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

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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.