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Determining Risk Features for Medulloblastoma in the Molecular Era. 在分子时代确定髓母细胞瘤的风险特征
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-25 DOI: 10.1093/neuonc/noae223
Nicholas G Gottardo, Amar Gajjar
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引用次数: 0
GDH1-catalytic glutaminolysis feedback activate EGFR/PI3K/AKT pathway and reprogram glioblastoma metabolism. GDH1催化谷氨酰胺分解反馈激活表皮生长因子受体/PI3K/AKT通路,重新规划胶质母细胞瘤的新陈代谢。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-24 DOI: 10.1093/neuonc/noae222
Rui Yang, Guanghui Zhang, Zhen Meng, Li Wang, Yanping Li, Haibin Li, Siyuan Yan, Xiaonan Wei, Shanshan Wang, Hongjuan Cui

Background: Glutamine is an important nutriment for cancer cell growth that provides biological sources for nucleic acid and fatty acid synthesis, but the role of glutaminolysis in signal transduction and glioblastoma (GBM) progression remains little known.

Methods: Knockdown and overexpression cells were obtained to explore the functional roles of GDH1 in cell proliferation, tumor formation and aerobic glycolysis. RNA-seq, Chromatin immunoprecipitation, luciferase assay and western blot were performed to verify the regulation of EGFR-AKT pathway by the glutamate dehydrogenase 1 (GDH1, also known as GLUD1) and KDM6A. Metabolite-level measurements and Seahorse Assay were performed to assess the functional role of GHD1 in reprogramming glycolysis.

Results: Here, we report that GDH1 catalytic glutaminolysis is essential for GBM cell line proliferation and brain tumorigenesis even in high-glucose conditions. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate (α-KG). We demonstrate that glutamine in combination with leucine activates mammalian TORC1 by enhancing glutaminolysis and α-KG production. α-KG increases the transcription of PDPK1 by reducing the suppressive histone modification H3K27me3, and then promotes the activation of PI3K/AKT/mTOR pathway. This transcriptional activation induced by α-KG requires histone demethylase KDM6A, which is a 2-oxoglutarate oxygenase that plays important roles in converting α-KG to succinate. Furthermore, we show that GDH1-catalytic glutaminolysis also increases the expression of HK2 and promotes glycolysis in high-glucose condition dependent on KDM6A-mediated demethylation of H3K27.

Conclusion: These findings suggest a novel function of glutaminolysis in regulation of signal transduction and metabolism reprograming, provide further evidence for unique role of glutaminolysis in GBM progression.

背景:谷氨酰胺是癌细胞生长的重要营养物质,它为核酸和脂肪酸的合成提供了生物来源,但谷氨酰胺酵解在信号转导和胶质母细胞瘤(GBM)进展中的作用仍鲜为人知:方法:通过敲除和过表达细胞来探索 GDH1 在细胞增殖、肿瘤形成和有氧糖酵解中的功能作用。通过RNA-seq、染色质免疫沉淀、荧光素酶检测和Western印迹,验证了谷氨酸脱氢酶1(GDH1,又称GLUD1)和KDM6A对表皮生长因子受体-AKT通路的调控作用。我们还进行了代谢物水平测定和海马测定,以评估 GHD1 在糖酵解重编程中的功能作用:结果:在此,我们报告了 GDH1 催化谷氨酰胺酵解对 GBM 细胞系的增殖和脑肿瘤的发生至关重要,即使在高葡萄糖条件下也是如此。谷氨酰胺通过谷氨酰胺分解代谢产生α-酮戊二酸(α-KG)。我们证明,谷氨酰胺与亮氨酸结合可通过增强谷氨酰胺分解和α-KG的产生来激活哺乳动物的TORC1。α-KG通过减少抑制性组蛋白修饰H3K27me3来增加PDPK1的转录,然后促进PI3K/AKT/mTOR通路的激活。α-KG诱导的这种转录激活需要组蛋白去甲基化酶KDM6A,而KDM6A是一种2-氧代戊二酸加氧酶,在将α-KG转化为琥珀酸的过程中发挥着重要作用。此外,我们还发现 GDH1 催化的谷氨酰胺酵解也会增加 HK2 的表达,并在高葡萄糖条件下促进糖酵解,这依赖于 KDM6A 介导的 H3K27 去甲基化:这些发现表明谷氨酰胺酵解在调节信号转导和代谢重编程方面具有新的功能,为谷氨酰胺酵解在 GBM 进展中的独特作用提供了进一步的证据。
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引用次数: 0
Chimeric antigen receptor T-cell therapy in patients with malignant glioma-From neuroimmunology to clinical trial design considerations. 用于恶性胶质瘤患者的嵌合抗原受体 T 细胞疗法--从神经免疫学到临床试验设计的考虑因素。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-24 DOI: 10.1093/neuonc/noae203
Marco Gallus, Jacob S Young, Sarah Cook Quackenbush, Mustafa Khasraw, John de Groot, Hideho Okada

