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。我们现已在外科神经病学分支设立脑肿瘤免疫学实验室。我们已经获得了建立一项试验的资金，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。我们已成功入组7名患者参与这项试点试验，预计将于2023财政年度完成入组。我们已经与NIH人类免疫学中心建立了合作关系，为我们的细胞因子微透析试验样品的蛋白质组学分析提供资金。我在许多国家和国际会议上介绍了我们在胶质母细胞瘤患者细胞因子微透析和生物标志物开发方面的工作。该方案已发表（Lynes J，杰克逊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，吉尔伯特MR，Nduom EK.细胞因子微透析用于接受检查点阻断的胶质母细胞瘤患者的实时免疫监测。神经外科2018年9月4日）。鉴于我们在进行胶质母细胞瘤的免疫治疗试验和建立新生物标志物方面的专业知识，我们还发表了关于在胶质母细胞瘤患者中使用生物标志物的特邀综述（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。JImmunother Cancer. 2020年5月;8（1）：e000348.）。在其他临床工作中，我们与NCI神经肿瘤学分支的NCI连接团队一起，完成了对美国神经外科医生协会和神经外科医生大会联合肿瘤科成员关于弥漫性中线胶质瘤患者实践模式的调查。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，以便我们更好地了解这些罕见肿瘤的生物学。这篇文章发表在《神经肿瘤学杂志》（Variations in attitudes towards stereotactic biopsy of adult diffuse midline glioma patients：a survey of members of the AANS/CNS Tumor Section）上。Lynes J，Acquaye AA，Sur H，Nwankwo A，Sanchez V，Vera E，Wu T，Theeler B，Armstrong TS，吉尔伯特MR，Nduom EK.神经肿瘤学杂志。2020年8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，我们已经开展了各种翻译项目，这些项目增加了我们对脑肿瘤免疫微环境的理解。我们在Scientific Reports上发表了一篇论文，评价了GL 261鼠神经胶质瘤模型系统和GL 261-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，Adamstein N，Edwards NA，Dagur P，Maric D，Munasighe J，Heiss J，Nduom EK.表达GL 261转移酶的细胞引起抗肿瘤免疫应答：鼠胶质瘤模型的评价2020年7月3日;10（1）：11003.）。我们发现，荧光素酶表达似乎增加了对植入免疫活性小鼠模型中的神经胶质瘤的免疫应答。我们已经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。我已经开始在具有免疫能力的小鼠模型中采用主动动物方案对各种检查点抑制剂和其他免疫调节剂组合的功效进行转化研究。在相关的翻译工作中，我是JCI Insight上发表的一篇论文的合著者，该论文评估了自然杀伤（NK）细胞与抗PD-L1抗体一起治疗脑膜瘤（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，詹森RL，吉莱斯皮D，Schlom J，吉尔伯特MR，Nduom EK，Yang C，Lee JH，Soon-Shiong P，Hodge JW，Park DM. JCI Insight。2019年9月19日）。