PDF(Pubmed)
Abstract：
CD19 chimeric antigen receptor (CAR) engineered NK cells have been used for treating patients with relapsed and/or refractory B cell malignancies and show encouraging outcomes and safety profile. However, the poor persistence of NK cells remains a major challenge for CAR NK cell therapy. Memory-like NK cells (MLNK) induced by IL-12, IL-15, and IL-18 have shown enhanced and prolonged responses to tumor re-stimulation, making them an attractive candidate for adoptive cellular immunotherapy. Here, we show efficient and stable gene delivery of CD19 CAR to memory-like NK cells using retroviral vectors with transduction efficiency comparable to those achieved with conventional NK cells. Analysis of surface molecules revealed a distinct phenotypic profile in CAR engineered memory-like NK cells (CAR MLNK), as evidenced by increased expression of CD94 and downregulation of NKp30 as well as KIR2DL1. Compared to conventional CAR NK cells, CAR MLNK cells exhibited significantly increased IFN-γ production and degranulation in response to CD19+ target cells, resulting in enhanced cytotoxic activity against CD19+ leukemia cells and lymphoma cells. Furthermore, memory properties induced by IL-12/-15/-18 improved the in vivo persistence of CAR MLNK cells and significantly suppressed tumor growth in a exnograft mouse model of lymphoma, leading to prolonged survival of CD19+ tumor-bearing mouse. Altogether, our data indicate that CD19 CAR engineered memory-like NK cells exhibited superior persistence and antitumor activity against CD19+ tumors, which might be an attractive approach for treating patient with relapse or refractory B cell malignancies.
摘要：
CD19嵌合抗原受体(CAR)工程化NK细胞已用于治疗患有复发性和/或难治性B细胞恶性肿瘤的患者,并显示出令人鼓舞的结果和安全性。然而,NK细胞的持久性差仍然是CARNK细胞治疗的主要挑战。由IL-12，IL-15和IL-18诱导的记忆样NK细胞（MLNK）显示出对肿瘤再刺激的增强和延长的反应。使它们成为过继性细胞免疫疗法的有吸引力的候选者。这里,我们显示了使用逆转录病毒载体将CD19CAR有效且稳定的基因递送至记忆样NK细胞，其转导效率与常规NK细胞相当。表面分子的分析揭示了CAR工程记忆样NK细胞（CARMLNK）的独特表型，如CD94的表达增加和NKp30以及KIR2DL1的下调所证明的。与传统的CARNK细胞相比，CARMLNK细胞表现出显著增加的IFN-γ产生和脱粒响应CD19+靶细胞，导致对CD19+白血病细胞和淋巴瘤细胞的细胞毒活性增强。此外，IL-12/-15/-18诱导的记忆特性改善了CAR-MLNK细胞的体内持久性，并显着抑制了淋巴瘤移植瘤小鼠模型中的肿瘤生长，导致CD19+荷瘤小鼠的生存期延长。总之,我们的数据表明，CD19CAR工程记忆样NK细胞表现出优异的持久性和抗肿瘤活性对CD19+肿瘤，这可能是治疗复发或难治性B细胞恶性肿瘤的有吸引力的方法。