Clinical trials evaluating chimeric antigen receptor (CAR) T-cell therapy in patients with malignant gliomas have shown some early promise in pediatric and adult patients. However, the long-term benefits and safety for patients remain to be established. The ultimate success of CAR T-cell therapy for malignant glioma will require the integration of an in-depth understanding of the immunology of the central nervous system (CNS) parenchyma with strategies to overcome the paucity and heterogeneous expression of glioma-specific antigens. We also need to address the cold (immunosuppressive) microenvironment, exhaustion of the CAR T-cells, as well as local and systemic immunosuppression. Here, we discuss the basics and scientific considerations for CAR T-cell therapies and highlight recent clinical trials. To help identify optimal CAR T-cell administration routes, we summarize our current understanding of CNS immunology and T-cell homing to the CNS. We also discuss challenges and opportunities related to clinical trial design and patient safety/monitoring. Finally, we provide our perspective on future prospects in CAR T-cell therapy for malignant gliomas by discussing combinations and novel engineering strategies to overcome immuno-regulatory mechanisms. We hope this review will serve as a basis for advancing the field in a multiple discipline-based and collaborative manner.

评估嵌合抗原受体(CAR)T细胞疗法治疗恶性胶质瘤患者的临床试验已在儿童和成人患者中显示出一些早期前景。然而,患者的长期获益和安全性仍有待确定。CAR T 细胞疗法治疗恶性胶质瘤的最终成功,需要对中枢神经系统(CNS)实质的免疫学有深入的了解,并采取相应的策略,克服胶质瘤特异性抗原的缺乏和异质性表达。我们还需要解决冷(免疫抑制)微环境、CAR T 细胞衰竭以及局部和全身免疫抑制等问题。在此,我们将讨论 CAR T 细胞疗法的基础知识和科学考虑因素,并重点介绍近期的临床试验。为了帮助确定最佳的 CAR T 细胞给药途径,我们总结了我们目前对中枢神经系统免疫学和中枢神经系统 T 细胞归巢的理解。我们还讨论了与临床试验设计和患者安全/监测相关的挑战和机遇。最后,我们通过讨论克服免疫调节机制的组合和新型工程策略,展望了CAR T细胞治疗恶性胶质瘤的未来前景。我们希望这篇综述能成为以多学科合作的方式推动该领域发展的基础。
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引用次数: 0
ROR1 facilitates glioblastoma growth via stabilizing GRB2 to promote c-Fos expression in glioma stem cells. ROR1 通过稳定 GRB2 促进胶质瘤干细胞中 c-Fos 的表达,从而促进胶质母细胞瘤的生长。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-24 DOI: 10.1093/neuonc/noae224
Hongtao Zhu, Lidong Cheng, Dan Liu, Xiaoyu Ma, Zhiye Chen, Heng Fan, Ran Li, Yang Zhang, Hailong Mi, Jun Li, Suojun Zhang, Xingjiang Yu, Kai Shu

Background: Glioma stem cells (GSCs) are the root cause of tumorigenesis, recurrence, and therapeutic resistance in glioblastoma (GBM), the most prevalent and lethal type of primary adult brain malignancy. The exploitation of novel methods targeting GSCs is crucial for the treatment of GBM. In this study, we investigate the function of the novel ROR1-GRB2-c-Fos axis in GSCs maintenance and GBM progression.

Methods: The expression characteristics of ROR1 in GBM and GSCs were assessed by bioinformatic analysis, patient specimens, and patient-derived GSCs. Lentivirus-mediated gene knockdown and overexpression were conducted to evaluate the effect of ROR1 on GSCs proliferation and self-renewal both in vitro and in vivo. The downstream signaling of ROR1 in GSCs maintenance was unbiasedly determined by RNA-seq and validated both in vitro and in vivo. Finally, rescue assays were performed to further validate the function of the ROR1-GRB2-c-Fos axis in GSCs maintenance and GBM progression.

Results: ROR1 is upregulated in GBM and preferentially expressed in GSCs. Disruption of ROR1 markedly impairs GSC proliferation and self-renewal, and inhibits GBM growth in vivo. Moreover, ROR1 stabilizes GRB2 by directly binding and reducing its lysosomal degradation, and ROR1 knockdown significantly inhibits GRB2/ERK/c-Fos signaling in GSCs. Importantly, ectopic expression of c-Fos counteracts the effects caused by ROR1 silencing both in vitro and in vivo.

Conclusions: ROR1 plays essential roles in GSCs maintenance through binding to GRB2 and activation of ERK/c-Fos signaling, which highlights the therapeutic potential of targeting the ROR1-GRB2-c-Fos axis.

