Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma.
Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma.
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DOI：
10.1038/s41467-021-21177-5
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发表时间：
2021-02-08
影响因子：
16.6
通讯作者：
Munshi NC
中科院分区：
文献类型：
--
作者：
Samur MK;Fulciniti M;Aktas Samur A;Bazarbachi AH;Tai YT;Prabhala R;Alonso A;Sperling AS;Campbell T;Petrocca F;Hege K;Kaiser S;Loiseau HA;Anderson KC;Munshi NC
BCMA靶向嵌合抗原受体（CAR） T细胞治疗多发性骨髓瘤显示出深刻和持久的反应。然而，治疗后复发是经常观察到的，耐药机制仍然不明确。在这里，我们对一名初次CAR - T细胞治疗后复发且对再治疗缺乏反应的患者的纵向样本进行单细胞基因组表征。我们报告了在初始CAR - T细胞输注后，通过删除一个等位基因和在第二个等位基因上产生早期停止密码子的突变获得BCMA双等位基因缺失的克隆的选择。这种损失导致CAR - T细胞在第二次输注后缺乏增殖，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。在多发性骨髓瘤（MM）患者中，经常观察到BCMA靶向CAR - t细胞治疗后复发。在这里，通过对连续收集的骨髓样本进行单细胞转录组分析，作者报告了BCMA双等位基因缺失是MM患者复发和对第二次CAR - T输注缺乏反应的耐药性机制。
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. Relapse following BCMA targeted CAR T-cell therapy is frequently observed in patients with multiple myeloma (MM). Here, by single cell transcriptome profiling on serially collected bone marrow samples, the authors report biallelic loss of BCMA as the mechanism of resistance underlying both relapse and lack of response to a second CAR T infusion in a patient with MM.
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影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
DOI：
10.1038/s41571-019-0184-6
发表时间：
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期刊：
Nature reviews. Clinical oncology
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作者：
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通讯作者：
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