CAR-T Therapy for Pediatric High-Grade Gliomas: Peculiarities, Current Investigations and Future Strategies.
CAR-T Therapy for Pediatric High-Grade Gliomas: Peculiarities, Current Investigations and Future Strategies.
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DOI：
10.3389/fimmu.2022.867154
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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高级别胶质瘤是儿科最致命的中枢神经系统恶性肿瘤之一。尽管积极的多模式治疗-包括手术切除、放射治疗和化疗-患者的长期预后仍然令人沮丧，5年生存率不到20%。随着对儿童HGGs(PHGGs)遗传和表观遗传学特征认识的加深，揭示了与成人胶质瘤的重要差异，需要考虑这些差异，以确定创新和更有效的治疗方法。免疫疗法基于不同的技术，旨在重新引导患者自身的免疫系统，以特别是对抗癌细胞。特别是，T淋巴细胞可以通过基因修饰来表达嵌合蛋白，称为嵌合抗原受体(CARS)，靶向选定的肿瘤相关抗原(TAA)。二唾液神经节苷脂GD2(GD-2)和B7-H3在PHGGs上高度表达，并已被评估为儿科临床试验的可能靶点，此外，成人胶质母细胞瘤的常见抗原--如白细胞介素13受体α2(IL-13α2)、人表皮生长因子受体2(HER-2)和产生促红细胞生成素的人肝细胞癌A2受体(EPA2)也被评估为可能的靶标。CAR-T疗法在PHGGs的临床前模型中显示出了希望，但未能达到对血液系统恶性肿瘤的同样成功。免疫抑制的肿瘤微环境(TME)、靶抗原表达的异质性以及肿瘤部位的难以进入等诸多限制因素影响了T细胞的治疗效果。PHGGs表现为免疫冷的TME，T细胞浸润少，免疫监视稀少。免疫抑制细胞因子(转化生长因子-β、IL-10)的分泌以及免疫抑制细胞如肿瘤相关巨噬细胞/小胶质细胞(TAMs)和髓系来源的抑制细胞(MDSCs)的存在限制了免疫系统清除肿瘤细胞的有效性。为了克服这些障碍，提高T细胞根除肿瘤的能力，创新的免疫治疗策略是必要的。在这篇综述中，我们描述了儿童人群和他们的TME的HGG的显著特征，重点是最有希望的CAR-T疗法，以克服这些障碍。
High-Grade Gliomas (HGG) are among the deadliest malignant tumors of central nervous system (CNS) in pediatrics. Despite aggressive multimodal treatment - including surgical resection, radiotherapy and chemotherapy - long-term prognosis of patients remains dismal with a 5-year survival rate less than 20%. Increased understanding of genetic and epigenetic features of pediatric HGGs (pHGGs) revealed important differences with adult gliomas, which need to be considered in order to identify innovative and more effective therapeutic approaches. Immunotherapy is based on different techniques aimed to redirect the patient own immune system to fight specifically cancer cells. In particular, T-lymphocytes can be genetically modified to express chimeric proteins, known as chimeric antigen receptors (CARs), targeting selected tumor-associated antigens (TAA). Disialoganglioside GD2 (GD-2) and B7-H3 are highly expressed on pHGGs and have been evaluated as possible targets in pediatric clinical trials, in addition to the antigens common to adult glioblastoma – such as interleukin-13 receptor alpha 2 (IL-13α2), human epidermal growth factor receptor 2 (HER-2) and erythropoietin-producing human hepatocellular carcinoma A2 receptor (EphA2). CAR-T therapy has shown promise in preclinical model of pHGGs but failed to achieve the same success obtained for hematological malignancies. Several limitations, including the immunosuppressive tumor microenvironment (TME), the heterogeneity in target antigen expression and the difficulty of accessing the tumor site, impair the efficacy of T-cells. pHGGs display an immunologically cold TME with poor T-cell infiltration and scarce immune surveillance. The secretion of immunosuppressive cytokines (TGF-β, IL-10) and the presence of immune-suppressive cells – like tumor-associated macrophages/microglia (TAMs) and myeloid-derived suppressor cells (MDSCs) - limit the effectiveness of immune system to eradicate tumor cells. Innovative immunotherapeutic strategies are necessary to overcome these hurdles and improve ability of T-cells to eradicate tumor. In this review we describe the distinguishing features of HGGs of the pediatric population and of their TME, with a focus on the most promising CAR-T therapies overcoming these hurdles.