Karbhari Nishika, Frechette Kelsey M, Burns Terry C, Parney Ian F, Campian Jian L, Breen William G, Sener Ugur T, Lehrer Eric J
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Cancers (Basel). 2025 May 31;17(11):1849. doi: 10.3390/cancers17111849.
High-grade gliomas (HGGs), particularly glioblastoma (GBM), are associated with exceptionally high mortality and inevitable recurrence. In considering novel treatment options for these devastating diseases, immunotherapies represent promising candidates. Immunotherapies have demonstrated efficacy for several advanced tumors outside the central nervous system, highlighting a potential role for these agents in treating HGGs. However, multiple challenges to immunotherapy efficacy have tempered therapeutic benefit in practice, including local and systemic immunosuppression, intratumoral heterogeneity, and various mechanisms of intrinsic and acquired resistance. In the past 30 years, diverse immunotherapeutic subclasses have been assessed for benefit against HGGs. We performed a PubMed search for randomized clinical trials performed within the last 30 years evaluating the following immunotherapy agents for high-grade gliomas: immune checkpoint inhibitors, vaccines, oncologic viruses, cytokines, and CAR T-cells. The present review offers a critical analysis of key pre-clinical and clinical trials that have shaped the immunotherapy landscape for high-grade gliomas over the past two decades. Across the different immunotherapeutic methods and modalities explored thus far, a recurring theme emerges: while therapeutic strategies with a compelling conceptual basis are continually under development and even demonstrate a benefit in preclinical and early-phase trials, larger and later-phase trials consistently fail to produce concordantly significant outcomes. To date, no large-scale clinical trial has demonstrated a benefit of sufficient consequence to change practice. Continued critical appraisal of the strengths and pitfalls of prior investigative work, optimization of treatment development and delivery, and innovative approaches to combination therapy design will collectively be integral to future therapeutic advancement.
高级别胶质瘤（HGGs），尤其是胶质母细胞瘤（GBM），与极高的死亡率和不可避免的复发相关。在考虑针对这些毁灭性疾病的新治疗方案时，免疫疗法是有前景的候选方案。免疫疗法已在中枢神经系统以外的几种晚期肿瘤中显示出疗效，突出了这些药物在治疗HGGs方面的潜在作用。然而，免疫疗法疗效面临的多重挑战削弱了其在实际治疗中的益处，包括局部和全身免疫抑制、肿瘤内异质性以及内在和获得性耐药的各种机制。在过去30年里，已评估了多种免疫治疗亚类对HGGs的疗效。我们在PubMed上搜索了过去30年内进行的随机临床试验，这些试验评估了以下用于高级别胶质瘤的免疫治疗药物：免疫检查点抑制剂、疫苗、肿瘤病毒、细胞因子和嵌合抗原受体T细胞（CAR T细胞）。本综述对过去二十年塑造高级别胶质瘤免疫治疗格局的关键临床前和临床试验进行了批判性分析。在迄今为止探索的不同免疫治疗方法和模式中，一个反复出现的主题是：虽然具有令人信服的概念基础的治疗策略不断在开发中，甚至在临床前和早期试验中显示出益处，但更大规模和后期的试验始终未能产生一致的显著结果。迄今为止，尚无大规模临床试验证明有足够显著的益处来改变临床实践。对先前研究工作的优势和缺陷进行持续的批判性评估、优化治疗开发和实施，以及创新联合治疗设计方法，对于未来的治疗进展将至关重要。
