超越 CAR-T:CAR-NK 细胞疗法在哮喘免疫治疗中的兴起。
Beyond CAR-T: The rise of CAR-NK cell therapy in asthma immunotherapy.
机构信息
Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.
出版信息
J Transl Med. 2024 Aug 5;22(1):736. doi: 10.1186/s12967-024-05534-8.
Asthma poses a major public health burden. While existing asthma drugs manage symptoms for many, some patients remain resistant. The lack of a cure, especially for severe asthma, compels exploration of novel therapies. Cancer immunotherapy successes with CAR-T cells suggest its potential for asthma treatment. Researchers are exploring various approaches for allergic diseases including membrane-bound IgE, IL-5, PD-L2, and CTLA-4 for asthma, and Dectin-1 for fungal asthma. NK cells offer several advantages over T cells for CAR-based immunotherapy. They offer key benefits: (1) HLA compatibility, meaning they can be used in a wider range of patients without the need for matching tissue types. (2) Minimal side effects (CRS and GVHD) due to their limited persistence and cytokine profile. (3) Scalability for "off-the-shelf" production from various sources. Several strategies have been introduced that highlight the superiority and challenges of CAR-NK cell therapy for asthma treatment including IL-10, IFN-γ, ADCC, perforin-granzyme, FASL, KIR, NCRs (NKP46), DAP, DNAM-1, TGF-β, TNF-α, CCL, NKG2A, TF, and EGFR. Furthermore, we advocate for incorporating AI for CAR design optimization and CRISPR-Cas9 gene editing technology for precise gene manipulation to generate highly effective CAR constructs. This review will delve into the evolution and production of CAR designs, explore pre-clinical and clinical studies of CAR-based therapies in asthma, analyze strategies to optimize CAR-NK cell function, conduct a comparative analysis of CAR-T and CAR-NK cell therapy with their respective challenges, and finally present established novel CAR designs with promising potential for asthma treatment.
哮喘是一个重大的公共健康负担。虽然现有的哮喘药物可以控制许多患者的症状,但仍有一些患者对此类药物有抗性。缺乏有效的治疗方法,特别是对于严重的哮喘,促使人们探索新的治疗方法。嵌合抗原受体 T 细胞(CAR-T)在癌症免疫治疗中的成功表明其在哮喘治疗中的潜力。研究人员正在探索针对过敏性疾病的各种方法,包括细胞膜结合 IgE、IL-5、PD-L2 和 CTLA-4 用于哮喘,以及 Dectin-1 用于真菌性哮喘。自然杀伤(NK)细胞在基于 CAR 的免疫治疗方面比 T 细胞具有几个优势。它们具有以下关键优势:(1)HLA 相容性,这意味着它们可以在更广泛的患者中使用,而无需匹配组织类型;(2)由于其持续时间和细胞因子谱有限,副作用最小(细胞因子释放综合征和移植物抗宿主病);(3)可从各种来源“现货供应”规模化生产。已经引入了几种策略,强调了 CAR-NK 细胞治疗在哮喘治疗中的优越性和挑战,包括白细胞介素-10(IL-10)、干扰素-γ(IFN-γ)、抗体依赖性细胞介导的细胞毒性(ADCC)、穿孔素-颗粒酶、Fas 配体(FASL)、杀伤细胞免疫球蛋白样受体(KIR)、自然细胞毒性受体(NCRs)(NKP46)、死亡结构域相关蛋白(DAP)、脱颗粒相关酶(DNAM-1)、转化生长因子-β(TGF-β)、肿瘤坏死因子-α(TNF-α)、趋化因子(CCL)、NKG2A、肿瘤相关成纤维细胞(TF)和表皮生长因子受体(EGFR)。此外,我们主张将人工智能(AI)纳入 CAR 设计优化,并利用 CRISPR-Cas9 基因编辑技术进行精确的基因操作,以生成高效的 CAR 构建体。本综述将深入探讨 CAR 设计的演变和生产,探讨基于 CAR 的疗法在哮喘中的临床前和临床研究,分析优化 CAR-NK 细胞功能的策略,对 CAR-T 和 CAR-NK 细胞治疗进行比较分析,并介绍具有哮喘治疗潜力的新型 CAR 设计。