Sustained and specific multiplexed immune checkpoint modulation in CAR T cells induced by targeted epigenome editing
Maria Silvia Roman Azcona, Gianni Monaco, Melissa Whitehead, Masako Monika Kaufmann, Jamal Alzubi, Toni Cathomen, Claudio Mussolino
Abstract
, both in primary human T cells and in prostate-cancer-specific CAR T cells. Epigenetically modified CAR T cells are indistinguishable from parental cells across a range of functional assays. Although the model does not fully mimic T cell exhaustion, limiting functional assessment, gene silencing remains durable across multiple divisions and repeated CAR stimulations. Furthermore, transcriptomic analysis revealed minimal off-target effects not directly attributable to the effectors used. We demonstrate that targeted epigenome editing is effective and safe for multiplexed gene inhibition and holds potential in engineering CAR T cells with enhanced and customizable features.