Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press38010.17650/2313-805X-2021-8-3-60-76REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИGlioblastoma: a molecular genetic portrait and modern therapeutic strategies for drug treatmentГлиобластома: молекулярно-генетический портрет и современные терапевтические стратегии лекарственного леченияhttps://orcid.org/0000-0001-8708-2712GuensG. P.ГенсГ. П.
Russian Federation

Bld. 1, 20 Delegatskaya St., Moscow 127473

127473 Москва, ул. Делегатская, 20

https://orcid.org/0000-0002-4840-4106SanikovichV. D.СаниковичВ. Д.
Russian Federation

Bld. 1, 20 Delegatskaya St., Moscow 127473

127473 Москва, ул. Делегатская, 20

https://orcid.org/0000-0002-0272-1747MileykoV. A.МилейкоВ. А.
Russian Federation

31 Malaya Nikitskaya St.

121069 Москва, ул. Малая Никитская, 31

LebedevaA. A.ЛебедеваА. А.
Russian Federation

31 Malaya Nikitskaya St.

121069 Москва, ул. Малая Никитская, 31

Department of Oncology and Radiation Therapy A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of RussiaКафедра онкологии и лучевой терапии ФГБОУ ВО «Московский государственный медико-стоматологический университет им. А.И. Евдокимова» Минздрава РоссииOncodiagnostics AtlasООО «Онкодиагностика Атлас»150920218360760511202105112021Copyright ©; 2021, Guens G.P., Sanikovich V.D., Mileyko V.A., Lebedeva A.A.Copyright ©; 2021, Генс Г.П., Саникович В.Д., Милейко В.А., Лебедева А.А.2021Guens G.P., Sanikovich V.D., Mileyko V.A., Lebedeva A.A.Генс Г.П., Саникович В.Д., Милейко В.А., Лебедева А.А.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/380

Glioblastoma multiforme is the most common and malignant primary tumor of the central nervous system. Despite the existing modern complex therapy and advances in the study of molecular genetic changes in this tumor, the prognosis for patients with glioblastoma is one of the most unfavorable in oncology. This overview reviews existing therapeutic agents and clinical studies of potential drugs for the treatment of patients with glioblastoma multiforme.Next-generation sequencing has become firmly established in the clinical practice of oncologists and allows detecting gene mutations in tumor cells, some of which can serve as targets for therapy. Glioblastoma is characterized by a large number of potentially targeted molecular genetic disorders. As in the case of other solid tumors, targeted and immunotherapy for glioblastomas is being actively studied, including the combination of drugs with physical methods of exposure. To date, new treatment methods of glioblastoma, including antiangiogenic therapy, immunotherapy, oncolytic viral therapy and gene therapy still have uncertain or very modest clinical results. There are many reasons for the lack of progress in the treatment of glioblastoma – from the banal inability of most molecules to overcome the blood-brain barrier to the wide genetic heterogeneity of these tumors. The most promising direction of studies is immunotherapy. But at this stage, we cannot say that there is an effective monotherapy for glioblastoma. The combination treatment with radiation therapy and chemotherapy increases the mutational load, the expression of stress and other factors, therefore, the researchers pin great hopes on the combined methods of treatment.

Мультиформная глиобластома – наиболее распространенная злокачественная первичная опухоль центральной нервной системы. Несмотря на применение современной комплексной терапии и успехи в изучении молекулярно-генетических изменений данной опухоли, прогноз при этом заболевании является крайне неблагоприятным. В данном обзоре рассмотрены существующие терапевтические агенты и клинические исследования потенциальных препаратов для лечения пациентов с мультиформной глиобластомой. Секвенирование нового поколения прочно вошло в клиническую практику онкологов и позволяет определять мутации генов в клетках опухоли, часть из которых может служить мишенями для терапии. Глиобластома характеризуется большим количеством потенциально таргетируемых молекулярно-генетических нарушений. Как и в случае с другими солидными опухолями, активно изучается таргетная и иммунная терапия глиобластом, в том числе комбинация лекарственных препаратов с физическими методами воздействия. На сегодняшний день новые методы лечения глиобластомы, включая антиангиогенную, иммунную и генную терапию, все еще имеют неопределенные или весьма скромные клинические результаты. Причин этому много: от неспособности большинства молекул преодолеть гематоэнцефалический барьер, заканчивая широкой генетической гетерогенностью данных опухолей. Наиболее перспективным направлением является иммунотерапия. Однако на данном этапе нельзя утверждать, что существует эффективная монотерапия глиобластомы. Комбинация иммунотерапии с лучевой и химиотерапией повышает мутационную нагрузку, экспрессию стрессовых и других факторов, поэтому исследователи возлагают большие надежды именно на комбинированные методы лечения. 

