肿瘤细胞治疗研究
英文原题：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.
异体自然杀伤（NK）细胞过继输注是多种癌症的一种有前景的治疗方法，但对多发性骨髓瘤的治疗效果较差。
同种异体自然杀伤（NK）细胞过继转移是一种有前景的治疗多种癌症的方法，但在多发性骨髓瘤治疗中效果较差。在本研究中，我们报告了四重基因工程化诱导多能干细胞（iPSC）来源NK细胞，其设计用于从可再生来源大规模生产，并通过引入针对B细胞成熟抗原（BCMA）的NK细胞优化嵌合抗原受体（CAR）以及高亲和力、不可切割的CD16，以在与治疗性抗CD38抗体联合时增强抗体依赖性细胞毒性，从而实现对多发性骨髓瘤的双重靶向。此外，这些细胞表达膜结合白细胞介素-15融合分子，以增强功能和持久性，同时敲除CD38，以防止抗体介导的同室相残并增强NK细胞代谢适应性。在多种临床前模型中，包括异种过继转移模型，四重基因工程化NK细胞一致表现出不依赖外源性细胞因子支持的持久抗肿瘤活性。本文所呈现的结果支持将这种现货型策略进行临床转化，以有效治疗多发性骨髓瘤。
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.
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