Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma.
Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma.
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DOI：
10.1038/s41467-022-35127-2
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发表时间：
2022-11-29
影响因子：
16.6
通讯作者：
Miller JS
中科院分区：
文献类型：
--
作者：
Cichocki F;Bjordahl R;Goodridge JP;Mahmood S;Gaidarova S;Abujarour R;Davis ZB;Merino A;Tuininga K;Wang H;Kumar A;Groff B;Witty A;Bonello G;Huffman J;Dailey T;Lee TT;Malmberg KJ;Walcheck B;Höpken U;Rehm A;Valamehr B;Miller JS
同种异体自然杀伤（NK）细胞过继转移是一种有前途的治疗几种癌症，但治疗多发性骨髓瘤的效果较差。在这项研究中，我们报告了四重基因工程诱导多能干细胞（iPSC）衍生的NK细胞，其设计用于从可再生来源大规模生产，并通过引入对B细胞成熟抗原（BCMA）特异的NK细胞优化的嵌合抗原受体（CAR）和高亲和力，当与治疗性抗-CD 38抗体组合时，不可切割的CD 16增强抗体依赖性细胞毒性。此外，这些细胞表达膜结合的白细胞介素-15融合分子以增强功能和持久性，沿着敲除CD 38以防止抗体介导的自相残杀并增强NK细胞代谢适应性。在各种临床前模型中，包括异种过继转移模型，四重基因工程NK细胞一致地显示出持久的抗肿瘤活性，不依赖于外源性细胞因子的支持。本文提供的结果支持这种现成的有效治疗多发性骨髓瘤的策略的临床翻译。嵌合抗原受体修饰的免疫细胞治疗剂的使用已经改善了一系列肿瘤的治疗。在这里，作者探索了一种双靶点iPSC衍生的NK细胞产物作为治疗多发性骨髓瘤的潜在治疗剂。
Allogeneic natural killer (NK) cell adoptive transfer is a promising treatment for several cancers but is less effective for the treatment of multiple myeloma. In this study, we report on quadruple gene-engineered induced pluripotent stem cell (iPSC)-derived NK cells designed for mass production from a renewable source and for dual targeting against multiple myeloma through the introduction of an NK cell-optimized chimeric antigen receptor (CAR) specific for B cell maturation antigen (BCMA) and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity when combined with therapeutic anti-CD38 antibodies. Additionally, these cells express a membrane-bound interleukin-15 fusion molecule to enhance function and persistence along with knock out of CD38 to prevent antibody-mediated fratricide and enhance NK cell metabolic fitness. In various preclinical models, including xenogeneic adoptive transfer models, quadruple gene-engineered NK cells consistently demonstrate durable antitumor activity independent of exogenous cytokine support. Results presented here support clinical translation of this off-the-shelf strategy for effective treatment of multiple myeloma. The use of chimeric antigen receptor modified immune cell therapeutics has improved the treatment of a range of tumours. Here the authors explore a dual-target iPSC-derived NK cell product as a potential therapeutic for the treatment of multiple myeloma.
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影响因子：
20.3
作者：
Kröger, N;Sayer, HG;Zander, AR
通讯作者：
Zander, AR
DOI：
10.1007/978-1-60761-362-6_2
发表时间：
2010-01-01
期刊：
NATURAL KILLER CELL PROTOCOLS
影响因子：
--
作者：
Cichocki, Frank;Miller, Jeffrey S.
通讯作者：
Miller, Jeffrey S.
影响因子：
3.7
作者：
Jing Y;Ni Z;Wu J;Higgins L;Markowski TW;Kaufman DS;Walcheck B
通讯作者：
Walcheck B
影响因子：
81.5
作者：
Kumar, Shaji K.;Rajkumar, Vincent;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
8.9
作者：
Kyle, RA;Gertz, MA;Greipp, PR
通讯作者：
Greipp, PR