Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising treatment strategy, however, therapeutic success against solid tumors such as neuroblastoma remains modest. Recurrence of antigen-poor tumor variants often ultimately results in treatment failure. Using antigen-independent killing mechanisms such as the FAS receptor (FAS)-FAS ligand (FASL) axis through epigenetic manipulation may be a way to counteract the escape achieved by antigen downregulation. Analysis of public RNA-sequencing data from primary neuroblastomas revealed that a particular epigenetic modifier, the histone lysine demethylase 1A (KDM1A), correlated negatively with FAS expression. KDM1A is known to interact with TP53 to repress TP53-mediated transcriptional activation of genes, including FAS. We showed that pharmacologically blocking KDM1A activity in neuroblastoma cells with the small molecule inhibitor, SP-2509, increased FAS cell-surface expression in a strictly TP53-dependent manner. FAS upregulation sensitized neuroblastoma cells to FAS-FASL-dependent killing and augmented L1CAM-directed CAR T cell therapy against antigen-poor or even antigen-negative tumor cells in vitro. The improved therapeutic response was abrogated when the FAS-FASL interaction was abolished with an antagonistic FAS antibody. Our results show that KDM1A inhibition unleashes an antigen-independent killing mechanism via the FAS-FASL axis to make tumor cell variants that partially or totally suppress antigen expression susceptible to CAR T cell therapy.

Background/Objectives: The aim of this study was to investigate the prognostic value of established response assessment tools for hepatocellular carcinoma (HCC) treated with high-dose-rate interstitial brachytherapy (iBT) alone or with transarterial chemoembolization (cTACE). Methods: (Non-)responders were categorized using size-based RECIST 1.1 and WHO criteria, enhancement-based mRECIST and EASL criteria, and the LI-RADS Treatment Response Algorithm (LR-TRA). The outcomes were the overall survival (OS), progression-free survival (PFS), and time to progression (TTP). The statistics used included Fisher’s exact test, a t-test, the Mann–Whitney-U test, and a Kaplan–Meier analysis. The median OS, PFS, and TTP were higher in patients following iBT (26.3, 9.1, and 13.0 months) than following cTACE/iBT (23.3, 7.6, and 9.2 months). Results: The enhancement-based criteria identified more responders and predicted PFS and TTP better compared to the size-based criteria. At two months, the cTACE/iBT responders showed improved PFS (mRECIST and EASL: 11.3 vs. 2.3 and 11.0 vs. 2.3, p < 0.01) and TTP (mRECIST and EASL: 11.9 vs. 2.4 months, p < 0.01) by the enhancement-based criteria. An EASL assessment at five months predicted improved survival following both cTACE/iBT (PFS: 11.9 vs. 5.1 months, p = 0.03; TTP: 12.4 vs. 5.0, p < 0.01) and iBT (11.1 vs. 5.1 months, p = 0.04; 13.0 vs. 5.3, p < 0.01). The LR-TRA showed OS benefits at five months for cTACE/iBT responders. Size-based criteria were not prognostic. Conclusions: Extending follow-up post-iBT or post-iBT/cTACE may improve responder stratification and prognostication.