背景:胶质瘤干细胞(GSCs)是胶质母细胞瘤(GBM)肿瘤发生、复发和耐药性的根源,而胶质母细胞瘤是最常见、最致命的原发性成人脑恶性肿瘤。开发针对 GSCs 的新方法对于治疗 GBM 至关重要。本研究探讨了新型 ROR1-GRB2-c-Fos 轴在 GSCs 维持和 GBM 进展中的功能:方法:通过生物信息学分析、患者标本和患者来源的 GSCs 评估 ROR1 在 GBM 和 GSCs 中的表达特征。通过慢病毒介导的基因敲除和过表达,评估 ROR1 在体外和体内对 GSCs 增殖和自我更新的影响。通过RNA-seq无偏确定了ROR1在GSCs维持过程中的下游信号转导,并在体外和体内进行了验证。最后,进行了拯救实验,进一步验证了 ROR1-GRB2-c-Fos 轴在 GSCs 维持和 GBM 进展中的功能:结果:ROR1在GBM中上调,并优先在GSCs中表达。结果:ROR1在GBM中上调,并优先在GSCs中表达。破坏ROR1会明显影响GSC的增殖和自我更新,并抑制GBM在体内的生长。此外,ROR1通过直接结合GRB2并减少其溶酶体降解来稳定GRB2,ROR1敲除可显著抑制GSCs中的GRB2/ERK/c-Fos信号传导。重要的是,c-Fos的异位表达可以抵消体外和体内ROR1沉默所造成的影响:结论:ROR1通过与GRB2结合和激活ERK/c-Fos信号在GSCs维持过程中发挥着重要作用,这凸显了靶向ROR1-GRB2-c-Fos轴的治疗潜力。
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引用次数: 0
Central nervous system tumors in adolescents and young adults: A Society for Neuro-Oncology consensus review on diagnosis, management, and future directions. 青少年中枢神经系统肿瘤:神经肿瘤学会关于诊断、管理和未来方向的共识综述。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-23 DOI: 10.1093/neuonc/noae186
Mary Jane Lim-Fat, Julie Bennett, Quinn Ostrom, Mehdi Touat, Enrico Franceschi, Jessica Schulte, Ranjit S Bindra, Jason Fangusaro, Girish Dhall, James Nicholson, Sadhana Jackson, Tom Belle Davidson, Gabriele Calaminus, Giles Robinson, James R Whittle, Peter Hau, Vijay Ramaswamy, Kristian W Pajtler, Roberta Rudà, Nicholas K Foreman, Shawn L Hervey-Jumper, Sunit Das, Peter Dirks, Wenya Linda Bi, Annie Huang, Thomas E Merchant, Maryam Fouladi, Kenneth Aldape, Martin J Van den Bent, Roger J Packer, Julie J Miller, David A Reardon, Susan M Chang, Daphne Haas-Kogan, Uri Tabori, Cynthia Hawkins, Michelle Monje, Patrick Y Wen, Eric Bouffet, Kee Kiat Yeo

Adolescents and young adults (AYAs; ages 15-39 years) are a vulnerable population facing challenges in oncological care, including access to specialized care, transition of care, unique tumor biology, and poor representation in clinical trials. Brain tumors are the second most common tumor type in AYA, with malignant brain tumors being the most common cause of cancer-related death. The 2021 WHO Classification for central nervous system (CNS) Tumors highlights the importance of integrated molecular characterization with histologic diagnosis in several tumors relevant to the AYA population. In this position paper from the Society for Neuro-Oncology (SNO), the diagnosis and management of CNS tumors in AYA is reviewed, focusing on the most common tumor types in this population, namely glioma, medulloblastoma, ependymoma, and CNS germ cell tumor. Current challenges and future directions specific to AYA are also highlighted. Finally, possible solutions to address barriers in the care of AYA patients are discussed, emphasizing the need for multidisciplinary and collaborative approaches that span the pediatric and adult paradigms of care, and incorporating advanced molecular testing, targeted therapy, and AYA-centered care.