glioblastomatargeted therapyimmunotherapynovel treatmentглиобластоматаргетная терапияиммунотерапияновые терапевтические стратегииWHO Classification of Tumours of the Central Nervous. System (Revised). Ed. by D.N. Louis, H. Ohgaki, O.D. Wiestler, W.K. Cavenee. 4th edn. Lyon: IARC, 2016. 408 p.Coleman N., Ameratunga M., Lopez J. Development of molecularly targeted agents and immunotherapies in glioblastoma: a personalized approach. Clin Med Insights Oncol 2018;12:1179554918759079. DOI: 10.1177/1179554918759079.Zhang H., Wang R., Yu Y., Liu J et al. Glioblastoma treatment modalities besides surgery. J Cancer 2019;10(20):4793–806. DOI: 10.7150/jca.32475.Kobyakov G.L., Bekyashev A.Kh., Golanov A.V. et al. Practical recommendations for the drug treatment of primary tumors of the central nervous system. Zlokachestvennye opuholi: Prakticheskie rekomendacii RUSSCO = Malignant tumors: Practical recommendations of RUSSCO 2018;8(3):83–99. Available at: https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-06.pdf. (In Russ.). DOI:10.18027/2224-5057-2017-7-3s2-77-92.Кобяков Г.Л., Бекяшев А.Х., Голанов А.В. и др. Практические рекомендации по лекарственному лечению первичных опухолей центральной нервной системы. Злокачественные опухоли: Практические рекомендации RUSSCO 2018;8(3):83–99. Доступно по: https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-06.pdf. DOI:10.18027/2224-5057-2017-7-3s2-77-92.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Central Nervous System Cancers. Version 2.2021. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf.Batchelor T. Initial postoperative therapy for glioblastoma and anaplastic astrocytoma. Availiable at: https://www.uptodate.com/contents/initial-treatment-and-prognosis-of-newly-diagnosed-glioblastoma-in-adults#H13374802.Inda M.M., Bonavia R., Seoane J. Glioblastoma multiforme: a look inside its heterogeneous nature. Cancer’s (Basel) 2014;6(1):226–39. DOI: 10.3390/cancers6010226(3).Krex D., Klink B., Hartmann C. et al. Long-term survival with glioblastoma multiforme. Brain 2007;130(Pt 10): 2596–606. DOI: 10.1093/brain/awm204.Batchelor T., Shih H.A., Carter B.S. Management of recurrent high-grade gliomas. Availiable at: https://www.uptodate.com/contents/management-of-recurrent-high-grade-gliomas.Batchelor T., Louis D.N. Molecular pathogenesis of diffuse gliomas. Availiable at: https://www.uptodate.com/contents/molecular-pathogenesis-of-diffuse-gliomas.Lobanova N.V., Shishkina L.V., Ryzhova M.V. et al. Clinical, immunohistochemical and molecular genetic prognostic factors in patients with glioblastoma. Arhiv patologii = Archive of Pathology 2016;78(4):10–9. (In Russ.). DOI: 10.17116/patol201678410-19.Лобанова Н.В., Шишкина Л.В., Рыжова М.В. и др. Клинические, иммуногистохимические и молекулярно-генетические факторы прогноза у больных c глиобластомой. Архив патологии 2016;78(4):10–9. DOI: 10.17116/patol201678410-19.Lewandowska M.A., Furtak J., Szylberg T. et al. An analysis of the prognostic value of IDH1 (isocitrate dehydrogenase 1) mutation in Polish glioma patients. Mol Diagn Ther 2014;18(1):45–53. DOI: 10.1007/s40291-013-0050-7.Рыжова М.В., Шишкина Л.В., Желудкова О.Г. и др. Сравнительная характеристика генетических аберраций в глиобластомах у детей и взрослых. Вопросы нейрохирургии им. Н.