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用T细胞重定向免疫疗法治疗多发性骨髓瘤的基因组抗原损失时间
Marios Papadimitriou1, Sungwoo Ahn2, Benjamin T Diamond1
1Sylvester Comprehensive Cancer Center, Miami, FL, United States.
Blood cancer discovery
|September 4, 2025
概括
在多发性骨髓瘤中,基因组抗原损失导致对CAR- T和T细胞抗原的耐药性是在治疗期间获得的,而不是先前存在的. 在治疗期间进行动态监测对于有效的治疗策略至关重要.
科学领域:
- 癌症学
- 免疫疗法
- 基因组学
背景情况:
- 在复发性/耐药性多发性骨髓瘤 (RRMM) 中,基因组抗原损失是已知对仿制抗原受体T细胞 (CAR-T) 和T细胞激活剂 (TCE) 疗法的抵抗机制.
- 不确定这些抗药性事件是在治疗期间获得的还是从先前存在的,无法检测的克隆中选择的.
研究的目的:
- 在接受CAR-T/ TCE治疗的RRMM患者中确定基因组抗原逃逸的时间.
- 评估抗原丢失突变的发病率和在治疗期间出现的突变.
主要方法:
- 全基因组测序 (WGS) 使用化疗突变特征作为时间条形码来定时基因组事件.
- 对11名接受BCMA和GPRC5D向CAR- T/ TCE治疗的RRMM患者进行分析.
- 纵向数字PCR (dPCR) 来追踪从治疗开始到复发的耐药性突变.
主要成果:
- 在11名RRMM患者中,有4名基因组抗原逃逸被定时,在CAR- T/ TCE暴露后获得了双性损失.
- 抗药性突变在基线和治疗开始时无法检测,在临床复发之前出现.
- 在一组752名新诊断的患者中,只有很小一部分TNFRSF17 (2. 7%) 或GPRC5D (9%) 的单基因失活,而没有双基因失活.
结论:
- 在RRMM中,基因组抗原损失是在治疗过程中获得的,而不是先前存在的,突出显示治疗诱导的耐药性.
- 治疗前对抗原损失的突变查对预测CAR- T/ TCE疗效具有有限的效用.
- 在治疗期间持续监测抗原表达对于控制RRMM的耐药性至关重要.
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