肿瘤细胞治疗研究
英文原题：Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia.
急性髓系白血病（AML）是一种源自肿瘤性髓系祖细胞的恶性疾病，其特征为异常增殖和分化。
急性髓系白血病（AML）是一种源于肿瘤性髓系祖细胞的恶性疾病，其特征为异常增殖和分化。尽管近年来已有新型治疗药物问世，AML仍是一个治疗难题，治愈率不足。近年来，免疫导向疗法如嵌合抗原受体（CAR）-T细胞被引入，在包括急性淋巴细胞白血病（ALL）在内的B细胞恶性肿瘤中展现出卓越的临床活性。然而，由于该疾病巨大的分子异质性以及潜在的长期造血抑制，CAR-T细胞的应用面临挑战。本文报道了通过使用狒狒包膜假型慢病毒载体（BaEV-LVs）转导血液来源的原代NK细胞，成功构建了靶向CD33的CAR修饰自然杀伤（NK）细胞。转导后的细胞表现出稳定的CAR表达、不受阻碍的增殖能力，以及在体外对CD33阳性OCI-AML2细胞和原代AML细胞增强的细胞毒活性。此外，在OCI-AML2异种移植小鼠模型中，CD33-CAR-NK细胞强烈降低了白血病负荷并阻止了白血病细胞的骨髓植入，且未观察到明显副作用。
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.
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