Department of Data Science, Dana Farber Cancer Institute, Boston, MA, USA.
Department of Biostatistics, Harvard T. H. Chan School of Public Health Boston, Boston, MA, USA.
Nat Commun. 2021 Feb 8;12(1):868. doi: 10.1038/s41467-021-21177-5.
BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.
BCMA 靶向嵌合抗原受体 (CAR) T 细胞疗法在多发性骨髓瘤中显示出深度和持久的应答。然而，治疗后经常观察到复发，并且耐药机制仍不清楚。在这里，我们对一名患者的纵向样本进行了单细胞基因组特征分析，该患者在初始 CAR T 细胞治疗后复发，对再治疗没有反应。我们报告了在初始 CAR T 细胞输注后选择的克隆，该克隆通过缺失一个等位基因和在第二个等位基因上产生一个提前终止密码子的突变获得了 BCMA 的双等位基因缺失。这种缺失导致第二次输注后 CAR T 细胞增殖缺乏，并反映在患者血清中缺乏可溶性 BCMA。我们的分析表明，在 CAR T 细胞治疗后复发的多发性骨髓瘤细胞中，需要仔细检测 BCMA 基因改变。
