PDF(Pubmed)
Abstract：
Recent data highlight genomic events driving antigen escape as a recurring cause of chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engager (TCE) resistance in multiple myeloma (MM). Yet, it remains unclear if these events, leading to clonal dominance at progression, result from acquisition under treatment selection or selection of pre-existing undetectable clones. This differentiation gains importance as these immunotherapies progress to earlier lines of treatment, prompting the need for innovative diagnostic testing to detect these events early on. By reconstructing phylogenetic trees and exploring chemotherapy mutational signatures as temporal barcodes in 11 relapsed refractory MM patients with available whole genome sequencing data before and after CART/TCE treatment, we demonstrated that somatic antigen escape mechanisms for BCMA- and GPRC5D-targeting therapies are acquired post-diagnosis, likely during CART/TCE treatment. Longitudinal tracking of these mutations using digital PCR in 4 patients consistently showed that genomic events promoting antigen escape were not detectable during the initial months of therapy but began to emerge nearly 1 year post therapy initiation. This finding reduces the necessity for a diagnostic panel to identify these events before CART/TCE. Instead, it underscores the importance of surveillance and identifying patients at higher risk of acquiring these events.
摘要：
最近的数据突出显示驱动抗原逃逸的基因组事件是多发性骨髓瘤（MM）中嵌合抗原受体T细胞（CAR-T）和双特异性T细胞衔接剂（TCE）抗性的复发原因。然而，目前还不清楚这些事件，在进展中导致克隆优势，在治疗选择或选择预先存在的不可检测的克隆下获得的结果。随着这些免疫疗法发展到更早的治疗路线，这种区别变得越来越重要。促使需要创新的诊断测试来及早发现这些事件。通过在CART/TCE治疗前后重建系统发育树并探索11例复发难治性MM患者的化疗突变特征作为时间条形码，并使用可用的全基因组测序数据，我们证明了BCMA和GPRC5D靶向治疗的体细胞抗原逃逸机制是诊断后获得的，可能在CART/TCE治疗期间。在4名患者中使用数字PCR对这些突变进行纵向跟踪一致表明，在治疗的最初几个月中无法检测到促进抗原逃逸的基因组事件，但在治疗开始近1年后开始出现。这一发现减少了诊断小组在CART/TCE之前识别这些事件的必要性。相反，它强调了监测和识别发生这些事件风险较高的患者的重要性.
结论：驱动抗原逃逸的基因组事件是多发性骨髓瘤对CART和T细胞衔接者耐药的复发机制。使用化疗突变特征，我们证明这些事件很可能是在治疗期间发生的.
结论：驱动抗原逃逸的基因组事件是多发性骨髓瘤对CART和T细胞衔接者耐药的复发机制。使用化疗突变特征，我们证明这些事件很可能是在治疗期间发生的.
