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

{"title":"Loss of p53 impairs death receptor expression and confers resistance to CD19 CAR T-cell therapy in BCP-ALL","authors":"Willem P. J. Cox ∗ ,&nbsp;Noël M. M. Dautzenberg ∗ ,&nbsp;Linde Dekker ,&nbsp;Tesa Klenovsek ,&nbsp;Annelisa M. Cornel ,&nbsp;Marliek van Hoesel ,&nbsp;Dorette S. van Ingen Schenau ,&nbsp;Reno S. Bladergroen ,&nbsp;Roland P. Kuiper ,&nbsp;Laurens T. van der Meer ,&nbsp;Friso G. Calkoen † ,&nbsp;Stefan Nierkens † ,&nbsp;Frank N. van Leeuwen †","doi":"10.1016/j.bneo.2024.100060","DOIUrl":null,"url":null,"abstract":"<div><h3>Abstract</h3><div>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 <em>TP53</em>-mutated (<em>TP53</em>^Mut) compared with <em>TP53</em>–wild-type (<em>TP53</em>^WT) BCP-ALL. To investigate the effect of p53 loss on CAR T therapy response, we modeled <em>TP53</em> 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 <em>TP53</em>^Mut BCP-ALL, they may also provide opportunities to enhance the efficacy of CAR T treatment both in patients with <em>TP53</em>^Mut and <em>TP53</em>^WT BCP-ALL. Furthermore, these data underscore the need for alternative curative therapies for this very high-risk patient group.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 1","pages":"Article 100060"},"PeriodicalIF":0.0000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Neoplasia","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2950328024000608","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}