青少年和年轻成人(AYAs,15-39 岁)是一个脆弱的群体,他们在肿瘤治疗方面面临着各种挑战,包括获得专业治疗、治疗过渡、独特的肿瘤生物学特性以及在临床试验中的代表性较差。脑肿瘤是亚健康人群中第二常见的肿瘤类型,恶性脑肿瘤是癌症相关死亡的最常见原因。2021 年世界卫生组织(WHO)中枢神经系统(CNS)肿瘤分类强调了在与亚青人群相关的几种肿瘤中将分子特征描述与组织学诊断相结合的重要性。在这份由神经肿瘤学会(SNO)撰写的立场文件中,对青少年中枢神经系统肿瘤的诊断和管理进行了回顾,重点关注这一人群中最常见的肿瘤类型,即胶质瘤、髓母细胞瘤、外胚瘤和中枢神经系统生殖细胞瘤。此外,还重点介绍了针对青少年的当前挑战和未来发展方向。最后,还讨论了解决青少年患者治疗障碍的可能方案,强调需要多学科协作的方法,跨越儿科和成人的治疗模式,并结合先进的分子检测、靶向治疗和以青少年为中心的治疗。
{"title":"Central nervous system tumors in adolescents and young adults: A Society for Neuro-Oncology consensus review on diagnosis, management, and future directions.","authors":"Mary Jane Lim-Fat, Julie Bennett, Quinn Ostrom, Mehdi Touat, Enrico Franceschi, Jessica Schulte, Ranjit S Bindra, Jason Fangusaro, Girish Dhall, James Nicholson, Sadhana Jackson, Tom Belle Davidson, Gabriele Calaminus, Giles Robinson, James R Whittle, Peter Hau, Vijay Ramaswamy, Kristian W Pajtler, Roberta Rudà, Nicholas K Foreman, Shawn L Hervey-Jumper, Sunit Das, Peter Dirks, Wenya Linda Bi, Annie Huang, Thomas E Merchant, Maryam Fouladi, Kenneth Aldape, Martin J Van den Bent, Roger J Packer, Julie J Miller, David A Reardon, Susan M Chang, Daphne Haas-Kogan, Uri Tabori, Cynthia Hawkins, Michelle Monje, Patrick Y Wen, Eric Bouffet, Kee Kiat Yeo","doi":"10.1093/neuonc/noae186","DOIUrl":"https://doi.org/10.1093/neuonc/noae186","url":null,"abstract":"<p><p>Adolescents and young adults (AYAs; ages 15-39 years) are a vulnerable population facing challenges in oncological care, including access to specialized care, transition of care, unique tumor biology, and poor representation in clinical trials. Brain tumors are the second most common tumor type in AYA, with malignant brain tumors being the most common cause of cancer-related death. The 2021 WHO Classification for central nervous system (CNS) Tumors highlights the importance of integrated molecular characterization with histologic diagnosis in several tumors relevant to the AYA population. In this position paper from the Society for Neuro-Oncology (SNO), the diagnosis and management of CNS tumors in AYA is reviewed, focusing on the most common tumor types in this population, namely glioma, medulloblastoma, ependymoma, and CNS germ cell tumor. Current challenges and future directions specific to AYA are also highlighted. Finally, possible solutions to address barriers in the care of AYA patients are discussed, emphasizing the need for multidisciplinary and collaborative approaches that span the pediatric and adult paradigms of care, and incorporating advanced molecular testing, targeted therapy, and AYA-centered care.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Reappraisal of prognostic factors in CNS WHO grade 3 oligodendrogliomas IDH-mutant and 1p/19q co-deleted: lessons from the French POLA cohort. 重新评估中枢神经系统 WHO 3 级少突胶质瘤 IDH 突变和 1p/19q 共同删除的预后因素:从法国 POLA 队列中汲取的教训。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-21 DOI: 10.1093/neuonc/noae221
Domique Figarella-Branger, Carole Colin, Karima Mokhtari, Emmanuelle Uro-Coste, Ahmed Idbaih, Romain Appay, Emeline Tabouret, Mehdi Touat, Antoine Seyve, Catherine Carpentier, Caroline Dehais, François Ducray

Background: In POLA cohort, three pathological groups of CNS WHO grade 3 oligodendroglioma IDH-mutant and 1p/19q co-deleted have been described: group 1 (high mitotic count only), group 2 (microvascular proliferation MVP and no necrosis), and group 3 (MVP and necrosis).

Methods: 494 patients from the POLA cohort, with a median follow up of 96 months were included. To identify the impact of the pathological groups and contrast enhancement in group 1 on overall survival (OS) or progression free survival (PFS), survival curves were obtained (Kaplan-Meier method) and compared (log-rank test). Prognostic value of clinical factors and CDKN2A homozygous deletion HD were also tested. Multivariate analysis was performed.

Results: Survival analysis demonstrated that the pathological groups were associated with both progression-free survival (PFS P=0.01) and overall survival (OS P=0.001). In group 1, patients with contrast enhancement (1CE+) had a poorer prognosis compared to those without (OS P=0.028, PFS P=0.006). Further stratification into group 1CE-, group 1CE+, group 2, and group 3 provided clearer prognostic distinctions (OS P=0.002, PFS P<0.0001). Other prognostic factors included age (OS P<0.0001, PFS P=0.002), extent of surgical resection (OS P=0.001, PFS P=0.003), KPS (OS P<0.0001, PFS P=0.002), postoperative treatment (OS P=0.007, PFS P<0.0001), and CDKN2A HD (OS and PFS P<0.0001). The pathological groups remained of prognostic significance for PFS in multivariate analysis.

Conclusion: Necrosis and CDKN2A HD are adverse prognostic factors of WHO grade 3 oligodendrogliomas, IDH mutant and 1p/19q co-deleted. Besides, in group 1 patients, lack of contrast enhancement is a factor of better prognosis.

