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

Nduom实验室继续建立我们的临床和转化研究工作。我们现在已经在外科神经病学分部建立了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。我们已经成功招募了7名患者进入该试点试验，并预计在2023财年完成招募。我们已经与美国国立卫生研究院人类免疫学中心建立了合作关系，为细胞因子微透析试验样品的蛋白质组学分析提供资金。我已经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, 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）。细胞因子微透析在接受检查点阻断的胶质母细胞瘤患者中的实时免疫监测。神经外科。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的生物标志物方面的专业知识，我们还发表了一篇关于胶质母细胞瘤患者使用生物标志物的特约综述（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。中国癌症杂志，2020;8(1):e000348。在其他临床工作中，我们与NCI神经肿瘤学分会的NCI连接小组一起，完成了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的实践模式的调查。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，这样我们就可以更好地了解这些罕见肿瘤的生物学。这篇论文发表在《神经肿瘤学杂志》（成人弥漫性中线胶质瘤患者立体定向活检态度的变化：AANS/CNS肿瘤科成员的调查）。Lynes J, Acquaye AA, Sur H, Nwankwo A, Sanchez V, Vera E, Wu T, Theeler B, Armstrong TS, Gilbert MR, Nduom EK。中国生物医学工程学报，2016,31(1):391 - 391。为了进一步提高我们开发胶质母细胞瘤免疫疗法的能力，我们进行了各种转化项目，这些项目增加了我们对脑肿瘤免疫微环境的理解。我们在Scientific Reports上发表了一篇论文，评估GL261小鼠胶质瘤模型系统和GL261-荧光素酶小鼠胶质瘤模型系统的免疫差异（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）。GL261荧光素酶表达细胞引发抗肿瘤免疫反应：小鼠胶质瘤模型的评估科学进展，2020,7(1):11003。我们发现荧光素酶的表达似乎增加了免疫能力小鼠模型中植入胶质瘤的免疫反应。我们已经在神经外科医师大会和神经肿瘤学会年会上介绍了这项工作。我已经开始在一个具有免疫能力的小鼠模型中对各种检查点抑制剂和其他免疫调节剂组合的疗效进行转化研究。在相关的翻译工作中，我是JCI Insight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（高效ADCC-通过avelumab和高亲和力自然杀伤细胞系haNK杀死脑膜瘤）。Giles AJ, Hao S, Padget MR, Song H，张伟，Lynes J, Sanchez VE，刘勇，Jung J，曹旭，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 9月19日)。

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.).