Entinostat, a Histone Deacetylase Inhibitor, improves Anti-Tumor Activity of CAR-NK Cells by Sustaining CAR Expression 4143

Abstract Description Allogeneic natural killer (NK) cell therapy has emerged as a promising approach in cancer immunotherapy. Chimeric antigen receptor (CAR)-engineered NK cells targeting CD138 present a novel therapeutic strategy for treating multiple myeloma (MM). However, maintaining CAR expression during ex vivo expansion remains a critical challenge, limiting therapeutic applications. In this study, primary NK cells were isolated, cryopreserved, and engineered to express anti-CD138 CARs using retroviral transduction. To address CAR expression downmodulation, histone deacetylase inhibitors (HDACi), particularly entinostat (ENT), were employed. Our results demonstrate that ENT treatment significantly restores CAR expression, thereby boosting the cytotoxic potency of CAR-NK cells against CD138-positive MM cells. In a mouse model of MM, ENT-treated CAR-NK cells exhibited superior tumor reduction, emphasizing their therapeutic efficacy. This study is the first to show that HDAC inhibitors can be used to restore CAR expression in CAR-NK cells through a promoter-dependent mechanism, enhancing anti-tumor activity in MM and warranting further clinical exploration. Funding Sources The Canadian Institutes of Health Research (PJT-178197, PJT-518790). Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)