Journal of Neurology

, Volume 265, Issue 4, pp 741–756 | Cite as

Advances in immunotherapeutic research for glioma therapy

  • Jeremy Tetsuo Miyauchi
  • Stella E. TsirkaEmail author


Gliomas are primary malignancies of the brain. Tumors are staged based on malignancy, nuclear atypia, and infiltration of the surrounding brain parenchyma. Tumors are often diagnosed once patients become symptomatic, at which time the lesion is sizable. Glioblastoma (grade IV glioma) is highly aggressive and difficult to treat. Most tumors are diagnosed de novo. The gold standard of therapy, implemented over a decade ago, consists of fractionated radiotherapy and temozolomide, but unfortunately, chemotherapeutic resistance arises. Recurrence is common after initial therapy. The tumor microenvironment plays a large role in cancer progression and its manipulation can repress progression. The advent and implementation of immunotherapy, via manipulation and activation of cytotoxic T cells, have had an outstanding impact on reducing morbidity and mortality associated with peripheral cancers under certain clinical circumstances. An arsenal of immunotherapeutics is currently under clinical investigation for safety and efficacy in the treatment of newly diagnosed and recurrent high grade gliomas. These immunotherapeutics encompass antibody–drug conjugates, autologous infusions of modified chimeric antigen receptor expressing T cells, peptide vaccines, autologous dendritic cell vaccines, immunostimulatory viruses, oncolytic viruses, checkpoint blockade inhibitors, and drugs which alter the behavior of innate immune cells. Effort is focusing on determining which patient populations will benefit the most from these treatments and why. Research addressing synergism between treatment options is gaining attention. While advances in the treatment of glioma stagnated in the past, we may see a considerable evolution in the management of the disease in the upcoming years.


Glioma Immunotherapies Clinical trials 


Compliance with ethical standards


Financial supports are received from NIH R01NS42168, NIH T32GM007518, NIH T32GM008444, NIH F30CA196110.

Conflicts of interest

Both authors state that there are no conflicts of interest.


