Ikaros degradation by mezigdomide reduces T-cell dysfunction and improves the efficacy of antimyeloma T-cell therapies

ABSTRACT: T-cell dysfunction is an important contributor to both multiple myeloma (MM) disease progression and failure of antimyeloma chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engager (TCE) therapies. Overcoming T-cell dysfunction is therefore key to improving outcomes of patients with MM. Immunomodulatory drugs and cereblon E3 ligase modulatory drugs have been observed to activate T cells and, more recently, reduce T-cell dysfunction; however, the underlying mechanisms behind this are incompletely understood. Here, using bone marrow samples from patients with MM, we demonstrate a significant reduction in dysfunctional T-cell populations expressing exhaustion markers, such as TIGIT, upon treatment with mezigdomide. We further demonstrate the ability of mezigdomide to improve T-cell function and cytotoxicity in primary T-cell models of T-cell dysfunction and bispecific TCE therapy in vitro. Using concurrent assay for transposase-accessible chromatin using sequencing, chromatin immunoprecipitation sequencing, high-throughput chromatin conformation capture, and RNA sequencing in primary T cells treated with mezigdomide, we demonstrate the novel role of transcription factor Ikaros in regulating an important T-cell exhaustion gene TIGIT. Finally, we demonstrate the ability of mezigdomide to enhance survival outcomes of anti-B-cell maturation antigen CAR-T therapy in vivo. Overall, our data show that mezigdomide treatment improves antimyeloma T-cell therapy efficacy and reduces T-cell dysfunction by abrogating Ikaros-mediated upregulation of exhaustion genes.