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Bispecific T-cells expressing polyclonal repertoire of endogenous γδ T-cell receptors and introduced CD19-specific chimeric antigen receptor

机译:表达内源性γδT细胞受体多克隆谱并导入CD19特异性嵌合抗原受体的双特异性T细胞

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Even though other γδ T-cell subsets exhibit antitumor activity, adoptive transfer of γδ Tcells is currently limited to one subset (expressing Vγ9Vδ2 T-cell receptor (TCR)) due to dependence on aminobisphosphonates as the only clinically appealing reagent for propagating γδ T cells. Therefore, we developed an approach to propagate polyclonal γδ T cells and rendered them bispecific through expression of a CD19-specific chimeric antigen receptor (CAR). Peripheral blood mononuclear cells (PBMC) were electroporated with Sleeping Beauty (SB) transposon and transposase to enforce expression of CAR in multiple γδ T-cell subsets. CAR+ γδ T cells were expanded on CD19+ artificial antigen-presenting cells (aAPC), which resulted in 10 9 CAR+ γδ T cells from 10 6 total cells. Digital multiplex assay detected TCR mRNA coding for Vδ1, Vδ2, and Vδ3 with Vγ2, Vγ7, Vγ8, Vγ9, and Vγ10 alleles. Polyclonal CAR+ γδ T cells were functional when TCRγδ and CAR were stimulated and displayed enhanced killing of CD19+ tumor cell lines compared with CAR neg γδ T cells. CD19+ leukemia xenografts in mice were reduced with CAR+ γδ T cells compared with control mice. Since CAR, SB, and aAPC have been adapted for human application, clinical trials can now focus on the therapeutic potential of polyclonal γδ T cells.
机译:尽管其他γδT细胞子集具有抗肿瘤活性,但由于依赖于氨基双膦酸盐作为传播γδT细胞的唯一临床吸引剂,γδT细胞的过继转移目前仅限于一个子集(表达Vγ9Vδ2T细胞受体(TCR))。 。因此,我们开发了一种传播多克隆γδT细胞并通过表达CD19特异性嵌合抗原受体(CAR)使它们成为双特异性的方法。用Sleeping Beauty(SB)转座子和转座酶对外周血单核细胞(PBMC)进行电穿孔,以增强CAR在多个γδT细胞亚群中的表达。 CAR +γδT细胞在CD19 +人工抗原呈递细胞(aAPC)上扩增,从总数小于10 6的细胞中产生> 10 9 CAR +γδT细胞。数字多重分析检测了带有Vγ2,Vγ7,Vγ8,Vγ9和Vγ10等位基因的TCR mRNA编码Vδ1,Vδ2和Vδ3。当刺激TCRγδ和CAR时,与CAR negγδT细胞相比,多克隆CAR +γδT细胞发挥功能,并显示出对CD19 +肿瘤细胞系杀伤力的增强。与对照小鼠相比,CAR +γδT细胞可减少小鼠的CD19 +白血病异种移植。由于CAR,SB和aAPC已适应人类应用,因此临床试验现在可以集中在多克隆γδT细胞的治疗潜力上。

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