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

在这个项目的第一年，我继续加强我的临床和翻译研究工作。我们现在已经在外科神经科建立了脑肿瘤免疫学实验室。我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检查点抑制剂在胶质母细胞瘤中的作用。我们已经成功地招募了7名患者参加这项试点试验，并预计在2021财年完成登记。我们已经与NIH人类免疫学中心建立了合作关系，为我们细胞因子微透析试验的样本进行蛋白质组分析提供资金。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记物开发方面的工作。本协议已公布(Lynes J、Jackson S、Sanchez V、Dominah G、Wang X、Kuek A、Hayes CP、Benzo S、Scott G、Chittiboina P、扎格卢尔·K、Park DM、Wu J、Hourigan CS、Giles AJ、Wu T、Maric D、Chen J、Quezado M、Heiss JD、Gilbert MR、Nduom EK。细胞因子微透析用于脑胶质母细胞瘤检查点阻断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生物标志物在胶质母细胞瘤患者中使用的特邀综述(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记物开发：当前技术和未来方向。日本免疫其他癌症。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，完成了对美国神经外科医生协会和神经外科医生大会联合肿瘤分会成员的调查，调查涉及弥漫性中线胶质瘤患者的实践模式。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。这篇手稿发表在《神经肿瘤学杂志》(对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肿瘤分会成员的调查)上。莱恩斯·J，Acquaye AA，Sur H，Nwankwo A，Sanchez V，Vera E，Wu T，Theeler B，Armstrong TS，Gilbert Mr，Nduom EK。 J Neuroonol。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，我们进行了各种翻译项目，增加了我们对脑肿瘤免疫微环境的了解。我们发表了一篇带有科学报告的手稿，评估了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GL261荧光素酶的细胞诱导抗肿瘤免疫反应：对小鼠胶质瘤模型的评估。《科学》杂志2020-07-3；10(1)：11003。我们发现，荧光素酶的表达似乎增加了对移植到免疫活性小鼠模型中的胶质瘤的免疫反应。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。我已经开始了一项关于各种检查点抑制剂和其他免疫调节剂组合在具有主动动物方案的免疫能力小鼠模型中的有效性的翻译研究。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)细胞和抗PD-L1抗体联合治疗脑膜瘤的使用(高效ADCC-通过Avelumab和高亲和力的自然杀伤细胞系Hank杀死脑膜瘤)。贾尔斯，S，Padget先生，宋H，张伟，Lynes J，Sanchez VE，刘勇，Jung J，曹X，Fujii R，Jensen RL，Gillesbie D，Schlom J，Gilbert先生，Nduom EK，杨C，Lee JH，Soon-雄P，Hodge JW，Park DM。JCI Insight。2019年9月19日)。 最后，我们利用这一年开始研究非编码RNA及其在胶质母细胞瘤发病机制中的作用。我的团队与医学博士Avi Nath一起，正在研究人类内源性逆转录病毒在胶质母细胞瘤患者中的表达。我们认为，这些非编码序列的失调可能与胶质瘤的发生有关。我们发现，与正常脑细胞相比，某些内源性逆转录病毒在胶质母细胞瘤细胞中过度表达。我们正在准备即将提交的这份手稿。这项工作在神经外科医生大会上发表。我们认为，免疫相关的非编码RNA可能是胶质母细胞瘤免疫抑制的临床相关来源。我们使用了商业上可用的长非编码RNA(LncRNA)阵列来研究胶质母细胞瘤患者和当地捐赠者免疫细胞中LncRNAs表达的差异。这一初步数据是在神经肿瘤学会年会上公布的。我们还在总结这项工作以供提交。

In the first year of this project, I have continued to build on my clinical and translational research efforts. We have now established the Brain Tumor Immunology Lab in the Surgical Neurology Branch. I 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 2021. 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.). Finally, we have used this year to begin to investigate non-coding RNAs and their role in the pathogenesis of glioblastoma. Together with Avi Nath, M.D., my team is investigating the expression of human endogenous retroviruses in glioblastoma patients. We believe that dysregulation of these non-coding sequences could be related to gliomagenesis. We found that certain endogenous retroviruses were over-expressed in glioblastoma cells versus normal brain cells. We are preparing this manuscript for imminent submission. This work was presented at the Congress of Neurological Surgeons meeting. We believe that immune-related non-coding RNAs may be a clinically relevant source of immune suppression in glioblastoma. We have used a commercially available long non-coding RNA (lncRNA) array to investigate the differences in expression of lncRNAs in the immune cells of glioblastoma patients versus local donors. This preliminary data was presented at the Annual meeting of the Society for Neuro-Oncology. We are also summarizing this work for submission.