文章：

靶向CD33的原代CAR-NK细胞治疗急性髓系白血病

Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia

原文发布日期：2022-04-13

DOI: 10.1038/s41408-022-00660-2

类型: Article

开放获取: 是

英文摘要：

Acute myeloid leukemia (AML) is a malignant disorder derived from neoplastic myeloid progenitor cells characterized by abnormal proliferation and differentiation. Although novel therapeutics have recently been introduced, AML remains a therapeutic challenge with insufficient cure rates. In the last years, immune-directed therapies such as chimeric antigen receptor (CAR)-T cells were introduced, which showed outstanding clinical activity against B-cell malignancies including acute lymphoblastic leukemia (ALL). However, the application of CAR-T cells appears to be challenging due to the enormous molecular heterogeneity of the disease and potential long-term suppression of hematopoiesis. Here we report on the generation of CD33-targeted CAR-modified natural killer (NK) cells by transduction of blood-derived primary NK cells using baboon envelope pseudotyped lentiviral vectors (BaEV-LVs). Transduced cells displayed stable CAR-expression, unimpeded proliferation, and increased cytotoxic activity against CD33-positive OCI-AML2 and primary AML cells in vitro. Furthermore, CD33-CAR-NK cells strongly reduced leukemic burden and prevented bone marrow engraftment of leukemic cells in OCI-AML2 xenograft mouse models without observable side effects.
 

摘要翻译： 

急性髓系白血病（AML）是一种源自髓系祖细胞肿瘤性病变的恶性疾病，其特征为异常增殖与分化。尽管近年来新型疗法不断涌现，AML的治疗仍面临挑战，治愈率尚未达到理想水平。过去几年中，免疫导向疗法如嵌合抗原受体（CAR）-T细胞已应用于临床，在治疗B细胞恶性肿瘤（包括急性淋巴细胞白血病）方面显示出卓越的临床活性。然而，由于该疾病巨大的分子异质性及可能对造血功能造成的长期抑制，CAR-T细胞的应用仍存在挑战。本研究报道了通过猿猴泡沫病毒包膜假型慢病毒载体转导外周血来源的原代自然杀伤（NK）细胞，成功构建了靶向CD33的CAR修饰NK细胞。转导细胞在体外表现出稳定的CAR表达、不受影响的增殖能力，以及对CD33阳性OCI-AML2细胞系和原代AML细胞增强的细胞毒性活性。此外，在OCI-AML2异种移植小鼠模型中，CD33-CAR-NK细胞能显著降低白血病负荷并阻止白血病细胞在骨髓中的定植，且未观察到明显副作用。

原文链接：

Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia