靶向叶酸受体的CAR-T细胞技术在急性髓性白血病中的研究

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Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells.

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.


靶向叶酸受体的CAR-T细胞技术在急性髓性白血病中的研究
CAR-T细胞技术在淋巴细胞白血病患者身上能够产生明显的治疗效果。然而，髓细胞性白血病到目前为止，治疗方案仍然很有限。 叶酸受体β(FRβ)是一个在70%的急性髓性白血病患者细胞表面都有表达的抗原。在这篇文章中，我们描述在体内和体外使用靶向FRβ的CAR-T细胞技术的发展和价值。m909 CAR T细胞在体外，针对修饰过的C30-FRβ和内源性的FRβ(+)AML细胞系展现了选择性的激活和细胞溶解功能。在人类AML细胞的小鼠模型体内，m909 CAR T细胞能够 介导转移的FRβ(+) THP1 AML细胞的减少。此外，我们发现，使用全反式维甲酸（ATRA）治疗AML，会增加FRβ的表达，从而增加m909 CAR T细胞的免疫识别。m909 CAR T细胞在体外对正常人类CD34(+)造血干细胞没有毒性。我们的结果表明，FRβ是一种很有前途的靶向治疗AML的靶点，也许与全反式维甲酸共同使用，能够增加治疗效果。
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