  1. 1.
    Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. JAMA 310:1842–1850CrossRefPubMedGoogle Scholar
  2. 2.
    Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R et al (2015) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol 17(Suppl 4):iv1–iv62CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Dubrow R, Darefsky AS (2011) Demographic variation in incidence of adult glioma by subtype, United States, 1992–2007. BMC Cancer 11:325CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Wang Z, Terakawa Y, Goto H, Tsuyuguchi N, Sato H et al (2016) Glioblastoma in long-term survivors of acute lymphoblastic leukemia: report of two cases. Pediatr Int 58:520–523CrossRefPubMedGoogle Scholar
  5. 5.
    Linet MS, Kim KP, Rajaraman P (2009) Children’s exposure to diagnostic medical radiation and cancer risk: epidemiologic and dosimetric considerations. Pediatr Radiol 39(Suppl 1):S4–S26CrossRefPubMedGoogle Scholar
  6. 6.
    Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL et al (2014) The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol 16:896–913CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Hou L, Veeravagu A, Hsu A, Tse V (2006) Recurrent glioblastoma multiforme: a review of natural history and management options. Neurosurg Focus 20:E3CrossRefGoogle Scholar
  8. 8.
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMedGoogle Scholar
  10. 10.
    Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507CrossRefPubMedGoogle Scholar
  11. 11.
    da Fonseca AC, Badie B (2013) Microglia and macrophages in malignant gliomas: recent discoveries and implications for promising therapies. Clin Dev Immunol 2013:264124PubMedGoogle Scholar
  12. 12.
    Schneider SW, Ludwig T, Tatenhorst L, Braune S, Oberleithner H et al (2004) Glioblastoma cells release factors that disrupt blood–brain barrier features. Acta Neuropathol 107:272–276CrossRefPubMedGoogle Scholar
  13. 13.
    Wolburg H, Noell S, Fallier-Becker P, Mack AF, Wolburg-Buchholz K (2012) The disturbed blood-brain barrier in human glioblastoma. Mol Asp Med 33:579–589CrossRefGoogle Scholar
  14. 14.
    Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT (2007) Angiogenesis in brain tumours. Nat Rev Neurosci 8:610–622CrossRefPubMedGoogle Scholar
  15. 15.
    Wolf RL, Wang J, Wang S, Melhem ER, O’Rourke DM et al (2005) Grading of CNS neoplasms using continuous arterial spin labeled perfusion MR imaging at 3 Tesla. J Magn Reson Imaging 22:475–482CrossRefPubMedGoogle Scholar
  16. 16.
    Alliot F, Godin I, Pessac B (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 117:145–152CrossRefPubMedGoogle Scholar
  17. 17.
    Chang AL, Miska J, Wainwright DA, Dey M, Rivetta CV et al (2016) CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res 76(19):5671–5682CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Domingues P, Gonzalez-Tablas M, Otero A, Pascual D, Miranda D et al (2016) Tumor infiltrating immune cells in gliomas and meningiomas. Brain Behav Immun 53:1–15CrossRefPubMedGoogle Scholar
  19. 19.
    Yang SH, Hong YK, Yoon SC, Kim BS, Lee YS et al (2007) Radiotherapy plus concurrent and adjuvant procarbazine, lomustine, and vincristine chemotherapy for patients with malignant glioma. Oncol Rep 17:1359–1364PubMedGoogle Scholar
  20. 20.
    Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR et al (2016) Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 374:1344–1355CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT et al (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Phillips AC, Boghaert ER, Vaidya KS, Mitten MJ, Norvell S et al (2016) ABT-414, an antibody–drug conjugate targeting a tumor-selective EGFR epitope. Mol Cancer Ther 15:661–669CrossRefPubMedGoogle Scholar
  23. 23.
    Larson SM, Carrasquillo JA, Cheung NK, Press OW (2015) Radioimmunotherapy of human tumours. Nat Rev Cancer 15:347–360CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Newick K, Moon E, Albelda SM (2016) Chimeric antigen receptor T-cell therapy for solid tumors. Mol Ther Oncolytics 3:16006CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Ren PP, Li M, Li TF, Han SY (2017) Anti-EGFRvIII chimeric antigen receptor-modified T cells for adoptive cell therapy of glioblastoma. Curr Pharm Des 23(14):2113–2116CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR et al (2016) Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med 375:2561–2569CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Platten M, Offringa R (2015) Cancer immunotherapy: exploiting neoepitopes. Cell Res 25:887–888CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Swartz AM, Li QJ, Sampson JH (2014) Rindopepimut: a promising immunotherapeutic for the treatment of glioblastoma multiforme. Immunotherapy 6:679–690CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Malkki H (2016) Trial watch: glioblastoma vaccine therapy disappointment in phase III trial. Nat Rev Neurol 12:190CrossRefPubMedGoogle Scholar
