PD-1 Inhibitors: Do they have a Future in the Treatment of Glioblastoma?
PD-1 Inhibitors: Do they have a Future in the Treatment of Glioblastoma?
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DOI：
10.1158/1078-0432.ccr-20-1135
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发表时间：
2020-10-15
期刊：
影响因子：
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通讯作者：
Sampson JH
中科院分区：
文献类型：
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作者：
Khasraw M;Reardon DA;Weller M;Sampson JH
胶质母细胞瘤（WHO四级胶质瘤）是成人最常见的恶性原发性脑肿瘤。几十年来，尽管在开发新的有效疗法方面做出了巨大努力，但生存率基本保持不变。免疫疗法，尤其是免疫检查点抑制剂和程序性细胞死亡(PD)-1/PD- l1抑制剂已经改变了癌症治疗的格局，提高了许多不同类型癌症患者的生存率。除了少数特定病例（如Lynch综合征患者）外，神经肿瘤学界仍在等待PD-1阻断可以导致胶质母细胞瘤有意义的临床获益的证据。该领域缺乏进展可能是由于多种原因造成的，包括脑肿瘤药物开发的固有挑战、血脑屏障、大脑中独特的免疫环境、皮质类固醇的影响以及肿瘤间和肿瘤内的异质性。在这里，我们批判性地回顾了临床文献，解决了胶质瘤免疫生物学的独特方面和潜在的免疫生物学进展障碍，并提出了提高PD-1/PD-L1抑制剂在胶质母细胞瘤中的疗效的新方法，这些方法可能会为未来的基础和临床研究发现空白并验证相关假设，并为进一步刺激临床前和临床研究提供新的视角，最终帮助胶质瘤患者。包括胶质母细胞瘤，这可以说是癌症中最大的未满足需求的领域之一。展望未来，我们需要在现有知识的基础上，开展进一步的神经胶质瘤免疫生物学基础研究，同时进行创新的、方法学上合理的临床试验。
Glioblastoma (WHO grade IV glioma) is the most common malignant primary brain tumor in adults. Survival has remained largely static for decades, despite significant efforts to develop new effective therapies. Immunotherapy, and especially immune checkpoint inhibitors and programmed cell death (PD)-1/PD-L1 inhibitors have transformed the landscape of cancer treatment and improved patient survival in a number of different cancer types. With the exception of few select cases (e.g., patients with Lynch syndrome) the neuro-oncology community is still awaiting evidence that PD-1 blockade can lead to meaningful clinical benefit in glioblastoma. This lack of progress in the field is likely to be due to multiple reasons, including inherent challenges in brain tumor drug development, the blood-brain barrier, the unique immune environment in the brain, the impact of corticosteroids, as well as inter- and intra-tumoral heterogeneity. Here we critically review the clinical literature, address the unique aspects of glioma immunobiology and potential immunobiological barriers to progress, and contextualize new approaches to increase the efficacy of PD-1/PD-L1 inhibitors in glioblastoma that may identify gaps and testable relevant hypotheses for future basic and clinical research and to provide a novel perspective to further stimulate pre-clinical and clinical research to ultimately help patients with glioma, including glioblastoma, which is arguably one of the greatest areas of unmet need in cancer. Moving forward, we need to build on our existing knowledge by conducting further fundamental glioma immunobiology research in parallel with innovative and methodologically sound clinical trials.