Clinical and Translational Investigations of Immune Suppression and Immune Modulation in Glioblastoma

胶质母细胞瘤免疫抑制和免疫调节的临床和转化研究

• 批准号: 10708639
• 负责人: Edjah Nduom
• 金额: $ 51.31万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708639
• 关键词: Address; Adult; Affinity; Aftercare; American; Animals; Attitude; Biological Markers; Biological Models; Biology; Biopsy; Brain; Brain Neoplasms; Cell Line; Cells; Central Nervous System Neoplasms; Cerebrum; Clinical; Clinical Research; Collaborations; Congresses; Data Collection; Enrollment; Evaluation; Funding; Future; Glioblastoma; Glioma; Goals; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunocompetent; Immunologic Monitoring; Immunology; Immunomodulators; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Implant; International; Investigation; Joints; Journals; Knowledge; Learning; Lesion; Luciferases; Malignant Neoplasms; Manuscripts; Microdialysis; Modeling; Mus; Natural Killer Cells; Neurologic; Neurology; Neurosurgeon; Operative Surgical Procedures; Patients; Pattern; Proteomics; Protocols documentation; Publishing; Reporting; Sampling; Secure; Societies; Source; Surgeon; Surveys; Technology; Therapy trial; Time; Translational Research; United States National Institutes of Health; Untranslated RNA; Variant; Work; Yang; anti-PD-L1 antibodies; anti-tumor immune response; biomarker development; cytokine; design; diffuse midline glioma; immune checkpoint blockade; immunoregulation; insight; meetings; member; meningioma; mouse model; neuro-oncology; neurosurgery; novel strategies; pilot trial; rare cancer; tumor; tumor immunology; tumor microenvironment; tumor-immune system interactions

The Nduom Lab has continued to build on our clinical and translational research efforts. We have now established the Brain Tumor Immunology Lab in the Surgical Neurology Branch. We have secured funding for the establishment of a trial to evaluate checkpoint inhibitors in glioblastoma by collecting cytokines via cerebral microdialysis. We have enrolled 7 patients successfully into this pilot trial and anticipate completion of enrollment in fiscal year 2023. We have established a collaboration with the NIH Center for Human Immunology to fund proteomic analysis for the samples from our cytokine microdialysis trial. I have presented our work on cytokine microdialysis and biomarker development for glioblastoma patients at numerous national and international meetings. This protocol has been published (Lynes J, Jackson S, Sanchez V, Dominah G, Wang X, Kuek A, Hayes CP, Benzo S, Scott G, Chittiboina P, Zaghloul K, Park DM, Wu J, Hourigan CS, Giles AJ, Wu T, Maric D, Chen J, Quezado M, Heiss JD, Gilbert MR, Nduom EK. Cytokine Microdialysis for Real-Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade. Neurosurgery. 2018 Sep 4). In view of our expertise in conducting immune therapy trials for glioblastoma and the establishment of new biomarkers, we have also published an invited review on the use of Biomarkers in Glioblastoma patients (Lynes J*, Nwankwo A*, Dominah G, Sanchez VE, Sarpong K, Ariyo O, Nduom EK. Biomarker Development for Immune Therapy in Glioblastoma: Current Technologies and Future Directions. JImmunother Cancer. 2020 May;8(1):e000348.). In other clinical work, together with the NCI Connect Team of the Neuro-Oncology Branch of NCI, we completed a survey of Joint Tumor Section members of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons on practice patterns involving patients with diffuse midline gliomas. Our goal was to determine what factors might make neurosurgeons more likely to biopsy these lesions, so that we can better understand the biology of these rare tumors. This manuscript was published in the Journal of Neuro-Oncology (Variations in attitudes towards stereotactic biopsy of adult diffuse midline glioma patients: a survey of members of the AANS/CNS Tumor Section. Lynes J, Acquaye AA, Sur H, Nwankwo A, Sanchez V, Vera E, Wu T, Theeler B, Armstrong TS, Gilbert MR, Nduom EK. J Neurooncol. 2020 Aug;149(1):161-170.). To further our ability to develop immune therapeutics for glioblastoma, we have pursued various translational projects which have increased our understanding of the immune microenvironment of brain tumors. We published a manuscript with Scientific Reports evaluating the immune differences between the GL261 murine glioma model system and the GL261-luciferase murine glioma model system (Sanchez V, Lynes J, Walbridge S, Wang X, Nwankwo AK, Dominah G, Sur H, Obungu A, Adamstein N, Edwards NA, Dagur P, Maric D, Munasighe J, Heiss J, Nduom EK. GL261 luciferase-expressing cells elicit an anti-tumor immune response: an evaluation of murine glioma models. Sci Rep. 2020 Jul 3;10(1):11003.). We showed that luciferase expression seems to increase immune response to gliomas implanted in an immune competent murine model. We have presented this work at the Congress of Neurological Surgeons meeting and at the Annual Meeting of the Society for Neuro-Oncology. I have begun a translational investigation of the efficacy of the combination of various checkpoint inhibitors and other immune-modulatory agents in an immune-competent murine model with an active animal protocol. In related translational work, I am a coauthor on a published manuscript in JCI Insight evaluating the use of Natural Killer (NK) cells together with an anti-PD-L1 antibody to treat meningiomas (Efficient ADCC- killing of meningioma by avelumab and a high-affinity natural killer cell line, haNK. Giles AJ, Hao S, Padget MR, Song H, Zhang W, Lynes J, Sanchez VE, Liu Y, Jung J, Cao X, Fujii R, Jensen RL, Gillespie D, Schlom J, Gilbert MR, Nduom EK, Yang C, Lee JH, Soon-Shiong P, Hodge JW, Park DM. JCI Insight. 2019 Sep 19.).