  30. 30.
    Wood CG, Mulders P (2009) Vitespen: a preclinical and clinical review. Future Oncol 5:763–774CrossRefPubMedGoogle Scholar
  31. 31.
    Schijns VE, Pretto C, Devillers L, Pierre D, Hofman FM et al (2015) First clinical results of a personalized immunotherapeutic vaccine against recurrent, incompletely resected, treatment-resistant glioblastoma multiforme (GBM) tumors, based on combined allo- and auto-immune tumor reactivity. Vaccine 33:2690–2696CrossRefPubMedGoogle Scholar
  32. 32.
    Phuphanich S, Rudnick J, Chu R, Mazer M, Wang H et al (2009) A phase I trial of tumor-associated antigen-pulsed dendritic cell immunotherapy for patients with brain stem glioma and glioblastoma. J Clin Oncol 27:2032Google Scholar
  33. 33.
    Garg AD, Vandenberk L, Koks C, Verschuere T, Boon L et al (2016) Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma. Sci Transl Med 8:328ra27CrossRefPubMedGoogle Scholar
  34. 34.
    Akimoto J (2016) Photodynamic therapy for malignant brain tumors. Neurol Med Chir (Tokyo) 56:151–157CrossRefGoogle Scholar
  35. 35.
    Bedrosian I, Mick R, Xu S, Nisenbaum H, Faries M et al (2003) Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol 21:3826–3835CrossRefPubMedGoogle Scholar
  36. 36.
    Polyzoidis S, Ashkan K (2014) DCVax(R)-L–developed by Northwest biotherapeutics. Hum Vaccines Immunother 10:3139–3145CrossRefGoogle Scholar
  37. 37.
    Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H et al (2013) Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother 62:125–135CrossRefPubMedGoogle Scholar
  38. 38.
    Yang L, Guo G, Niu XY, Liu J (2015) Dendritic cell-based immunotherapy treatment for glioblastoma multiforme. Biomed Res Int 2015:717530PubMedCentralPubMedGoogle Scholar
  39. 39.
    Goetz C, Dobrikova E, Shveygert M, Dobrikov M, Gromeier M (2011) Oncolytic poliovirus against malignant glioma. Future Virol 6:1045–1058CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Saha D, Ahmed SS, Rabkin SD (2015) Exploring the antitumor effect of virus in malignant glioma. Drugs Future 40:739–749CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Ji N, Weng D, Liu C, Gu Z, Chen S et al (2016) Adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of recurrent high-grade glioma. Oncotarget 7:4369–4378PubMedGoogle Scholar
  42. 42.
    Lasek W, Zagozdzon R, Jakobisiak M (2014) Interleukin 12: still a promising candidate for tumor immunotherapy? Cancer Immunol Immunother 63:419–435CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Chiu TL, Wang MJ, Su CC (2012) The treatment of glioblastoma multiforme through activation of microglia and TRAIL induced by rAAV2-mediated IL-12 in a syngeneic rat model. J Biomed Sci 19:45CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    He Y, Rivard CJ, Rozeboom L, Yu H, Ellison K et al (2016) Lymphocyte-activation gene-3, an important immune checkpoint in cancer. Cancer Sci 107:1193–1197CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I et al (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25:9543–9553CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC et al (2013) Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest 123:2447–2463CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ et al (2016) Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol Res 4:124–135CrossRefPubMedGoogle Scholar
  48. 48.
    Wang Z, Zhang C, Liu X, Wang Z, Sun L et al (2016) Molecular and clinical characterization of PD-L1 expression at transcriptional level via 976 samples of brain glioma. Oncoimmunology 5:e1196310CrossRefPubMedCentralPubMedGoogle Scholar
  49. 49.
    De Palma M, Lewis CE (2013) Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23:277–286CrossRefPubMedGoogle Scholar
  50. 50.
    Johanns TM, Miller CA, Dorward IG, Tsien C, Chang E et al (2016) Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov 6:1230–1236CrossRefPubMedCentralPubMedGoogle Scholar
  51. 51.
