Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity.
Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity.
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DOI：
10.1038/leu.2017.226
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发表时间：
2018-03
期刊：
影响因子：
11.4
通讯作者：
Rezvani K
中科院分区：
文献类型：
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作者：
Liu E;Tong Y;Dotti G;Shaim H;Savoldo B;Mukherjee M;Orange J;Wan X;Lu X;Reynolds A;Gagea M;Banerjee P;Cai R;Bdaiwi MH;Basar R;Muftuoglu M;Li L;Marin D;Wierda W;Keating M;Champlin R;Shpall E;Rezvani K
嵌合抗原受体（汽车）已被用于重定向自体T细胞针对白血病和淋巴瘤的特异性，具有有希望的临床结果。将这种方法扩展到同种异体T细胞是有问题的，因为它们携带移植物抗宿主病（GVHD）的显著风险。自然杀伤（NK）细胞是高度细胞毒性效应物，以非抗原特异性方式杀死其靶而不引起GVHD。脐带血（CB）为免疫治疗提供了一种有吸引力的同种异体自体NK细胞来源。我们用逆转录病毒载体转导CB衍生的NK细胞，该逆转录病毒载体整合了CAR-CD 19、IL-15和基于诱导型半胱天冬酶-9的自杀基因（iC 9）的基因，并证明了在体外有效杀死表达CD 19的细胞系和原代白血病细胞，在异种移植Raji淋巴瘤小鼠模型中存活期显著延长。转导的CB-NK细胞产生的IL-15显著改善了它们的功能。此外，iC 9/CAR.19/IL-15 CB-NK细胞在iC 9自杀基因的药理学激活后易于消除。总之，我们已经开发了一种新的免疫治疗方法，使用工程化的CB衍生NK细胞，其易于生产，表现出惊人的疗效，并结合安全措施以限制毒性。这种方法应该大大改善将这种疗法提供给大量患者的物流，这是目前CAR-T细胞疗法的主要限制。
Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T-cells against leukemia and lymphoma with promising clinical results. Extending this approach to allogeneic T-cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with dramatic prolongation of survival in a xenograft Raji lymphoma murine model. IL-15 production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T cell therapies.
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DOI：
10.1038/nri2635
发表时间：
2009-10
期刊：
Nature reviews. Immunology
影响因子：
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作者：
通讯作者：
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影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
通讯作者：
Sadelain M
DOI：
10.1073/pnas.0604236103
发表时间：
2006-07-05
影响因子：
11.1
作者：
Chen, Xi;Allan, David S. J.;Strominger, Jack L.
通讯作者：
Strominger, Jack L.
影响因子：
11.4
作者：
通讯作者：
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DOI：
10.1038/mto.2016.11
发表时间：
2016
期刊：
Molecular therapy oncolytics
影响因子：
--
作者：
通讯作者：
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