肿瘤细胞治疗研究
英文原题：The Future of Natural Killer Cell Immunotherapy for B Cell Non-Hodgkin Lymphoma (B Cell NHL).
自然杀伤（NK）细胞自25年前引入以利妥昔单抗为基础的CD20靶向免疫治疗作为B细胞非霍奇金淋巴瘤（NHL）治疗的基石以来，在B细胞NHL的治疗中发挥了关键作用——尽管这一作用在很大程度上未被认识或被忽视。
自然杀伤（NK）细胞在B细胞非霍奇金淋巴瘤（NHL）的治疗中发挥了关键作用——尽管在很大程度上未被认识或忽视——自25年前引入以利妥昔单抗为基础的CD20靶向免疫治疗作为治疗基石以来。NK细胞通过抗体依赖性细胞毒性（ADCC）参与裂解NHL靶细胞是利妥昔单抗作用机制的关键组成部分。尽管发挥了这一重要作用，B细胞NHL治疗中唯一被采纳为标准治疗且即使间接增强或恢复NK细胞功能的手段是引入奥妥珠单抗，一种增强与NK细胞结合能力的CD20抗体。然而，在过去5年中，利用效应淋巴细胞对B细胞NHL进行过继免疫治疗经历了巨大发展，目前已有五种不同的CAR T细胞产品获得FDA批准，其中四种靶向CD19并已获批用于某些B细胞NHL亚型的适应症——阿基仑赛、brexucabtagene autoleucel、lisocabtagene maraleucel和tisagenlecleucel。这些基于T细胞的免疫治疗本质上模拟了CD19抗体与NK细胞和淋巴瘤靶细胞结合的识别、激活通路和细胞毒机制。尽管这些基于T细胞的免疫治疗有效，但其难以实施，因为它们需要4-6周的生产时间、成本高昂，且具有显著毒性。对细胞免疫潜力的重新关注——以及这些新药物所解决的生产、供应链和给药物流问题——激发了NHL中NK细胞靶向治疗的新一轮热情。凭借高安全性特征和已证实的抗淋巴瘤疗效，未来几年内，一种或多种新的NK细胞导向治疗方式必将被纳入NHL治疗的标准工具箱，无论是功能增强型细胞因子突变蛋白、多结构域NK细胞衔接器，还是过继性输注扩增或基因修饰的NK细胞。
Natural killer (NK) cells have played a critical-if largely unrecognized or ignored-role in the treatment of B cell non-Hodgkin lymphoma (NHL) since the introduction of CD20-directed immunotherapy with rituximab as a cornerstone of therapy over 25 years ago. Engagement with NK cells leading to lysis of NHL targets through antibody-dependent cellular cytotoxicity (ADCC) is a critical component of rituximab's mechanism of action. Despite this important role, the only aspect of B cell NHL therapy that has been adopted as standard therapy that even indirectly augments or restores NK cell function is the introduction of obinutuzumab, a CD20 antibody with enhanced ability to engage with NK cells. However, over the last 5 years, adoptive immunotherapy with effector lymphocytes of B cell NHL has experienced tremendous growth, with five different CAR T cell products now licensed by the FDA, four of which target CD19 and have approved indications for some subtype of B cell NHL-axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, and tisagenlecleucel. These T cell-based immunotherapies essentially mimic the recognition, activation pathway, and cytotoxic machinery of a CD19 antibody engaging NK cells and lymphoma targets. Despite their efficacy, these T cell-based immunotherapies have been difficult to implement because they require 4-6 weeks of manufacture, are costly, and have significant toxicities. This renewed interest in the potential of cellular immunity-and the manufacturing, supply chain, and administration logistics that have been addressed with these new agents-have ignited a new wave of enthusiasm for NK cell-directed therapies in NHL. With high safety profiles and proven anti-lymphoma efficacy, one or more new NK cell-directed modalities are certain to be introduced into the standard toolbox of NHL therapy within the next few years, be it function-enhancing cytokine muteins, multi-domain NK cell engagers, or adoptive therapy with expanded or genetically modified NK cells.
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