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利用叶酸受体β修饰的嵌合抗原受体靶向治疗急性髓性白血病的爆发

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发表于 2015-11-26 22:23:23 | 显示全部楼层 |阅读模式
Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor–expressing T cells
Key Points
l Human FRβ-specific CAR T cells target AML in vitro and in vivo without toxicity against healthy bone marrow HSCs.
l Combination with ATRA-mediated receptor upregulation may augment FRβ-directed CAR therapy of AML.
Abstract
T cells expressing a chimeric antigen receptor (CAR) can produce dramatic results in lymphocytic leukemia patients; however, therapeutic strategies for myeloid leukemia remain limited. Folate receptor β (FRβ) is a myeloid-lineage antigen expressed on 70% of acute myeloid leukemia (AML) patient samples. Here, we describe the development and evaluation of the first CARs specific for human FRβ (m909) in vitro and in vivo. m909 CAR T cells exhibited selective activation and lytic function against engineered C30-FRβ as well as endogenous FRβ+ AML cell lines in vitro. In mouse models of human AML, m909 CAR T cells mediated the regression of engrafted FRβ+ THP1 AML in vivo. In addition, we demonstrated that treatment of AML with all-trans retinoic acid (ATRA) enhanced FRβ expression, resulting in improved immune recognition by m909 CAR T cells. Because many cell surface markers are shared between AML blasts and healthy hematopoietic stem and progenitor cells (HSCs), we evaluated FRβ expression and recognition of HSCs by CAR T cells. m909 CAR T cells were not toxic against healthy human CD34+ HSCs in vitro. Our results indicate that FRβ is a promising target for CAR T-cell therapy of AML, which may be augmented by combination with ATRA.
Submitted November 18, 2014.
Accepted April 9, 2015.
利用叶酸受体β修饰的嵌合抗原受体靶向治疗急性髓性白血病的爆发       
关键观点:
l 叶酸受体β修饰的CAR-T细胞在体内和体外靶向治疗AML,对骨髓造血干细胞没有毒性。
l 与全反式维甲酸受体表达上调的组合也许会增加叶酸受体β修饰的CAR-T细胞对AML的治疗。
摘要:
CAR-T细胞治疗对淋巴白血病患者有明显的治疗效果,然而,对髓性白血病的治疗方案仍然很有限。叶酸受体β (FRβ)是一个在70%AML病人细胞样本表面表达的髓系抗原。这篇文章中,我们描述了第一个人类叶酸受体β (FRβ) (m909)修饰的CAR-T细胞在体内和体外试验的发展和评估。m909 CAR-T细胞对改造后的C30-Frβ和内源性的FRβ阳性 AML细胞株表达了选择性的活性和溶解功能。在人AML小鼠模型体内,m909 CAR T细胞会使得体内嫁接的FRβ阳性AML THP1细胞发生衰退。此外,我们发现,在治疗AML时,使用全反式维甲酸(ATRA处理后,会增加FRβ的表达,从而增加m909 CAR-T 细胞的免疫识别作用。由于AML细胞和健康的造血干细胞和祖细胞(HSC有着许多共同的细胞表面标记物,我们通过CAR-T细胞评估了FRβ的表达并识别造血干细胞。m909 CAR T细胞在体外对健康人CD34+造血干细胞没有毒性。我们的结果显示FRβ是CAR-T细胞治疗AML有前途的靶标,在共同使用ATRA时疗效可能会增强。
提交20141118日。
接受201549日。
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