CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration
CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration
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DOI：
10.1172/jci130144
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发表时间：
2020-02-03
影响因子：
15.9
通讯作者：
Bushman, Frederic D.
中科院分区：
文献类型：
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作者：
Nobles, Christopher L.;Sherrill-Mix, Scott;Bushman, Frederic D.
靶向CD19的嵌合抗原受体工程化T细胞（CART19）为儿科急性淋巴细胞白血病提供了有效的治疗，但对慢性淋巴细胞白血病（CLL）的疗效较差，因此将注意力集中在提高疗效上。CART 19具有工程化受体，其通过慢病毒载体整合递送，从而标记细胞谱系并通过插入诱变修饰细胞基因组。我们最近报道了载体整合到宿主TET2基因中与CLL缓解相关。在这里，我们研究了克隆群体结构和治疗结果在另外39例患者的高通量测序载体整合位点。在反应者中富集的整合位点处的基因通常存在于细胞信号传导和染色质修饰途径中，这表明这些基因中的插入诱变促进了治疗性T细胞增殖。我们还开发了一个基于整合位点分布的多变量模型，发现来自预输注产品的数据在发现和验证队列中成功预测了CLL的应答，并且在第28天的样本中，报告了对CLL治疗的应答者，具有很高的准确性。这些数据阐明了插入突变如何调节CART 19治疗中的细胞增殖，以及整合位点分布的数据如何与治疗结果联系起来。
Chimeric antigen receptor-engineered T cells targeting CD19 (CART19) provide an effective treatment for pediatric acute lymphoblastic leukemia but are less effective for chronic lymphocytic leukemia (CLL), focusing attention on improving efficacy. CART19 harbor an engineered receptor, which is delivered through lentiviral vector integration, thereby marking cell lineages and modifying the cellular genome by insertional mutagenesis. We recently reported that vector integration within the host TET2 gene was associated with CLL remission. Here, we investigated clonal population structure and therapeutic outcomes in another 39 patients by high-throughput sequencing of vector-integration sites. Genes at integration sites enriched in responders were commonly found in cell-signaling and chromatin modification pathways, suggesting that insertional mutagenesis in these genes promoted therapeutic T cell proliferation. We also developed a multivariate model based on integration-site distributions and found that data from preinfusion products forecasted response in CLL successfully in discovery and validation cohorts and, in day 28 samples, reported responders to CLL therapy with high accuracy. These data clarify how insertional mutagenesis can modulate cell proliferation in CART19 therapy and how data on integration-site distributions can be linked to treatment outcomes.