Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, Italy.
Neurosurgery Unit, Head-Neck and NeuroScience Department, University Hospital of Udine, p.le S. Maria della Misericordia 15, 33100 Udine, Italy.
Int J Mol Sci. 2024 Jun 29;25(13):7174. doi: 10.3390/ijms25137174.
The most common primary brain tumor is glioblastoma (GBM), yet the current therapeutic options for this disease are not promising. Although immunotherapeutic techniques have shown poor success in GBM thus far despite efforts, new developments provide optimism. One of these developments is chimeric antigen receptor (CAR)-T cell treatment, which includes removing and genetically modifying autologous T cells to produce a receptor that targets a GBM antigen before reintroducing the cells into the patient's body. A number of preclinical studies have produced encouraging results, which have led to the start of clinical trials assessing these CAR-T cell treatments for GBM and other brain tumors. Although results in tumors such as diffuse intrinsic pontine gliomas and lymphomas have been promising, preliminary findings in GBM have not produced any clinical benefits. The paucity of particular antigens in GBM, their inconsistent expression patterns, and the possible immunoediting-induced loss of these antigens after antigen-targeted therapy are some possible causes for this discrepancy. The goal of this systematic literature review is to assess potential approaches for creating CAR-T cells that are more effective for this indication, as well as the clinical experiences that are already being had with CAR-T cell therapy in GBM. Up until 9 May 2024, a thorough search was carried out across the three main medical databases: PubMed, Web of Science, and Scopus. Relevant Medical Subject Heading (MeSH) terms and keywords associated with "glioblastoma", "CAR-T", "T cell therapy", "overall survival", and "progression free survival" were employed in the search approach. Preclinical and clinical research on the application of CAR-T cells as a therapeutic approach for GBM are included in the review. A total of 838 papers were identified. Of these, 379 articles were assessed for eligibility, resulting in 8 articles meeting the inclusion criteria. The included studies were conducted between 2015 and 2023, with a total of 151 patients enrolled. The studies varied in CAR-T cell types. EGFRvIII CAR-T cells were the most frequently investigated, used in three studies (37.5%). Intravenous delivery was the most common method of delivery (62.5%). Median OS ranged from 5.5 to 11.1 months across the studies. PFS was reported in only two studies, with values of 7.5 months and 1.3 months. This systematic review highlights the evolving research on CAR-T cell therapy for GBM, emphasizing its potential despite challenges. Targeting antigens like EGFRvIII and IL13Rα2 shows promise in treating recurrent GBM. However, issues such as antigen escape, tumor heterogeneity, and immunosuppression require further optimization. Innovative delivery methods, combination therapies, and personalized approaches are crucial for enhancing CAR-T cell efficacy. Ongoing research is essential to refine these therapies and improve outcomes for GBM patients.
最常见的原发性脑肿瘤是胶质母细胞瘤（GBM），但目前针对这种疾病的治疗选择并不乐观。尽管免疫治疗技术在 GBM 中迄今为止尽管付出了努力，但收效甚微，新的发展带来了乐观情绪。其中一种发展是嵌合抗原受体 (CAR)-T 细胞治疗，包括取出并遗传修饰自体 T 细胞，以产生针对 GBM 抗原的受体，然后将细胞重新引入患者体内。许多临床前研究取得了令人鼓舞的结果，这导致开始进行临床试验，评估这些 CAR-T 细胞治疗 GBM 和其他脑肿瘤的效果。虽然弥漫性内在脑桥胶质瘤和淋巴瘤等肿瘤的结果令人鼓舞，但 GBM 的初步发现并未产生任何临床益处。GBM 中特定抗原的缺乏、它们不一致的表达模式以及抗原靶向治疗后这些抗原可能发生的免疫编辑丢失是造成这种差异的一些可能原因。本系统文献综述的目的是评估为该适应症创建更有效的 CAR-T 细胞的潜在方法，以及已经在 GBM 中进行的 CAR-T 细胞治疗的临床经验。截至 2024 年 5 月 9 日，在三个主要医学数据库：PubMed、Web of Science 和 Scopus 中进行了全面搜索。在搜索方法中使用了与“胶质母细胞瘤”、“CAR-T”、“T 细胞治疗”、“总生存期”和“无进展生存期”相关的相关医学主题词 (MeSH) 术语和关键词。该综述包括 CAR-T 细胞作为 GBM 治疗方法的应用的临床前和临床研究。共确定了 838 篇论文。其中，有 379 篇文章被评估为符合条件，最终有 8 篇文章符合纳入标准。纳入的研究在 2015 年至 2023 年间进行，共有 151 名患者入组。这些研究在 CAR-T 细胞类型上有所不同。EGFRvIII CAR-T 细胞是研究最多的，在三项研究中使用（37.5%）。静脉给药是最常用的给药方式（62.5%）。研究中的中位 OS 从 5.5 到 11.1 个月不等。只有两项研究报告了 PFS，值分别为 7.5 个月和 1.3 个月。本系统综述强调了 CAR-T 细胞治疗 GBM 的不断发展的研究，强调了尽管存在挑战，但仍具有潜力。针对 EGFRvIII 和 IL13Rα2 等抗原显示出治疗复发性 GBM 的潜力。然而，抗原逃逸、肿瘤异质性和免疫抑制等问题需要进一步优化。创新的给药方法、联合疗法和个性化方法对于提高 CAR-T 细胞的疗效至关重要。正在进行的研究对于完善这些疗法和改善 GBM 患者的预后至关重要。
