Characterization of Leukemic Resistance to CD19-Targeted CAR T-cell Therapy through Deep Genomic Sequencing.
Characterization of Leukemic Resistance to CD19-Targeted CAR T-cell Therapy through Deep Genomic Sequencing.
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DOI：
10.1158/2326-6066.cir-22-0095
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发表时间：
2023-01-03
影响因子：
10.1
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中科院分区：
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靶向CD19的嵌合抗原受体（CAR） t细胞治疗已经成为儿童b细胞急性淋巴细胞白血病（B-ALL）的临床突破，白血病细胞上CD19靶抗原的缺失是复发的主要机制。先前的研究已经观察到CD19 -复发特异性的CD19突变，我们试图通过在患者来源的异种移植物中扩增的白血病细胞中进行深度全外显子组测序来澄清和加强这种关系。通过评估13名接受CAR -t细胞治疗的患者的治疗前和复发细胞，其中8人发生CD19 -复发，5人发生CD19+复发，我们证明了复发特异性单核苷酸变异和高等位基因频率的小indel与CD19基因缺失以CD19 -复发患者特有的方式结合在一起。在CAR - t细胞输注之前，一名患者被发现在基因组不稳定的背景下存在预先存在的CD19缺失，这可能是导致患者随后CD19复发的第一个打击。在患者中，先前存在的突变和基因组不稳定性不是患者随后CD19复发的显著预测因素，样本量是一个潜在的限制因素。总之，我们的研究结果阐明并加强了基因组事件与CD19 -复发之间的关系，证明了这种对靶向癌症免疫治疗的耐受性的有趣机制。
Chimeric Antigen Receptor (CAR) T-cell therapy targeting CD19 has been a clinical breakthrough for pediatric B-cell acute lymphoblastic leukemia (B-ALL), and loss of the CD19 target antigen on leukemic cells represents a major mechanism of relapse. Previous studies have observed CD19 mutations specific to CD19− relapses, and we sought to clarify and strengthen this relationship using deep whole-exome sequencing in leukemic cells expanded in a patient-derived xenograft. By assessing pre-treatment and relapse cells from 13 patients treated with CAR T-cell therapy, 8 of whom developed CD19− relapse and 5 of whom developed CD19+ relapse, we demonstrate that relapse-specific single-nucleotide variants and small indels with high allele frequency combined with deletions in the CD19 gene in a manner specific to those patients with CD19− relapse. Prior to CAR T-cell infusion, one patient was found to harbor a pre-existing CD19 deletion in the context of genomic instability, which likely represented the first hit leading to the patient’s subsequent CD19− relapse. Across patients, pre-existing mutations and genomic instability were not significant predictors of subsequent CD19− relapse across patients, with sample size as a potential limiting factor. Together, our results clarify and strengthen the relationship between genomic events and CD19− relapse, demonstrating this intriguing mechanism of resistance to a targeted cancer immunotherapy.