背景:在POLA队列中,描述了中枢神经系统WHO 3级少突胶质细胞瘤IDH突变和1p/19q共缺失的三个病理组别:第1组(仅有丝分裂计数高)、第2组(微血管增生MVP和无坏死)和第3组(MVP和坏死)。方法:纳入了POLA队列中的494例患者,中位随访时间为96个月。为了确定病理分组和第 1 组对比度增强对总生存期(OS)或无进展生存期(PFS)的影响,研究人员绘制了生存曲线(Kaplan-Meier 法)并进行了比较(log-rank 检验)。此外,还检验了临床因素和 CDKN2A 同源缺失 HD 的预后价值。进行了多变量分析:生存期分析表明,病理分组与无进展生存期(PFS P=0.01)和总生存期(OS P=0.001)相关。在第 1 组中,有对比增强(1CE+)的患者与无对比增强的患者相比预后较差(OS P=0.028,PFS P=0.006)。进一步将患者分为 1CE- 组、1CE+ 组、2 组和 3 组后,预后区分更加明确(OS P=0.002,PFS PConclusion):坏死和CDKN2A HD是WHO 3级少突胶质瘤、IDH突变和1p/19q共缺失的不良预后因素。此外,在第1组患者中,缺乏对比增强是预后较好的一个因素。
{"title":"Reappraisal of prognostic factors in CNS WHO grade 3 oligodendrogliomas IDH-mutant and 1p/19q co-deleted: lessons from the French POLA cohort.","authors":"Domique Figarella-Branger, Carole Colin, Karima Mokhtari, Emmanuelle Uro-Coste, Ahmed Idbaih, Romain Appay, Emeline Tabouret, Mehdi Touat, Antoine Seyve, Catherine Carpentier, Caroline Dehais, François Ducray","doi":"10.1093/neuonc/noae221","DOIUrl":"https://doi.org/10.1093/neuonc/noae221","url":null,"abstract":"<p><strong>Background: </strong>In POLA cohort, three pathological groups of CNS WHO grade 3 oligodendroglioma IDH-mutant and 1p/19q co-deleted have been described: group 1 (high mitotic count only), group 2 (microvascular proliferation MVP and no necrosis), and group 3 (MVP and necrosis).</p><p><strong>Methods: </strong>494 patients from the POLA cohort, with a median follow up of 96 months were included. To identify the impact of the pathological groups and contrast enhancement in group 1 on overall survival (OS) or progression free survival (PFS), survival curves were obtained (Kaplan-Meier method) and compared (log-rank test). Prognostic value of clinical factors and CDKN2A homozygous deletion HD were also tested. Multivariate analysis was performed.</p><p><strong>Results: </strong>Survival analysis demonstrated that the pathological groups were associated with both progression-free survival (PFS P=0.01) and overall survival (OS P=0.001). In group 1, patients with contrast enhancement (1CE+) had a poorer prognosis compared to those without (OS P=0.028, PFS P=0.006). Further stratification into group 1CE-, group 1CE+, group 2, and group 3 provided clearer prognostic distinctions (OS P=0.002, PFS P<0.0001). Other prognostic factors included age (OS P<0.0001, PFS P=0.002), extent of surgical resection (OS P=0.001, PFS P=0.003), KPS (OS P<0.0001, PFS P=0.002), postoperative treatment (OS P=0.007, PFS P<0.0001), and CDKN2A HD (OS and PFS P<0.0001). The pathological groups remained of prognostic significance for PFS in multivariate analysis.</p><p><strong>Conclusion: </strong>Necrosis and CDKN2A HD are adverse prognostic factors of WHO grade 3 oligodendrogliomas, IDH mutant and 1p/19q co-deleted. Besides, in group 1 patients, lack of contrast enhancement is a factor of better prognosis.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Is modulation of immune checkpoints on glioblastoma-infiltrating myeloid cells a viable therapeutic strategy? 调节胶质母细胞瘤浸润髓系细胞上的免疫检查点是一种可行的治疗策略吗?
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-19 DOI: 10.1093/neuonc/noae193
Ruochen Du, Jianzhong Zhang, Rimas V Lukas, Shashwat Tripathi, Jared T Ahrendsen, Michael A Curran, Crismita Dmello, Peng Zhang, Roger Stupp, Ganesh Rao, Amy B Heimberger

The field of immunology has traditionally focused on immune checkpoint modulation of adaptive immune cells. However, many malignancies such as glioblastoma are mostly devoid of T cells and rather are enriched with immunosuppressive myeloid cells of the innate immune system. While some immune checkpoint targets are shared between adaptive and innate immunity, myeloid-specific checkpoints could also serve as potential therapeutics. To better understand the impact of immune checkpoint blockade on myeloid cells, we systematically summarize the current literature focusing on the direct immunological effects of PD-L1/PD-1, CD24/Siglec-10, collagen/LAIR-1, CX3CL1/CX3CR1, and CXCL10/CXCR3. By synthesizing the molecular mechanisms and the translational implications, we aim to prioritize agents in this category of therapeutics for glioblastoma.