Nduom 实验室继续加强我们的临床和转化研究工作。我们现在在神经外科分院建立了脑肿瘤免疫学实验室。我们已获得资金用于建立一项试验，通过脑微透析收集细胞因子来评估胶质母细胞瘤中的检查点抑制剂。我们已成功招募 7 名患者参加该试点试验，预计在 2023 财年完成招募。我们已与 NIH 人类免疫学中心建立合作，资助对我们的细胞因子微透析试验样本进行蛋白质组分析。我在许多国内和国际会议上介绍了我们在胶质母细胞瘤患者的细胞因子微透析和生物标志物开发方面的工作。该协议已发布 (Lynes J, Jackson S, Sanchez V, Dominah G, Wang X, Kuek A, Hayes CP, Benzo S, Scott G, Chittiboina P, Zaghloul K, Park DM, Wu J, Hourigan CS, Giles AJ , Wu T, Maric D, Chen J, Quezado M, Heiss JD, Gilbert MR, Nduom EK 实时细胞因子微透析。接受检查点封锁的胶质母细胞瘤患者的免疫监测，2018 年 9 月 4 日。鉴于我们在胶质母细胞瘤免疫治疗试验和建立新生物标志物方面的专业知识，我们还发表了一篇关于生物标志物在胶质母细胞瘤患者中的使用的邀请综述（Lynes J*、Nwankwo A*、Dominah G、Sanchez VE、Sarpong K、Ariyo O、Nduom EK。胶质母细胞瘤免疫治疗的生物标志物开发：当前技术和未来方向。 2020 年 5 月；8(1):e000348.)。在其他临床工作中，我们与 NCI 神经肿瘤学分会的 NCI Connect 团队一起，完成了一项针对美国神经外科医生协会和神经外科医生大会关节肿瘤科成员的关于弥漫性中线患者实践模式的调查神经胶质瘤。我们的目标是确定哪些因素可能使神经外科医生更有可能对这些病变进行活检，以便我们能够更好地了解这些罕见肿瘤的生物学。该手稿发表在《神经肿瘤学杂志》上（成人弥漫性中线胶质瘤患者立体定向活检的态度变化：对 AANS/CNS 肿瘤科成员的调查。Lynes J、Acquaye AA、Sur H、Nwankwo A、Sanchez V，维拉 E，吴 T，Theeler B，阿姆斯特朗 TS，吉尔伯特 MR，Nduom J Neurooncol 2020。八月；149(1)：161-170。）。为了进一步提高我们开发胶质母细胞瘤免疫疗法的能力，我们开展了各种转化项目，这些项目增加了我们对脑肿瘤免疫微环境的了解。我们在科学报告中发表了一篇手稿，评估 GL261 鼠神经胶质瘤模型系统和 GL261-荧光素酶鼠神经胶质瘤模型系统之间的免疫差异（Sanchez V、Lynes J、Walbridge S、Wang X、Nwankwo AK、Dominah G、Sur H、Obungu） A、亚当斯坦 N、爱德华兹 NA、达古尔 P、马里克 D、穆纳西格 J、海斯 J、恩多姆 EK。 GL261 荧光素酶表达细胞引发抗肿瘤免疫反应：对小鼠神经胶质瘤模型的评估。Sci Rep. 2020 年 7 月 3 日；10(1):11003。）。我们发现，荧光素酶的表达似乎会增加对植入免疫能力小鼠模型中的神经胶质瘤的免疫反应。我们在神经外科医生大会和神经肿瘤学会年会上介绍了这项工作。我已经开始对各种检查点抑制剂和其他免疫调节剂组合在具有活性动物方案的免疫活性小鼠模型中的功效进行转化研究。在相关的转化工作中，我是 JCI Insight 上发表的一篇手稿的合著者，该手稿评估了自然杀伤 (NK) 细胞与抗 PD-L1 抗体一起治疗脑膜瘤的效果（Efficient ADCC-通过 avelumab 和高浓度杀灭脑膜瘤） -亲和自然杀伤细胞系，haNK AJ，Hao S，Padget MR，Song H，Zhang W，Lynes J，Sanchez VE，Liu Y，Jung J，Cao。 X、Fujii R、Jensen RL、Gillespie D、Schlom J、Gilbert MR、Nduom EK、Yang C、Lee JH、Soon-Shiong P、Hodge JW、Park DM 2019 年 9 月 19 日。