2026-05-18 マウントサイナイ医療システム（MSHS）
＜関連情報＞
- https://www.mountsinai.org/about/newsroom/2026/reversing-t-cell-exhaustion-improves-effectiveness-of-myeloma-immunotherapies
- https://ashpublications.org/blood/article/doi/10.1182/blood.2025030873/568350/Mezigdomide-reverses-T-cell-exhaustion-through
- https://ashpublications.org/blood/article/doi/10.1182/blood.2025030891/568277/Ikaros-degradation-by-mezigdomide-reduces-T-cell
メジグドミドは、IKZF1/IKZF3の分解とサイトカイン産生経路の活性化を介してT細胞疲弊を逆転させる Mezigdomide reverses T-cell exhaustion through degradation of IKZF1/IKZF3 and reinvigoration of cytokine production pathways
Hsiling Chiu,Junfei Zhao,Tara Basavanhally,Chih-Chao Hsu,Michael D Amatangelo,Gaurav Jain,Chad C Bjorklund,Ting-Hsiang Huang,Lucia Y Chen,Thomas A Milne,Sarah Gooding,Samir Parekh,Anita Krithivas Gandhi,Maria Ortiz Estevez,Patrick Ryan Hagner
Blood Published:May 12, 2026
DOI:https://doi.org/10.1182/blood.2025030873
Key Points
- IKZF1 and IKZF3 promote T-cell exhaustion via epigenetic control leading to reduced cytokines and increased exhaustion genes
- Mezigdomide mediated degradation of IKZF1/IKZF3 restores function in exhausted T cells, leading to enhanced BCMA TCE activity
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 MM patients. 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, using their autologous activated T cells as a comparison. Our study reveals that IKZF1 and IKZF3 are critical regulators contributing 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 enhancement of transcription, while binding to cytokine genes results in transcription repression. Mezigdomide treatment in exhausted T cells results in decreased expression of exhaustion-related markers, increased proinflammatory cytokine expression, and enhanced target cell killing with Alnuctamab, a B-cell maturation antigen (BCMA) 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 TCEs to enhance therapeutic outcomes in MM.
メジグドミドによるイカロスの分解はT細胞機能障害を軽減し、抗骨髄腫T細胞療法の有効性を向上させる Ikaros degradation by mezigdomide reduces T-cell dysfunction and improves the efficacy of antimyeloma T-cell therapies
Lucia Y Chen,Adolfo Aleman,Marta Larrayoz,Hsiling Chiu,Junfei Zhao,Oliver Van Oekelen,Geoffrey Kelly,Seunghee Kim-Schulze,Alessandro Lagana,Sundar Jagannath,Tracy T. Chow,Teresa Lozano,Juan J Lasarte,Joseph C. Hamley,Warren Baker,Benjamin L Ebert,Udo Oppermann,Michael D Amatangelo,Anita Krithivas Gandhi,Patrick Ryan Hagner,Jose A Martínez-Climent,Sarah Gooding,Thomas A Milne,Samir Parekh
Blood Published:May 8, 2026
DOI:https://doi.org/10.1182/blood.2025030891
Key Points
- Mezigdomide treatment activates T cells and reduces exhausted-like T cell populations in myeloma patients
- Ikaros degradation by Mezigdomide enhances anti-BCMA CAR-T and bispecific TCE therapy efficacy in vitro and in vivo
T cell dysfunction is an important contributor to both multiple myeloma (MM) disease progression and failure of anti-myeloma chimeric antigen receptor (CAR) T cell and bispecific T cell engager (TCE) therapies. Overcoming T cell dysfunction is therefore key to improving MM patient outcomes. Immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs) 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 MM patients, 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 ATAC-seq, ChIP-seq, HiC and RNA-seq 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 from anti-BCMA CAR-T therapy in vivo. Overall, our data show that Mezigdomide treatment improves anti-myeloma T cell therapy efficacy and reduces T cell dysfunction by abrogating Ikaros-mediated upregulation of exhaustion genes.
