Schonfeld Ethan, Choi John, Tran Andrew, Kim Lily H, Lim Michael
Stanford University School of Medicine, Stanford University, Stanford, California, USA.
Department of Neurosurgery, Stanford University School of Medicine, Stanford University, Stanford, California, USA.
Neurooncol Adv. 2024 Nov 12;6(1):vdae174. doi: 10.1093/noajnl/vdae174. eCollection 2024 Jan-Dec.
Glioblastoma is characterized by rapid tumor growth and high invasiveness. The tumor microenvironment of glioblastoma is highly immunosuppressive with both intrinsic and adaptive resistance mechanisms that result in disease recurrence despite current immunotherapeutic strategies.
In this systematic review of clinical trials involving immunotherapy for glioblastoma using ClinicalTrials.gov and PubMed databases from 2016 and onward, we explore immunotherapeutic modalities involving immune checkpoint blockade (ICB).
A total of 106 clinical trials were identified, 18 with clinical outcomes. ICB in glioblastoma has failed to improve overall survival compared to the current standard of care, including those therapies inhibiting multiple checkpoints. Among all immune checkpoint trials, targets included programmed cell death protein-1 (PD-1) (35/48), PD-L1 (12/48), cytotoxic T-lymphocyte-associated protein-4 (6/48), TIGIT (2/48), B7-H3 (2/48), and TIM-3 (1/48). Preliminary results from combination immunotherapies (32.1% of all trials) demonstrated improved treatment efficacy compared to monotherapy, specifically those combining checkpoint therapy with another immunotherapy modality.
Clinical trials involving ICB strategies for glioblastoma have not demonstrated improved survival. Comparison of therapeutic efficacy across trials was limited due to heterogeneity in the study population and outcome operationalization. Standardization of future trials could facilitate comparison across immunotherapy modalities for robust meta-analysis. Current immunotherapy trials have shifted focus toward combination strategies; preliminary results suggest that they are more encouraging than mono-modality immunotherapies. Given the intrinsic heterogeneity of glioblastoma, the utilization of immune markers will be key for the development of future immunotherapy approaches.
胶质母细胞瘤的特点是肿瘤生长迅速且侵袭性强。胶质母细胞瘤的肿瘤微环境具有高度免疫抑制性，存在内在和适应性抗性机制，导致尽管有当前的免疫治疗策略，疾病仍会复发。
在这项对2016年及以后使用ClinicalTrials.gov和PubMed数据库进行的胶质母细胞瘤免疫治疗临床试验的系统评价中，我们探索了涉及免疫检查点阻断（ICB）的免疫治疗方式。
共确定了106项临床试验，其中18项有临床结果。与当前的护理标准相比，胶质母细胞瘤中的ICB未能提高总生存期，包括那些抑制多个检查点的疗法。在所有免疫检查点试验中，靶点包括程序性细胞死亡蛋白1（PD-1）（35/48）、PD-L1（12/48）、细胞毒性T淋巴细胞相关蛋白4（6/48）、TIGIT（2/48）、B7-H3（2/48）和TIM-3（1/48）。联合免疫疗法（占所有试验的32.1%）的初步结果表明，与单一疗法相比，治疗效果有所改善，特别是那些将检查点疗法与另一种免疫治疗方式相结合的疗法。
涉及胶质母细胞瘤ICB策略的临床试验尚未证明生存期有所改善。由于研究人群和结果操作的异质性，各试验间治疗效果的比较受到限制。未来试验的标准化有助于对免疫治疗方式进行比较，以进行有力的荟萃分析。当前的免疫治疗试验已将重点转向联合策略；初步结果表明，它们比单模态免疫疗法更具前景。鉴于胶质母细胞瘤固有的异质性，免疫标志物的利用将是未来免疫治疗方法发展的关键。
