肿瘤细胞治疗研究
英文原题：CAR-T Therapy for Pediatric High-Grade Gliomas: Peculiarities, Current Investigations and Future Strategies.
尽管采用了积极的多模式治疗——包括手术切除、放疗和化疗——患者的长期预后仍然很差，5年生存率低于20%。
高级别胶质瘤（HGG）是儿科中枢神经系统（CNS）最致命的恶性肿瘤之一。尽管采用了积极的多模式治疗——包括手术切除、放疗和化疗——患者的长期预后仍然极差，5年生存率低于20%。对儿童HGG（pHGG）遗传和表观遗传特征的深入了解揭示了其与成人胶质瘤的重要差异，为确定创新且更有效的治疗方法，这些差异需要被纳入考量。免疫治疗基于不同技术，旨在重定向患者自身免疫系统以特异性攻击癌细胞。特别是，T淋巴细胞可经基因修饰以表达嵌合蛋白，即嵌合抗原受体（CAR），靶向选定的肿瘤相关抗原（TAA）。双唾液酸神经节苷脂GD2（GD-2）和B7-H3在pHGG上高表达，除成人胶质母细胞瘤常见的抗原——如白细胞介素-13受体α2（IL-13 2）、人表皮生长因子受体2（HER-2）和促红细胞生成素产生性人肝细胞癌A2受体（EphA2）——之外，已在儿科临床试验中作为可能的靶点进行评估。CAR-T疗法在pHGG临床前模型中显示出前景，但未能取得与血液系统恶性肿瘤相同的成功。若干局限性，包括免疫抑制性肿瘤微环境（TME）、靶抗原表达的异质性以及难以到达肿瘤部位，削弱了T细胞的疗效。pHGG呈现免疫冷TME，T细胞浸润差且免疫监视匮乏。免疫抑制性细胞因子（TGF-、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）和髓源性抑制细胞（MDSCs）——的存在，限制了免疫系统清除肿瘤细胞的有效性。需要创新的免疫治疗策略来克服这些障碍并提高T细胞清除肿瘤的能力。在这篇综述中，我们描述了儿童人群HGG及其TME的显著特征，重点关注克服这些障碍的最有前景的CAR-T疗法。
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-13 2), 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- , 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.
MEMBER ACCOUNT
登录成功会直接打开下一页。