Н. Бурденко 2014;78(2):3–11.Thomas P.R., Recht L., Nagpal S. Advances in the management of glioblastoma: the role of temozolomide and MGMT testing. Clin Pharmacol 2013;5:1–9. DOI: 10.2147/CPAA.S26586.Morokoff A., Ng W., Gogos A., Kaye A.H. Molecular subtypes, stem cells and heterogeneity: implications for personalised therapy in glioma. J Clin Neurosci 2015;22(8):1219–26. DOI: 10.1016/j.jocn.2015.02.008(5).Wang X., Venugopal C., Singh S.K. Cancer stem cells in brain cancer. In: Cancer stem cells in solid tumors. Ed. by Alison L. Allan. Springer Science, Business Media, 2011. Pp. 37–56.Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Cancer Genome Atlas Research Network. Nature 2008;455(7216):1061–8. DOI: 10.1038/nature07385.Blumenthal D.T., Dvir A., Lossos A. et al. Clinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients. J Neurooncol 2016;130(1):211–9. DOI: 10.1007/s11060-016-2237-3.Neftel C., Laffy J., Filbin M.G. et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell 2019;178(4):835–49.e21. DOI: 10.1016/j.cell.2019.06.024.Yap T.A., Gerlinger M., Futreal P.A. et al. Intratumor heterogeneity: seeing the wood for the trees. Sci Transl Med 2012;4(127):127ps10. DOI: 10.1126/scitranslmed.3003854.Shergalis A., Bankhead A. 3th , Luesakul U. et al. Current challenges and opportunities in treating glioblastoma. Pharmacol Rev 2018;(70):412–45. DOI: 10.1124/pr.117.014944.Messaoudi K., Clavreul A,. Lagarce F. Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide. Drug Discov Today 2015;20(7):899–905. DOI: 10.1016/j.drudis.2015.02.011.Monticelli M., Zeppa P., Zenga F. et al. The post-surgical era of GBM: how molecular biology has impacted on our clinical management. A review. Clin Neurol Neurosurg 2018;170:120–6. DOI: 10.1016/j.clineuro.2018.05.015.Westphal M., Maire C.L., Lamszus K. EGFR as a target for glioblastoma treatment: an unfulfilled promise. CNS Drugs 2017;31(9):723–35. DOI: 10.1007/s40263-017-0456-6.Westphal M., Maire C.L., Lamszus K. EGFR as a target for glioblastoma treatment: an unfulfilled promise. CNS Drugs 2017;31(9):723–35. DOI: 10.1007/s40263-017-0456-6.Peereboom D.M., Shepard D.R., Ahluwalia M.S. et al. Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme. J Neurooncol 2010;98(1):93–9. DOI: 10.1007/s11060-009-0067-2.Raizer J.J., Abrey L.E., Lassman A.B. et al. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol 2010;12(1):95–103. DOI: 10.1093/neuonc/nop015.Raizer J.J., Giglio P., Hu J. et al. A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients. J Neurooncol 2016;126(1):185–92. DOI: 10.1007/s11060-015-1958-z.Wen P.Y., Chang S.M., Lamborn K.R. et al. Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02. Neuro Oncol 2014;16(4):567–78. DOI: 10.1093/neuonc/not247.Uhm J.H., Ballman K.V., Wu W. et al. Phase II evaluation of gefitinib in patients with newly diagnosed Grade 4 astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074. Int J Radiat Oncol Biol Phys 2011;80(2):347–53. DOI: 10.1016/j.ijrobp.2010.01.070.Chakravarti A., Wang M., Robins H.I. et al. RTOG 0211: a phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients. Int J Radiat Oncol Biol Phys 2013;85(5):1206–11. DOI: 10.1016/j.ijrobp.2012.10.008.Reardon D.A., Groves M.D., Wen P.Y. et al. A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma. Clin Cancer Res 2013;19(4):900–8. DOI: 10.1158/1078-0432.CCR-12-1707.Reardon D.A., Nabors L.B., Mason W.P. et al. Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma. Neuro Oncol 2015;17(3):430–9. DOI: 10.1093/neuonc/nou160.Neyns B., Sadones J., Joosens E. et al. Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann Oncol 2009;20(9): 1596–603. DOI: 10.1093/annonc/mdp032.Solomon M.T., Miranda N., Jorrín E. et al. Nimotuzumab in combination with radiotherapy in high grade glioma patients: a single institution experience. Cancer Biol Ther 2014;15(5):504–9. DOI: 10.4161/cbt.28021.Kleinschmidt-DeMasters B.K., Aisner D.L., Foreman N.K. BRAF VE1 immunoreactivity patterns in epithelioid glioblastomas positive for BRAF V600E mutation. Am J Surg Pathol 2015;39(4):528–40. DOI: 10.1097/PAS.0000000000000363.Vuong H.G., Altibi A.M.A., Duong U.N.P. et al. BRAF mutation is associated with an improved survival in glioma – a systematic review and meta-analysis. Mol Neurobiol 2018;55(5):3718–24. DOI: 10.1007/s12035-017-0599-y.Horbinski C., Nikiforova M.N., Hagenkord J.M. et al. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol 2012;14(6):777–89. DOI: 10.1093/neuonc/nos077.Burger M.C., Ronellenfitsch M.W., Lorenz N.I. et al. Dabrafenib in patients with recurrent, BRAF V600E mutated malignant glioma and leptomeningeal disease. Oncol Rep 2017;38(6):3291–6. DOI: 10.3892/or.2017.6013.Dasgupta T., Olow A.K., Yang X. et al. Survival advantage combining a BRAF inhibitor and radiation in BRAF V600Emutant glioma. J Neurooncol 2016;126(3):385–93. DOI: 10.1007/s11060-015-1939-2.Kanemaru Y., Natsumeda M., Okada M. et al. Dramatic response of BRAF V600Emutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy. Acta Neuropathol Commun 2019;7(1):119. DOI: 10.1186/s40478-019-0774-7.Kushnirsky M., Feun L.G., Gultekin S.H. et al. Prolonged complete response with combined dabrafenib and trametinib after BRAF inhibitor failure in BRAF-mutant glioblastoma. JCO Precision Oncology 2020;4(PO.19.00272):44–50. DOI: 10.1200/po.19.00272.Ceccon G., Werner J.M., Dunkl V. et al. Dabrafenib Treatment in a Patient with an Epithelioid Glioblastoma and BRAF V600E Mutation. Int J Mol Sci 2018;19(4):1090. DOI: 10.3390/ijms19041090.Mendes-Pereira A.M., Martin S.A., Brough R. et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO molecular medicine. 2009;1(6-7):315–22. DOI: 10.1002/emmm.200900041.Shen W.H., Balajee A.S., Wang J. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 2007;128(1):157–70. DOI: 10.1016/j.cell.2006.11.042.Hermanowski H., Huebert B., Aldrighetti C. et al. Role of PARylation and PTEN mutation on PARP and PARG inhibitor efficacy on glioblastoma. Available at: https://www.biorxiv.org/content/10.1101/2020.06.30.180216v1. DOI: 10.1101/2020.06.30.180216.Plummer R., Jones C., Middleton M. et al. Phase I study of the poly (ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 2008;14(23):7917–23. DOI: 10.1158/1078-0432.CCR-08-1223.Kleinberg L., Supko J.G., Mikkelsen T. et al. Phase I adult brain tumor consortium (ABTC) trial of ABT-888 (veliparib), temozolomide (TMZ), and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM) including pharmacokinetic (PK) data. J Clin Oncol. 2013;31 (Suppl. 15):2065. DOI: 10.1200/jco.2013.31.15_suppl.2065–2065.Clinical Trials.gov.identifier NCT03581292. Veliparib, radiation therapy, and temozolomide in treating patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations. Available at: https:// clinicaltrials.gov/ct2/show/ NCT03581292.Clinical Trials.gov.identifier NCT02152982. Temozolomide with or without veliparib in treating patients with newly diagnosed glioblastoma multiforme. Available at: https://clinicaltrials.gov/ct2/ show/NCT02152982.Gupta S.K., Smith E.J., Mladek A.C. et al. PARP inhibitors for sensitization of alkylation chemotherapy in glioblastoma: impact of blood-brain barrier and molecular heterogeneity. Front Oncol 2019;8:670. DOI: 10.3389/fonc.2018.00670.Lesueur P., Lequesne J., Grellard J.M. et al. Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZRTE-01 trial protocol. BMC Cancer 2019;19(1):198. DOI: 10.1186/s12885-019-5413-y.Clinical Trials.gov.identifier NCT03150862. A Study assessing pamiparib with radiation and/or temozolomide (TMZ) in participants with newly diagnosed or recurrent glioblastoma. Available at: https://clinicaltrials.gov/ct2/show/NCT03150862.Fulton B., Short S.C., James A. et al. PARADIGM-2: two parallel phase I studies of olaparib and radiotherapy or olaparib and radiotherapy plus temozolomide in patients with newly diagnosed glioblastoma, with treatment stratified by MGMT status. Clin Transl Radiat Oncol 2017;8:12–6. DOI: 10.1016/j.ctro.2017.11.003.Halford S.E.R., Cruickshank G., Dunn L. et al. Results of the OPARATIC trial: a phase I dose escalation study of olaparib in combination with temozolomide (TMZ) in patients with relapsed glioblastoma (GBM). J Clin Oncol 2017; 35(15_suppl):2022. DOI: 10.1200/jco.2017.35.15_suppl.2022.Wu S., Gao F., Zheng S. et al. EGFR amplification induces increased DNA damage response and renders selective sensitivity to talazoparib (PARP inhibitor) in glioblastoma. Clin Cancer Res 2020;26(6):1395–407. DOI: 10.1158/1078-0432.CCR-19-2549.Wang Y., Wild A.T., Turcan S. et al. Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDHmutant gliomas and cholangiocarcinomas. Sci Adv 2020;6(17). DOI: 10.1126/sciadv.aaz3221.Wen P.Y., de Groot J., Battiste J.D. et al. Abstract CT205: Phase 2 study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K / mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status. Cancer Res 2020;80(Suppl 6):vi23. DOI: 10.1093/neuonc/noy148.083.Wen P.Y., Touat M., Alexander B.M. et al. Buparlisib in patients with recurrent glioblastoma harboring phosphatidylinositol 3-kinase pathway activation: an openlabel, multicenter, multi-arm, phase II trial. J Clin Onc 2019;37(9):741–50. DOI: 10.1200/jco.18.01207.Reitman Z.J., Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 2010;102(13): 932–41. DOI: 10.1093/jnci/djq187.Parsons D.W., Jones S., Zhang X. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008;321(5897):1807–12. DOI: 10.1126/science.1164382.Yang H., Ye D., Guan K.L. et al. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res 2012;18(20):5562–71. DOI: 10.1158/1078-0432.CCR-12-1773.Huang J., Yu J., Tu L. et al. Isocitrate dehydrogenase mutations in glioma: from basic discovery to therapeutics development. Front Oncol 2019;9:506. DOI: 10.3389/fonc.2019.00506.Han S., Liu Y., Cai S.J. et al. IDH mutation in glioma: molecular mechanisms and potential therapeutic targets. British J Cancer 2020;122(11):1580–9. DOI: 10.1038/s41416-020-0814-x.Weller M., Felsberg J., Hartmann C. et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol 2009;27(34): 5743–50. DOI: 10.1200/JCO.2009.23.0805.Mellinghoff I.K., Ellingson B.M., Touat M. et al. Ivosidenib in isocitrate dehydrogenase 1-mutated advanced glioma. J Clin Oncol 2020;38(29):3398– 406. DOI: 10.1200/JCO.19.03327.Tejera D., Kushnirsky M., Gultekin S.H. et al. Ivosidenib, an IDH1 inhibitor, in a patient with recurrent, IDH1-mutant glioblastoma: a case report from a phase I study. CNS Oncol 2020;9(3):CNS62. DOI: 10.2217/cns-2020-0014.Mellinghoff I.K., Cloughesy T.F., Wen P.Y. et al. A phase I, open label, perioperative study of AG-120 and AG-881 in recurrent IDH1 mutant, low-grade glioma: results from cohort 1. J Clin Oncol 2019;37(15_suppl):2003. DOI: 10.1200/jco.2019.37.15_suppl.2003.Mellinghoff I.K., Cloughesy T.F., Wen P.Y. et al. A phase I, open label, perioperative study of AG-120 and AG-881 in recurrent IDH1 mutant, low-grade glioma: results from cohort 1. J Clin Oncol 2019;37(15_suppl):2003. DOI: 10.1200/jco.2019.37.15_suppl.2003.Kleber S., Sancho-Martinez I., Wiestler B. et al. Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell 2008;13(3):235–48. DOI: 10.1016/j.ccr.2008.02.003.Platten M., Fricke H., Junge K. et al. Final results of APG101_CD_002: APG101 plus reirradiation versus reirradiation in the treatment of patients with progressive glioblastoma. J Clin Oncol 2014;32(15_suppl):2006. DOI: 10.1200/jco.2014.32.15_suppl.2006.Kong X.T., Nguyen N.T., Choi J.Y. et al. Phase 2 study of bortezomib combined with temozolomide and regional radiation therapy for upfront treatment of patients with newly diagnosed glioblastoma multiforme: safety and efficacy assessment. Int J Radiat Oncol Biol Phys 2018;100(5):1195–203. DOI: 10.1016/j.ijrobp.2018.01.001.Clinical Trials.gov.identifier: NCT03345095. A phase iii trial of with marizomib in patients with newly diagnosed glioblastoma (MIRAGE). Available at: https://clinicaltrials.gov/ct2/show/NCT03345095.Yang I., Han S.J., Kaur G. et al. The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci 2010;17(1):6–10. DOI: 10.1016/j.jocn.2009.05.006.Karman J., Ling C., Sandor M. et al. Dendritic cells in the initiation of immune responses against central nervous systemderived antigens. Immunol Lett 2004;92(1–2):107–15. DOI: 10.1016/j.imlet.2003.10.017.Zeng J., See A.P., Phallen J. et al. AntiPD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys 2013;86:343–9. DOI: 10.1016/j.ijrobp.2012.12.025.Reardon D.A., Brandes A.A., Omuro A. et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the checkmate 143 phase 3 randomized clinical trial. JAMA Oncol 2020;6(7):1003–10. DOI: 10.1001/jamaoncol.2020.1024.Sampson J.H., Omuro A.M.P., Preusser M. et al. A randomized, phase 3, open-label study of nivolumab versus temozolomide (TMZ) in combination with radiotherapy (RT) in adult patients (pts) with newly diagnosed, O-6-methylguanine DNA methyltransferase (MGMT)-unmethylated glioblastoma (GBM): CheckMate-498. J Clin Oncol 2016;34(15):TPS2079. DOI: 10.1200/jco.2016.34.15_suppl. tps2079.Sampson J.H., Omuro A.M.P., Preusser M. et al. A randomized, phase 3, open-label study of nivolumab versus temozolomide (TMZ) in combination with radiotherapy (RT) in adult patients (pts) with newly diagnosed, O-6-methylguanine DNA methyltransferase (MGMT)-unmethylated glioblastoma (GBM): CheckMate-498. J Clin Oncol 2016;34(15):TPS2079. DOI: 10.1200/jco.2016.34.15_suppl. tps2079.Bristol-Myers Squibb provides update on phase 3 Opdivo (nivolumab) CheckMate-548 trial in patients with newly diagnosed MGMT-methylated glioblastoma multiforme. News release. Available at: https://news.bms.com/news/details/2020/Bristol-Myers-SquibbAnnounces-Update-on-Phase-3CheckMate-548-Trial-EvaluatingPatients-with-Newly-Diagnosed-MGMTMethylated-Glioblastoma-Multiforme/ default.aspx.Cloughesy T.F., Mochizuki A.Y., Orpilla J.R. et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med 2019;25(3):477–86. DOI: 10.1038/s41591-018-0337-7.Schalper K.A., Rodriguez-Ruiz M.E., Diez-Valle R. et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat Med 2019;25(3):470–6. DOI: 10.1038/s41591-018-0339-5.Zhao J., Chen A.X., Gartrell R.D. et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nat Med 2019;25(3):462–9. DOI: 10.1038/s41591-019-0349-y.Reardon D.A., Kaley T.J., Dietrich J. et al. Phase II study to evaluate safety and efficacy of MEDI4736 (durvalumab) + radiotherapy in patients with newly diagnosed unmethylated MGMT glioblastoma (new unmeth GBM). J Clin Oncol 2019;37(15_suppl):2032. DOI: 10.1200/jco.2019.37.15_suppl.2032.Jacques F.H., Nicholas G., Lorimer I. et al. Avelumab