    Graeber MB, Scheithauer BW, Kreutzberg GW (2002) Microglia in brain tumors. Glia 40:252–259CrossRefPubMedGoogle Scholar
  52. 52.
    Cai J, Zhang W, Yang P, Wang Y, Li M et al (2015) Identification of a 6-cytokine prognostic signature in patients with primary glioblastoma harboring M2 microglia/macrophage phenotype relevance. PLoS ONE 10:e0126022CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    Zhai H, Heppner FL, Tsirka SE (2011) Microglia/macrophages promote glioma progression. Glia 59:472–485CrossRefPubMedGoogle Scholar
  54. 54.
    Du R, Lu KV, Petritsch C, Liu P, Ganss R et al (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    Li M, Li Z, Ren H, Jin WN, Wood K et al (2016) Colony stimulating factor 1 receptor inhibition eliminates microglia and attenuates brain injury after intracerebral hemorrhage. J Cereb Blood Flow Metab 37(7):2383–2395CrossRefPubMedCentralPubMedGoogle Scholar
  56. 56.
    Stafford JH, Hirai T, Deng L, Chernikova SB, Urata K et al (2016) Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization. Neuro Oncol 18:797–806CrossRefPubMedGoogle Scholar
  57. 57.
    Butowski N, Colman H, De Groot JF, Omuro AM, Nayak L et al (2016) Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro Oncol 18:557–564CrossRefPubMedGoogle Scholar
  58. 58.
    Katoh H, Watanabe M (2015) Myeloid-derived suppressor cells and therapeutic strategies in cancer. Mediat Inflamm 2015:159269CrossRefGoogle Scholar
  59. 59.
    Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L et al (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264–1272CrossRefPubMedCentralPubMedGoogle Scholar
  60. 60.
    Kloepper J, Riedemann L, Amoozgar Z, Seano G, Susek K et al (2016) Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc Natl Acad Sci USA 113:4476–4481CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    Sarkar S, Doring A, Zemp FJ, Silva C, Lun X et al (2014) Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells. Nat Neurosci 17:46–55CrossRefPubMedGoogle Scholar
  62. 62.
    Xu S, Wei J, Wang F, Kong LY, Ling XY et al (2014) Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma. J Natl Cancer Inst. Google Scholar
  63. 63.
    Frei K, Gramatzki D, Tritschler I, Schroeder JJ, Espinoza L et al (2015) Transforming growth factor-beta pathway activity in glioblastoma. Oncotarget 6:5963–5977CrossRefPubMedCentralPubMedGoogle Scholar
  64. 64.
    Maxwell M, Galanopoulos T, Neville-Golden J, Antoniades HN (1992) Effect of the expression of transforming growth factor-beta 2 in primary human glioblastomas on immunosuppression and loss of immune surveillance. J Neurosurg 76:799–804CrossRefPubMedGoogle Scholar
  65. 65.
    Platten M, Wick W, Weller M (2001) Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. Microsc Res Tech 52:401–410CrossRefPubMedGoogle Scholar
  66. 66.
    Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R et al (2005) Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA 102:419–424CrossRefPubMedGoogle Scholar
  67. 67.
    Thomas DA, Massague J (2005) TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8:369–380CrossRefPubMedGoogle Scholar
  68. 68.
    Wesolowska A, Kwiatkowska A, Slomnicki L, Dembinski M, Master A et al (2008) Microglia-derived TGF-beta as an important regulator of glioblastoma invasion–an inhibition of TGF-beta-dependent effects by shRNA against human TGF-beta type II receptor. Oncogene 27:918–930CrossRefPubMedGoogle Scholar
  69. 69.
    Uhl M, Aulwurm S, Wischhusen J, Weiler M, Ma JY et al (2004) SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res 64:7954–7961CrossRefPubMedGoogle Scholar
  70. 70.
    Ueda R, Fujita M, Zhu X, Sasaki K, Kastenhuber ER et al (2009) Systemic inhibition of transforming growth factor-beta in glioma-bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Clin Cancer Res 15:6551–6559CrossRefPubMedCentralPubMedGoogle Scholar
  71. 71.
    Rodon J, Carducci MA, Sepulveda-Sanchez JM, Azaro A, Calvo E et al (2015) First-in-human dose study of the novel transforming growth factor-beta receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res 21:553–560CrossRefPubMedGoogle Scholar
  72. 72.
    Hagner PR, Man HW, Fontanillo C, Wang M, Couto S et al (2015) CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood 126:779–789CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Program in Molecular and Cellular Pharmacology, Department of PharmacologyStony Brook UniversityStony BrookUSA

Personalised recommendations