免疫学领域的传统重点是对适应性免疫细胞进行免疫检查点调节。然而,许多恶性肿瘤(如胶质母细胞瘤)大多没有 T 细胞,而是富含免疫抑制性的先天性免疫系统髓系细胞。虽然适应性免疫和先天性免疫共享一些免疫检查点靶点,但髓系特异性检查点也可作为潜在的治疗药物。为了更好地了解免疫检查点阻断对髓系细胞的影响,我们系统地总结了目前的文献,重点研究了PD-L1/PD-1、CD24/Siglec-10、胶原/LAIR-1、CX3CL1/CX3CR1和CXCL10/CXCR3的直接免疫学效应。通过综合分子机制和转化意义,我们旨在优先选择这类治疗胶质母细胞瘤的药物。
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引用次数: 0
Intracranial administration of anti-PD-1 and anti-CTLA-4 immune checkpoint-blocking monoclonal antibodies in patients with recurrent high-grade glioma. 对复发性高级别胶质瘤患者颅内注射抗PD-1和抗CTLA-4免疫检查点阻断单克隆抗体。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-16 DOI: 10.1093/neuonc/noae177
Johnny Duerinck, Louise Lescrauwaet, Iris Dirven, Jacomi Del'haye, Latoya Stevens, Xenia Geeraerts, Freya Vaeyens, Wietse Geens, Stefanie Brock, Anne-Marie Vanbinst, Hendrik Everaert, Ben Caljon, Michaël Bruneau, Laetitia Lebrun, Isabelle Salmon, Marc Kockx, Sandra Tuyaerts, Bart Neyns

Background: Recurrent high-grade glioma (rHGG) lacks effective life-prolonging treatments and the efficacy of systemic PD-1 and CTLA-4 immune checkpoint inhibitors is limited. The multi-cohort Glitipni phase I trial investigates the safety and feasibility of intraoperative intracerebral (iCer) and postoperative intracavitary (iCav) nivolumab (NIVO) ± ipilimumab (IPI) treatment following maximal safe resection (MSR) in rHGG.

Materials and methods: Patients received 10 mg IV NIVO within 24 h before surgery, followed by MSR, iCer 5 mg IPI and 10 mg NIVO, and Ommaya catheter placement in the resection cavity. Biweekly postoperative iCav administrations of 1-5-10 mg NIVO (cohort 4) or 10 mg NIVO plus 1-5-10 mg IPI (cohort 7) were combined with 10 mg IV NIVO for 11 cycles.

Results: 42 rHGG patients underwent MSR with iCer NIVO + IPI. 16 pts were treated in cohort 4 (postoperative iCav NIVO at escalating doses) while 28 patients were treated in cohort 7 (intra and postoperative iCav NIVO and escalating doses of IPI). The most common TRAE was fatigue; no grade 5 AE occurred. Dose-limiting toxicity was grade 3 neutrophilic pleocytosis (4 pts) receiving iCav NIVO plus 5 or 10 mg IPI. PFS and OS did not significantly differ between cohorts (median OS: 42 [95% CI 26-57] vs. 35 [29-40] weeks; 1-year OS rate: 37% vs. 29%). Baseline B7-H3 expression significantly correlated with worse survival. OS compared favorably to a historical pooled cohort (n = 469) of Belgian rHGG pts treated with anti-VEGF therapies (log-rank P = .015).

Conclusion: Intraoperative iCer IPI + NIVO with postoperative iCav NIVO ± IPI up to biweekly doses of 1 mg IPI + 10 mg NIVO is feasible and safe, showing encouraging OS in rHGG patients. ClinicalTrials.gov registration: NCT03233152.

