CAR-T(CAR-T)细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T(CAR-T)细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:Chronic inflammatory demyelinating polyneuropathy (CIDP) after cilta-cel therapy.
Chronic inflammatory demyelinating polyneuropathy (CIDP) after cilta-cel therapy.
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Ciltacabtagene autoleucel(cilta-cel)是一种对复发/难治性多发性骨髓瘤具有高度活性的CAR-T 细胞疗法,但可能诱发严重的免疫介导毒性。本文介绍2例接受cilta-cel后发生慢性炎性脱髓鞘性多发性神经病(CIDP)的患者。患者1在输注后112天出现步态共济失调迅速进展、弛缓性轻瘫和动眼神经麻痹;患者2于第19天出现类似综合征。两例患者的肌电图和神经传导检查均证实感觉运动性轴索-脱髓鞘性神经病;脑MRI和脑脊液感染检测均无异常。血液和脑脊液中均可检测到CAR-T 细胞,但以CD8非CAR-T 细胞为主。TCR测序显示,患者1存在高度扩增的克隆(约占全部测序读段的30%),患者2则为多克隆受体库。大剂量地塞米松联合静脉注射免疫球蛋白未能改善神经症状,因此给予可清除T细胞的环磷酰胺治疗,CAR及非CAR-T 细胞数量均随之下降。患者1因呼吸衰竭死亡,患者2病情改善并出院。这些观察表明,CIDP是cilta-cel治疗的一种严重并发症,可能由自身反应性CD8 T细胞旁观者扩增所致,而非CAR-T 细胞的直接作用。及时升级至清除T细胞的治疗可能改善结局。
Ciltacabtagene-autoleucel (cilta-cel) is a CAR-T cell therapy highly active in relapsed/refractory multiple myeloma but can induce severe immune-mediated toxicities.
We describe two patients who developed chronic inflammatory demyelinating polyneuropathy (CIDP) after cilta-cel. Patient 1 presented with rapidly progressive gait ataxia, flaccid paraparesis, and oculomotor palsy 112 days post infusion; Patient 2 developed an analogous syndrome on day 19. In both patients, electromyography and nerve-conduction studies confirmed sensorimotor axonal-demyelinating neuropathy; brain MRI and CSF infection panels were unremarkable. CAR-T cells were detectable in blood and CSF, yet a predominance of CD8 non-CAR-Tcells was observed.
TCR- sequencing revealed a hyper-expanded clone (~30% of all reads) in patient 1 versus a polyclonal repertoire in patient 2. High-dose dexamethasone plus intravenous immunoglobulin failed to improve neurologic symptoms and prompted T-cell-depleting cyclophosphamide, which lowered CAR- and non-CAR-T cells.
Patient 1 died from respiratory failure, whereas patient 2 improved and could be discharged. These observations indicate that CIDP is a severe complication of cilta-cel therapy and may arise from bystander expansion of autoreactive CD8 T-cells rather than direct CAR-T cell activity. Timely escalation to T-cell-depleting therapy may improve outcomes.
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