016/j.bneo.2024.100060
DO - 10.1016/j.bneo.2024.100060
M3 - Article
C2 - 40454411
VL - 2
SP - 100060
JO - Blood Neoplasia
JF - Blood Neoplasia
IS - 1
ER -