What is the burden of proof for tumor mutational burden in gliomas?
What is the burden of proof for tumor mutational burden in gliomas?
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DOI：
10.1093/neuonc/noaa256
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发表时间：
2021-01-01
期刊：
影响因子：
15.9
通讯作者：
Ashley, David M.
中科院分区：
文献类型：
--
作者：
Khasraw, Mustafa;Walsh, Kyle M.;Ashley, David M.
多种实体瘤患者的治疗受益于针对抗程序性细胞死亡 1 (PD-1)/程序性细胞死亡配体 1 (PD-L1) 轴的免疫检查点抑制。美国食品和药物管理局 (FDA) 加速批准 PD-1 抑制剂派姆单抗 (pembrolizumab)，用于治疗高肿瘤突变负荷 (TMB-H)、实体瘤在既往治疗后进展以及没有其他治疗选择（包括扩展到中枢神经系统 (CNS) 肿瘤）的成人和儿童患者。一般来说，泛癌批准被积极地视为赋予患者和临床医生权力。有一些子集（例如 BRAF、NTRK）适合这种批准途径。然而，FDA 对帕博利珠单抗的泛癌批准引起了人们对证据对其他肿瘤类型的普遍适用性的担忧，包括治疗神经胶质瘤和其他中枢神经系统肿瘤患者。 TMB-H 的截止值尚未明确定义。神经胶质瘤和其他癌症类型之间存在内在的免疫学差异，包括免疫抑制性神经胶质瘤微环境、肿瘤对全身免疫功能的影响以及神经胶质瘤中 T 细胞群向耗尽表型的转变。在这里，我们讨论了有关神经胶质瘤和独特 CNS 免疫环境复杂性的泛癌批准的注意事项，讨论了潜在的预测生物标志物，包括 TMB，并解释了为什么最近的批准应谨慎应用于 CNS 肿瘤。
The treatment of patients with a variety of solid tumors has benefitted from immune checkpoint inhibition targeting the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis. The US Food and Drug Administration (FDA) granted accelerated approval of PD-1 inhibitor, pembrolizumab, for the treatment of adult and pediatric patients with high tumor mutational burden (TMB-H), solid tumors that have progressed following prior treatment, and who have no other treatment options, including the extension to tumors of the central nervous system (CNS). In general, pan-cancer approvals are viewed positively to empower patients and clinicians.There are subsets (eg, BRAF, NTRK) for which this pathway for approval is appropriate. However, the pan-cancer FDA approval of pembrolizumab raises several concerns regarding the generalizability of the evidence to other tumor types, including managing patients with gliomas and other CNS tumors. The cutoff forTMB-H is not well defined.There are intrinsic immunological differences between gliomas and other cancers types, including the immunosuppressive glioma microenvironment, the tumor's effects on systemic immune function, and the transformation of theT-cell populations to an exhausted phenotype in glioma. Here, we address the caveats with pan-cancer approvals concerning gliomas and complexities of the unique CNS immune environment, discuss potential predictive biomarkers, including TMB, and explain why the recent approval should be applied with caution in CNS tumors.