Khouri Jack, Sborov Douglas, Rossi Adriana, Martin Thomas, Kashyap Trinayan, Mark Tomer, Baljevic Muhamed
Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH 44195, USA.
University of Utah Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
J Clin Med. 2025 Jun 9;14(12):4071. doi: 10.3390/jcm14124071.
The remarkable efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapy (CAR-T) has had a significant impact on treatment strategies for relapsed/refractory multiple myeloma (RRMM). However, response durability remains a concern, necessitating the optimization of CAR-T procedures. Therapies preceding CAR-T therapy are crucial for disease control and preserving T-cell fitness. This review summarizes the evidence supporting the potential of selinexor-based regimens as holding or bridging therapy with preclinical research, demonstrating selinexor's ability to foster an anti-inflammatory tumor microenvironment. Selinexor enhances CD8+ T-lymphocyte and NK cell activation, re-polarizes macrophages, and inhibits immunosuppressive cells. Bone marrow samples from patients in clinical studies show that selinexor increases CD8 and granzyme B expression in T-cells. Selinexor also disrupts NK cell inhibition, enhances anti-tumor activity, and reduces pro-inflammatory cytokines. Selinexor may upregulate BCMA expression and increase myeloma cell immunogenicity. Real-world data suggests selinexor as bridging therapy does not compromise CAR-T outcomes and may even improve them. Overall, the evidence indicates selinexor's potential to optimize CAR-T outcomes, warranting further investigation as a holding or bridging therapy for CAR-T.
靶向B细胞成熟抗原（BCMA）的嵌合抗原受体T细胞疗法（CAR-T）的显著疗效对复发/难治性多发性骨髓瘤（RRMM）的治疗策略产生了重大影响。然而，缓解的持久性仍然是一个问题，因此需要优化CAR-T程序。CAR-T治疗之前的疗法对于疾病控制和维持T细胞健康至关重要。本综述总结了支持基于塞利尼索的方案作为维持或桥接疗法潜力的证据，并结合临床前研究，证明了塞利尼索促进抗炎肿瘤微环境的能力。塞利尼索可增强CD8 + T淋巴细胞和NK细胞的活化，使巨噬细胞重新极化，并抑制免疫抑制细胞。临床研究中患者的骨髓样本显示，塞利尼索可增加T细胞中CD8和颗粒酶B的表达。塞利尼索还可解除NK细胞的抑制，增强抗肿瘤活性，并减少促炎细胞因子。塞利尼索可能上调BCMA表达并增加骨髓瘤细胞的免疫原性。真实世界数据表明，塞利尼索作为桥接疗法不会影响CAR-T疗效，甚至可能改善疗效。总体而言，证据表明塞利尼索具有优化CAR-T疗效的潜力，值得作为CAR-T的维持或桥接疗法进行进一步研究。
