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通过激活 iNKT 和 NK 细胞增强神经母细胞瘤免疫疗法。

Enhancing Neuroblastoma Immunotherapies by Engaging iNKT and NK Cells.

机构信息

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, United States.

School of Medicine, European University Cyprus, Nicosia, Cyprus.

出版信息

Front Immunol. 2020 May 8;11:873. doi: 10.3389/fimmu.2020.00873. eCollection 2020.

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor in children and, in the high-risk group, has a 5-year mortality rate of ~50%. The high mortality rate and significant treatment-related morbidities associated with current standard of care therapies belie the critical need for more tolerable and effective treatments for this disease. While the monoclonal antibody dinutuximab has demonstrated the potential for immunotherapy to improve overall NB outcomes, the 5-year overall survival of high-risk patients has not yet substantially changed. The frequency and type of invariant natural killer T cells (iNKTs) and natural killer cells (NKs) has been associated with improved outcomes in several solid and liquid malignancies, including NB. Indeed, iNKTs and NKs inhibit tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs), kill cancer stem cells (CSCs) and neuroblasts, and robustly secrete cytokines to recruit additional immune effectors. These capabilities, and promising pre-clinical and early clinical data suggest that iNKT- and NK-based therapies may hold promise as both stand-alone and combination treatments for NB. In this review we will summarize the biologic features of iNKTs and NKs that confer advantages for NB immunotherapy, discuss the barriers imposed by the NB tumor microenvironment, and examine the current state of such therapies in pre-clinical models and clinical trials.

摘要

神经母细胞瘤(NB)是儿童中最常见的颅外实体瘤,在高危组中,5 年死亡率约为 50%。目前标准治疗方案相关的高死亡率和显著治疗相关的发病率表明,迫切需要更耐受和有效的治疗方法来治疗这种疾病。尽管单克隆抗体度伐鲁单抗已证明免疫疗法有可能改善 NB 的总体预后,但高危患者的 5 年总生存率尚未发生实质性变化。不变自然杀伤 T 细胞(iNKTs)和自然杀伤细胞(NKs)的频率和类型与几种实体瘤和液体瘤的改善预后有关,包括 NB。事实上,iNKTs 和 NKs 可抑制肿瘤相关巨噬细胞(TAMs)和髓系来源抑制细胞(MDSCs),杀死癌症干细胞(CSCs)和神经母细胞,并强力分泌细胞因子招募更多的免疫效应细胞。这些功能以及有前途的临床前和早期临床数据表明,iNKT 和 NK 为基础的治疗方法可能作为 NB 的单独治疗和联合治疗具有前景。在这篇综述中,我们将总结赋予 NB 免疫治疗优势的 iNKTs 和 NKs 的生物学特征,讨论 NB 肿瘤微环境所施加的障碍,并研究这些疗法在临床前模型和临床试验中的现状。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bc/7225357/84ae729f553e/fimmu-11-00873-g0001.jpg

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