Department of Chemical Engineering, University of Puerto Rico-Mayagüez, Mayagüez, Puerto Rico.
Cancer Research Clinic, Carolina BioOncology Institute (CBOI), Huntersville, NC, United States.
Front Immunol. 2023 May 2;14:1167666. doi: 10.3389/fimmu.2023.1167666. eCollection 2023.
Cellular immunotherapy has revolutionized the oncology field, yielding improved results against hematological and solid malignancies. NK cells have become an attractive alternative due to their capacity to activate upon recognition of "stress" or "danger" signals independently of Major Histocompatibility Complex (MHC) engagement, thus making tumor cells a perfect target for NK cell-mediated cancer immunotherapy even as an allogeneic solution. While this allogeneic use is currently favored, the existence of a characterized memory function for NK cells ("memory-like" NK cells) advocates for an autologous approach, that would benefit from the allogeneic setting discoveries, but with added persistence and specificity. Still, both approaches struggle to exert a sustained and high anticancer effect due to the immunosuppressive tumor micro-environment and the logistical challenges of cGMP production or clinical deployment. Novel approaches focused on the quality enhancement and the consistent large-scale production of highly activated therapeutic memory-like NK cells have yielded encouraging but still unconclusive results. This review provides an overview of NK biology as it relates to cancer immunotherapy and the challenge presented by solid tumors for therapeutic NKs. After contrasting the autologous and allogeneic NK approaches for solid cancer immunotherapy, this work will present the current scientific focus for the production of highly persistent and cytotoxic memory-like NK cells as well as the current issues with production methods as they apply to stress-sensitive immune cells. In conclusion, autologous NK cells for cancer immunotherapy appears to be a prime alternative for front line therapeutics but to be successful, it will be critical to establish comprehensives infrastructures allowing the production of extremely potent NK cells while constraining costs of production.
细胞免疫疗法彻底改变了肿瘤学领域,为血液系统恶性肿瘤和实体恶性肿瘤带来了更好的疗效。自然杀伤 (NK) 细胞由于能够在识别“应激”或“危险”信号时独立于主要组织相容性复合体 (MHC) 结合而被激活,因此成为一种有吸引力的替代方法,使肿瘤细胞成为 NK 细胞介导的癌症免疫治疗的完美靶点,即使是同种异体解决方案。虽然这种同种异体的用途目前是首选,但 NK 细胞存在特征性的记忆功能(“记忆样”NK 细胞),这支持了自体方法,这种方法将受益于同种异体设置的发现,但具有更好的持久性和特异性。尽管如此,由于免疫抑制性肿瘤微环境和 cGMP 生产或临床部署的后勤挑战,这两种方法都难以发挥持续且高效的抗癌作用。专注于提高质量和一致的大规模生产高度激活的治疗性记忆样 NK 细胞的新方法取得了令人鼓舞但仍不确定的结果。
本文综述了 NK 生物学与癌症免疫治疗的关系,以及实体肿瘤对治疗性 NK 细胞提出的挑战。在对比了用于实体瘤免疫治疗的自体和异体 NK 方法之后,本工作将介绍目前用于生产高度持久和细胞毒性记忆样 NK 细胞的科学重点,以及目前生产方法在应用于应激敏感免疫细胞时存在的问题。总之,用于癌症免疫治疗的自体 NK 细胞似乎是一线治疗的首选,但要取得成功,建立允许生产极其有效的 NK 细胞同时限制生产成本的全面基础设施至关重要。
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