肿瘤细胞治疗研究
英文原题：CD28 signaling domain boosts persistence and in vivo anti-tumor activity of stem cell-derived CD19-CAR-NK cells.
CD28 signaling domain boosts persistence and in vivo anti-tumor activity of stem cell-derived CD19-CAR-NK cells.
异体自然杀伤（NK）细胞疗法具有出色的安全性，是癌症免疫治疗中自体T细胞方法的有力替代方案，其固有的肿瘤杀伤能力可通过引入肿瘤抗原特异性嵌合抗原受体（CAR）进一步增强。
异体自然杀伤（NK）细胞疗法安全性突出，是癌症免疫治疗中自体T细胞疗法的有力替代方案。NK细胞具有先天肿瘤杀伤能力，还可通过导入肿瘤抗原特异性嵌合抗原受体（CAR）进一步增强。本研究采用携带不同铰链、跨膜及信号结构域CD19 CAR盒的优化慢病毒载体，对原代人造血干细胞进行基因工程改造，以评估这些结构域在CAR-NK细胞发育和功能中的作用。我们的平台将早期基因修饰与独特的扩增/分化系统相结合，可在较低载体拷贝数下实现高CAR表达。值得注意的是，包含CD28跨膜和信号结构域并带有CD3ζ的CAR可增强基础性信号、加速NK细胞分化、增强抗原特异性激酶组活化，并改善体内外细胞毒性和持久性。这些发现为开发干细胞来源CAR-NK免疫疗法提供了稳健策略，可结合强效先天及抗原特异性抗肿瘤应答。
Allogeneic natural killer (NK) cell-based therapies with an outstanding safety profile, are a compelling alternative to autologous T cell-based approaches for cancer immunotherapy, offering innate tumor-killing ability that can be further augmented via introduction of tumor antigen-specific chimeric antigen receptors (CARs). In this study, we genetically engineered primary human hematopoietic stem cells using an optimized lentiviral backbone carrying CD19 CAR cassettes with varied hinge, transmembrane, and signaling domains to evaluate their role in CAR-NK development and function. Our platform integrates early genetic modification with our unique expansion/differentiation system, enabling high CAR expression with low vector copy numbers. Notably, CARs incorporating CD28 transmembrane and signaling domains with CD3 , promoted enhanced tonic signaling, accelerated NK differentiation, enhanced antigen-specific kinome activation, and improved cytotoxicity and persistence both in vitro and in vivo . These findings offer a robust strategy for development of stem cell-based CAR-NK immunotherapies, combining potent innate, and antigen-specific antitumor responses.
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