Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients
Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients
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DOI：
10.1002/ijc.33212
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发表时间：
2020-07-28
影响因子：
6.4
通讯作者：
Sellner, Leopold
中科院分区：
文献类型：
--
作者：
Fan, Fuli;Yoo, Hyeon Joo;Sellner, Leopold
针对CD19的嵌合抗原受体T(CART)细胞在慢性淋巴细胞白血病(CLL)的治疗中显示出良好的效果。然而，与弥漫性大B细胞淋巴瘤或急性淋巴细胞性白血病相比，其疗效似乎较差。CLL患者T细胞功能受损可能与治疗失败有关。分化较差的幼稚样T细胞在体内对CART的扩张和长期存活起着重要作用。在CLL患者中，这些细胞稀疏。因此，优化CART细胞生产方案以丰富分化较少的T细胞亚群可能会克服治疗耐药性。针对Bruton‘s酪氨酸激酶(BTK)的B细胞受体抑制剂ibrutinib被批准用于治疗CLL。除BTK外，伊布鲁替尼还抑制与T细胞分化有关的白介素2诱导的T细胞激酶(ITK)。为了评价伊布鲁替尼对CART细胞产生的影响，用9名健康献血员和8名慢性淋巴细胞性白血病患者的外周血单个核细胞培养CART细胞。检测T细胞的扩增和表型、归巢和力竭标志物的表达以及CART细胞的功能。在伊布鲁替尼存在的情况下，CART细胞的生成导致了CLL患者来源的CART细胞的细胞活性和扩增。此外，伊布鲁替尼使CART细胞具有较低分化的幼稚样表型，并减少了PD-1、TIM-3和LAG-3等耗竭标志物的表达。此外，ibrutinib增加了CLL患者来源的CART细胞的细胞因子释放能力。总之，在CART细胞培养过程中使用ibrutinib抑制BTK/ITK可以提高CLL患者来源的CART细胞产品的产量和功能。
Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naive-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naive-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.