背景:复发性高级别胶质瘤(rHGG)缺乏有效的延长生命的治疗方法,全身性PD-1和CTLA-4免疫检查点抑制剂的疗效有限。多队列Glitipni I期试验研究了rHGG最大安全切除术(MSR)后术中脑内(iCer)和术后腔内(iCav)nivolumab(NIVO)± ipilimumab(IPI)治疗的安全性和可行性:患者在术前24小时内接受10毫克静脉注射NIVO,随后接受MSR、5毫克IPI和10毫克NIVO的iCer治疗,并在切除腔内置入Ommaya导管。术后每两周在iCav中注射1-5-10毫克NIVO(第4组)或10毫克NIVO加1-5-10毫克IPI(第7组),同时静脉注射10毫克NIVO,共11个周期:42名rHGG患者接受了iCer NIVO + IPI的MSR治疗。16例患者接受了第4组治疗(术后使用递增剂量的iCav NIVO),28例患者接受了第7组治疗(术中和术后使用iCav NIVO和递增剂量的IPI)。最常见的TRAE是疲劳;没有发生5级AE。剂量限制性毒性是接受iCav NIVO加5或10毫克IPI治疗的3级中性粒细胞增多(4例)。各组间的 PFS 和 OS 无明显差异(中位 OS:42 [95% CI 26-57] 周 vs. 35 [29-40] 周;1 年 OS 率:37% vs. 29%):37%对29%)。基线B7-H3表达与较差的生存期显著相关。与接受抗血管内皮生长因子疗法治疗的比利时rHGG患者的历史汇总队列(n = 469)相比,OS更佳(log-rank P = .015):结论:术中使用 iCer IPI + NIVO,术后使用 iCav NIVO ± IPI(最高双周剂量为 1 毫克 IPI + 10 毫克 NIVO)是可行且安全的,在 rHGG 患者中显示出令人鼓舞的 OS。ClinicalTrials.gov 注册:NCT03233152。
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引用次数: 0
The Immune Landscape in Brain Metastasis. 脑转移中的免疫格局
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-15 DOI: 10.1093/neuonc/noae219
Luca D Schreurs, Alexander F Vom Stein, Stephanie T Jünger, Marco Timmer, Ka-Won Noh, Reinhard Buettner, Hamid Kashkar, Volker Neuschmelting, Roland Goldbrunner, Phuong-Hien Nguyen

The prognosis for patients with brain metastasis remains dismal despite intensive therapy including surgical resection, radiotherapy, chemo-, targeted and immunotherapy. Thus, there is a high medical need for new therapeutic options. Recent advances employing high-throughput and spatially resolved single-cell analyses have provided unprecedented insights into the composition and phenotypes of the diverse immune cells in the metastatic brain, revealing a unique immune landscape starkly different from that of primary brain tumours or other metastatic sites. This review summarises the current evidence on the composition and phenotypes of the most prominent immune cells in the brain metastatic niche, along with their dynamic interactions with metastatic tumour cells and each other. As the most abundant immune cell types in this niche, we explore in detail the phenotypic heterogeneity and functional plasticity of tumour-associated macrophages, including both resident microglia and monocyte-derived macrophages, as well as the T-cell compartment. We also review pre-clinical and clinical trials evaluating the therapeutic potential of targeting the immune microenvironment in brain metastasis. Given the substantial evidence highlighting a significant role of the immune microenvironmental niche in brain metastasis pathogenesis, a comprehensive understanding of the key molecular and cellular factors within this niche holds great promise for developing novel therapeutic approaches as well as innovative combinatory treatment strategies for brain metastasis.

尽管进行了手术切除、放疗、化疗、靶向治疗和免疫治疗等强化治疗,脑转移患者的预后仍然不容乐观。因此,医学界亟需新的治疗方案。最近,采用高通量和空间分辨单细胞分析方法的研究取得了进展,对转移性脑肿瘤中各种免疫细胞的组成和表型提供了前所未有的见解,揭示了与原发性脑肿瘤或其他转移部位截然不同的独特免疫景观。本综述总结了目前有关脑转移龛中最主要的免疫细胞的组成和表型,以及它们与转移瘤细胞和相互之间的动态相互作用的证据。肿瘤相关巨噬细胞(包括常住小胶质细胞和单核细胞衍生的巨噬细胞)是该龛位中最丰富的免疫细胞类型,我们将详细探讨它们的表型异质性和功能可塑性,以及 T 细胞区系。我们还回顾了评估针对脑转移免疫微环境的治疗潜力的临床前和临床试验。有大量证据表明,免疫微环境在脑转移瘤的发病机制中发挥着重要作用,因此全面了解免疫微环境中的关键分子和细胞因素,对于开发新型治疗方法以及创新的脑转移瘤联合治疗策略大有希望。
{"title":"The Immune Landscape in Brain Metastasis.","authors":"Luca D Schreurs, Alexander F Vom Stein, Stephanie T Jünger, Marco Timmer, Ka-Won Noh, Reinhard Buettner, Hamid Kashkar, Volker Neuschmelting, Roland Goldbrunner, Phuong-Hien Nguyen","doi":"10.1093/neuonc/noae219","DOIUrl":"https://doi.org/10.1093/neuonc/noae219","url":null,"abstract":"<p><p>The prognosis for patients with brain metastasis remains dismal despite intensive therapy including surgical resection, radiotherapy, chemo-, targeted and immunotherapy. Thus, there is a high medical need for new therapeutic options. Recent advances employing high-throughput and spatially resolved single-cell analyses have provided unprecedented insights into the composition and phenotypes of the diverse immune cells in the metastatic brain, revealing a unique immune landscape starkly different from that of primary brain tumours or other metastatic sites. This review summarises the current evidence on the composition and phenotypes of the most prominent immune cells in the brain metastatic niche, along with their dynamic interactions with metastatic tumour cells and each other. As the most abundant immune cell types in this niche, we explore in detail the phenotypic heterogeneity and functional plasticity of tumour-associated macrophages, including both resident microglia and monocyte-derived macrophages, as well as the T-cell compartment. We also review pre-clinical and clinical trials evaluating the therapeutic potential of targeting the immune microenvironment in brain metastasis. Given the substantial evidence highlighting a significant role of the immune microenvironmental niche in brain metastasis pathogenesis, a comprehensive understanding of the key molecular and cellular factors within this niche holds great promise for developing novel therapeutic approaches as well as innovative combinatory treatment strategies for brain metastasis.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma. 靶向注射萘普卡西与放射治疗可改善弥漫中线胶质瘤的疗效。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-12 DOI: 10.1093/neuonc/noae215
Matthew Gallitto, Xu Zhang, Genesis De Los Santos, Hong-Jian Wei, Ester Calvo Fernández, Shoufu Duan, Geoffrey Sedor, Nina Yoh, Danae Kokosi, J Carlos Angel, Yi-Fang Wang, Erin White, Connor J Kinslow, Xander Berg, Lorenzo Tomassoni, Fereshteh Zandkarimi, Iok In Christine Chio, Peter D Canoll, Jeffrey N Bruce, Neil A Feldstein, Robyn D Gartrell, Simon Cheng, James H Garvin, Stergios Zacharoulis, Robert J Wechsler-Reya, Jovana Pavisic, Andrea Califano, Zhiguo Zhang, Cheng-Chia Wu

