CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Genomic and immune determinants of resistance to anti-CD38 monoclonal antibody-based therapy in relapsed refractory multiple myeloma.
Genomic and immune determinants of resistance to anti-CD38 monoclonal antibody-based therapy in relapsed refractory multiple myeloma.
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抗CD38抗体疗法已改变多发性骨髓瘤（MM）的治疗格局。然而，很大一部分患者不可避免地会复发。为了理解这一现象，我们研究了32例接受daratumumab、lenalidomide和dexamethasone（Dara-Rd；NCT03848676）治疗的复发MM患者。治疗前后的全基因组测序（WGS）精准识别了与早期进展相关的基因组驱动因素，包括RPL5缺失和APOBEC突变。对31例患者每三个月采集直至进展的202份血液样本进行流式细胞术分析，揭示了显著影响临床结局的独特免疫变化。进展患者的CD38+ NK细胞显著耗竭，T细胞耗竭持续存在，且随时间推移T-reg细胞耗竭减少。这些发现强调了免疫组成及daratumumab诱导的免疫变化在促进MM耐药中的作用。整合基因组学和流式细胞术揭示了不良基因组特征与免疫模式之间的关联。
总体而言，本研究揭示了基因组复杂性与免疫微环境之间错综复杂的相互作用，这种相互作用驱动了对Dara-Rd的耐药。
Anti-CD38 antibody therapies have transformed multiple myeloma (MM) treatment.
However, a large fraction of patients inevitably relapses. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676 ). Whole genome sequencing (WGS) before and after treatment pinpointed genomic drivers associated with early progression, including RPL5 loss and APOBEC mutagenesis.
Flow cytometry on 202 blood samples, collected every three months until progression for 31 patients, revealed distinct immune changes significantly impacting clinical outcomes. Progressing patients exhibited significant depletion of CD38+ NK cells, persistence of T cell exhaustion, and reduced depletion of T-reg cells over time.
These findings underscore the influence of immune composition and daratumumab-induced immune changes in promoting MM resistance. Integrating genomics and flow cytometry unveiled associations between adverse genomic features and immune patterns.
Overall, this study sheds light on the intricate interplay between genomic complexity and the immune microenvironment driving resistance to Dara-Rd.
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