Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in Multiple Myeloma

BCMA targeting CAR T cell therapy have shown deep and durable responses in multiple myeloma. However, intrinsic and acquired resistance to therapy is frequently observed, and mechanisms of resistance remain ill-defined. We have performed single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T 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 2nd infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations with CAR T cell therapy in myeloma.

B细胞成熟抗原（BCMA）靶向的嵌合抗原受体T细胞（CAR T）疗法在多发性骨髓瘤中已展现出深度且持久的临床应答。然而，该疗法的固有耐药与获得性耐药现象频发，但其具体耐药机制仍未明确。我们对一名在初始CAR T治疗后复发、且对再次治疗无应答的患者的纵向样本进行了单细胞基因组学表征。本研究报道了初始CAR T细胞输注后筛选得到的一个克隆：该克隆通过缺失一个等位基因，并在第二个等位基因上产生导致翻译提前终止的密码子突变，从而发生BCMA双等位基因缺失。此类BCMA缺失会导致第二次输注后CAR T细胞增殖受阻，且患者血清中可溶性BCMA的缺失也印证了这一现象。我们的分析提示，在骨髓瘤患者接受CAR T细胞疗法的临床实践中，需谨慎检测BCMA基因的变异情况。