Department of Medical and Surgical Specialties, Division of Neurosurgery, Radiological Sciences and Public Health, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, Italy.
Department of Ophthalmology, University Hospital of Udine, P.le S. Maria della Misericordia 15, 33100 Udine, Italy.
Int J Mol Sci. 2023 Oct 10;24(20):15037. doi: 10.3390/ijms242015037.
Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "glioblastomas," "immunotherapies," and "treatment." The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability.
胶质母细胞瘤(GBM)的特征是生长迅速且复发率高。尽管常规疗法有所进展,但 GBM 患者的预后仍然较差。免疫疗法最近已成为一种潜在的治疗选择。本系统评价旨在评估 GBM 免疫治疗策略的当前策略和未来前景。我们在主要医学数据库(PubMed、Embase 和 Cochrane Library)中进行了系统搜索,截至 2023 年 9 月 3 日。搜索策略使用了与“glioblastomas”、“immunotherapies”和“treatment”相关的相关医学主题词(MeSH)术语和关键词。本综述中包括的研究包括随机对照试验、非随机对照试验和队列研究,报告了免疫疗法在人类受试者中治疗神经胶质瘤的情况。最初确定了 1588 篇论文。确认了 752 篇文章的资格,而其他 655 篇由于与研究主题无关(627 篇)、方法和结果细节不足(12 篇)以及为病例系列或队列研究(22 篇)、系统文献综述或荟萃分析(3 篇)而被排除在外。本系统评价中的所有研究均为 1995 年至 2023 年期间的临床试验,涉及 6383 名患者。神经肿瘤学发表了最多的与胶质母细胞瘤免疫治疗相关的临床试验(15/97,16%)。大多数研究发表于 2018 年至 2022 年之间,在此期间平均每年发表 9 篇。嵌合抗原受体(CAR)T 细胞的过继细胞转移是 11%研究的主要关注点,免疫检查点抑制剂(ICIs)、溶瘤病毒(OVs)和癌症疫苗(CVs)分别占 26%、12%和 51%。一期试验占大多数,为 51%,而三期试验仅占总数的 7%。在这些试验中,60%为单臂,39%为双臂,1 个为多臂。免疫疗法主要用于复发性 GBM(55%)。该综述还揭示了正在进行的临床试验,包括 9 项针对 ICI、7 项针对 CV、10 项针对 OV 和 8 项针对 CAR T 细胞的试验,共计 34 项试验,其中一期试验占大多数,为 53%,仅一项为三期试验。克服免疫耐受、刺激强烈的肿瘤抗原反应和对抗免疫抑制微环境机制对于治愈性 GBM 免疫治疗至关重要。免疫检查点抑制剂,如 PD-1 和 CTLA-4 抑制剂,显示出希望,正在进行的研究旨在提高它们的有效性。个性化癌症疫苗,特别是针对新抗原的疫苗,具有很大的潜力。溶瘤病毒在临床试验中表现出双重机制和突破性地位。针对特定抗原的 CAR T 细胞疗法产生了令人鼓舞的结果,特别是针对 IL13 Rα2 和 EGFRvIII。具有改进特异性的第二代 CAR T 细胞的开发体现了它们的适应性。
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