Mezigdomide reverses T-cell exhaustion through degradation of IKZF1/IKZF3 and reinvigoration of cytokine production pathways

ABSTRACT: T-cell exhaustion has been shown to be a key resistance mechanism to efficacy of T-cell engagers (TCE) in multiple myeloma (MM). Mezigdomide, a potent cereblon E3 ligase modulator that targets IKZF1 and IKZF3 simultaneously for proteasomal degradation, has been shown to modulate T-cell activity in patients with MM. We explored the possibility that targeting IKZF1/IKZF3 could address T-cell exhaustion and restore functionality. We conducted extensive transcriptomic and epigenetic profiling on ex vivo generated exhausted T cells (Tex), using their autologous activated T cells as a comparison. Our study revealed that IKZF1 and IKZF3 are critical regulators that contribute to the development and maintenance of T-cell exhaustion. They regulate transcription by directly binding to promoters and enhancers, both proximal and distal, thereby altering transcriptional potential. Increased IKZF1 binding to exhaustion genes after multiple T-cell stimulations results in the enhancement of transcription, whereas binding to cytokine genes results in transcription repression. Mezigdomide treatment in Tex results in decreased expression of exhaustion-related markers, increased proinflammatory cytokine expression, and enhanced target cell killing with alnuctamab, a B-cell maturation antigen targeting TCE. This study provides crucial mechanistic insights into the roles of IKZF1/IKZF3 in T-cell exhaustion, supporting the rationale for combining mezigdomide with TCE to enhance therapeutic outcomes in MM.