in newly diagnosed glioblastoma multiforme: The SEJ study. J Clin Oncol 2019;37(15_suppl):e13571. DOI: 10.1200/jco.2019.37.15_suppl. e13571.Kaufman H.L., Kohlhapp F.J., Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov 2015;14(9):642–62. DOI: 10.1038/nrd4663.Foreman P.M., Friedman G.K., Cassady K.A., Markert J.M. Oncolytic virotherapy for the treatment of malignant glioma. Neurotherapeutics 2017;14(2):333–44. DOI: 10.1007/s13311-017-0516-0.Philbrick B.D., Adamson D.C. Early clinical trials of Toca 511 and Toca FC show a promising novel treatment for recurrent malignant glioma. Expert Opin Investig Drugs 2019;28(3):207–16. DOI: 10.1080/13543784.2019.1572112.Markert J.M., Razdan S.N., Kuo H.C. et al. A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol Ther 2014;22(5):1048–55. DOI: 10.1038/mt.2014.22.Zadeh G., Lang F., Daras M. et al. Interim results of a phase II multicenter study of the conditionally replicative oncolytic adenovirus DNX-2401 with pembrolizumab (Keytruda) for recurrent glioblastoma; CAPTIVE study (KEYNOTE-192). Neuro Oncol 2018;20(Suppl 6):vi6. DOI: 10.1093/neuonc/noy148.019.Liau L.M., Ashkan K., Tran D.D. et al. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med 2018;16(1):142. DOI: 10.1186/s12967-018-1507-6.Liau L.M., Ashkan K., Tran D.D. et al. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med 2018;16:142. DOI: 10.1186/s12967-018-1507-6.Wen P.Y., Reardon D.A., Phuphanich S. et al. A randomized, double-blind, placebo-controlled phase 2 trial of dendritic cell (DC) vaccination with ICT-107 in newly diagnosed glioblastoma (GBM) patients. J Clin Oncol 2014;32:2005. DOI: 10.1200/jco.2014.32.15_suppl.2005.NCT01454596. CAR T cell receptor immunotherapy targeting EGFRvIII for patients with malignant gliomas expressing EGFRvIII. Available at: https:// clinicaltrials.gov/ct2/show/ NCT01454596.O’Rourke D.M., Nasrallah M., Morrissette J.J. et al. Pilot study of T cells redirected to EGFRvIII with a chimeric antigen receptor in patients with EGFRvIII+ glioblastoma. J Clin Oncol 2016;34(15_suppl):2067–2067. DOI: 10.1200/jco.2016.34.15_suppl.2067.Del Vecchio C.A., Li G., Wong A.J. Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Expert Rev Vaccines 2012;11(2):133–44. DOI: 10.1586/erv.11.177.Swartz A.M., Li Q.J., Sampson J.H. Rindopepimut: a promising immunotherapeutic for the treatment of glioblastoma multiforme. Immunotherapy 2014;6(6):679–90. DOI: 10.2217/imt.14.21.Rich J.N., Reardon D.A., Peery T. et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004;22(1):133–142. DOI: 10.1200/JCO.2004.08.110.Gan H.K., Papadopoulos K.P., Fichtel L. et al. Phase I study of ABT-414 monoor combination therapy with temozolomide (TMZ) in recurrent glioblastoma (GBM). ASCO Meet Abstr 2015;33:2016. DOI: 10.1200/JCO.2017.77.6385.Weller M., Butowski N., Tran D.D. et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIIIexpressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol 2017(10):1373–85. DOI: 10.1016/s1470-2045(17)30517-x.Wen P.Y., De Groot J.F., Battiste J.D. et al. Escalation portion of phase II study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K/mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status. J Clin Oncol 202038(15_suppl):2550. DOI: 10.1200/jco.2020.38.15_suppl.2550.Zadeh G., Lang F., Daras M. et al. Atim-24. Interim results of a phase II multicenter study of the conditionally replicative oncolytic adenovirus dnx-2401 with pembrolizumab (keytruda) for recurrent glioblastoma; captive study (keynote-192). Neuro Oncology 2018;20(suppl_6):vi6. DOI: 10.1093/neuonc/noy148.019.