Background: Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. All previous studies examining the role of systemic agents have failed to demonstrate a survival benefit; the only standard of care is radiation therapy (RT). Successful implementation of radiosensitization strategies in DMG remains an essential and promising avenue of investigation. We explore the use of Napabucasin, an NAD(P)H quinone dehydrogenase 1 (NQO1)-bioactivatable reactive oxygen species (ROS)-inducer, as a potential therapeutic radiosensitizer in DMG.

Methods: In this study, we conduct in vitro and in vivo assays using patient-derived DMG cultures to elucidate the mechanism of action of Napabucasin and its radiosensitizing properties. As penetration of systemic therapy through the blood-brain barrier (BBB) is a significant limitation to the success of DMG therapies, we explore focused ultrasound (FUS) and convection-enhanced delivery (CED) to overcome the BBB and maximize therapeutic efficacy.

Results: Napabucasin is a potent ROS-inducer and radiosensitizer in DMG, and treatment-mediated ROS production and cytotoxicity are dependent on NQO1. In subcutaneous xenograft models, combination therapy with RT improves local control. After optimizing targeted drug delivery using CED in an orthotopic mouse model, we establish the novel feasibility and survival benefit of CED of Napabucasin concurrent with RT.

Conclusions: As nearly all DMG patients will receive RT as part of their treatment course, our validation of the efficacy of radiosensitizing therapy using CED to prolong survival in DMG opens the door for exciting novel studies of alternative radiosensitization strategies in this devastating disease while overcoming limitations of the BBB.

背景:弥漫中线胶质瘤(DMG)是儿童中最具侵袭性的原发性脑肿瘤。以往所有关于全身用药作用的研究都未能证明其对生存有好处;唯一的治疗标准是放射治疗(RT)。在DMG中成功实施放射增敏策略仍是一个重要且前景广阔的研究方向。我们探索了Napabucasin(一种NAD(P)H醌脱氢酶1(NQO1)-可生物活化的活性氧(ROS)诱导剂)作为DMG潜在治疗性放射增敏剂的用途:在这项研究中,我们利用源自患者的 DMG 培养物进行了体外和体内试验,以阐明纳帕布卡辛的作用机制及其放射增敏特性。由于全身治疗通过血脑屏障(BBB)的渗透是DMG治疗成功的一个重要限制因素,我们探索了聚焦超声(FUS)和对流增强递送(CED)来克服BBB并最大限度地提高疗效:结果:萘普卡辛是一种强效的ROS诱导剂和DMG放射增敏剂,治疗介导的ROS产生和细胞毒性依赖于NQO1。在皮下异种移植模型中,与 RT 联合治疗可改善局部控制。在正位小鼠模型中使用 CED 优化靶向给药后,我们证实了在 RT 治疗的同时使用 CED 给药纳帕布卡辛的新可行性和生存益处:由于几乎所有的 DMG 患者都将接受 RT 作为其治疗过程的一部分,我们对使用 CED 延长 DMG 患者生存期的放射增敏疗法疗效的验证,为在这种毁灭性疾病中开展令人兴奋的放射增敏替代策略的新研究打开了大门,同时克服了 BBB 的局限性。
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引用次数: 0
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Neuro-oncology
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