Skip to main content
    • Aa
    • Aa

Immunological Aspects of Malignant Gliomas

  • Or Cohen-Inbar (a1) (a2) (a3) (a4) and Menashe Zaaroor (a1) (a2) (a3)

Glioblastoma Multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival time of <24 months. This figure remains constant, despite significant progress in medical research and treatment. The lack of an efficient anti-tumor immune response and the micro-invasive nature of the glioma malignant cells have been explained by a multitude of immune-suppressive mechanisms, proven in different models. These immune-resistant capabilities of the tumor result in a complex interplay this tumor shares with the immune system. We present a short review on the immunology of GBM, discussing the different unique pathological and molecular features of GBM, current treatment modalities, the principles of cancer immunotherapy and the link between GBM and melanoma. Current knowledge on immunological features of GBM, as well as immunotherapy past and current clinical trials, is discussed in an attempt to broadly present the complex and formidable challenges posed by GBM.


Aspects immunologiques des gliomes malins. Le glioblastome multiforme (GBM) est le plus fréquent des néoplasmes cérébraux primaires malins. La survie moyenne est de moins de 24 mois et demeure inchangée malgré les progrès importants réalisés par la recherche médicale et les essais thérapeutiques. L’absence de réponse immunitaire anti-tumeur efficace et la nature micro-invasive des cellules malignes du gliome ont été expliquées par une multitude de mécanismes immunosuppresseurs, démontrés dans différents modèles expérimentaux. L’immunorésistance de la tumeur donne lieu à une interaction complexe entre la tumeur et le système immunitaire. Nous présentons une courte revue de l’immunologie du GBM et nous discutons de ses caractéristiques anatomopathologiques et moléculaires uniques, des modalités actuelles de traitement, des principes de l’immunothérapie du cancer et du lien entre le GBM et le mélanome. Nous exposons les connaissances actuelles sur les caractéristiques immunologiques du GBM ainsi que les essais thérapeutiques antérieurs et actuels d’immunothérapie, afin d’esquisser quels sont les défis considérables et complexes que pose le GBM.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Immunological Aspects of Malignant Gliomas
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about sending content to Dropbox.

      Immunological Aspects of Malignant Gliomas
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about sending content to Google Drive.

      Immunological Aspects of Malignant Gliomas
      Available formats
Corresponding author
Correspondence to: Or Cohen-Inbar, 137 Yellowstone Drive, Charlottesville, VA 22903, USA. Email:
Hide All
3. AH Habberstad , T Lind-Landström , S Sundstrøm , SH Torp . Primary human glioblastomas - prognostic value of clinical and histopathological parameters. Clin Neuropathol. 2012;31:361-368.

4. JC Buckner . Factors influencing survival in high-grade gliomas. Semin Oncol. 2003;30:10-14.

5. R Stupp , WP Mason , MJ van den Bent , et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.

6. LM DeAngelis . Brain tumors. N Engl J Med. 2001;344:114-123.

7. KL Chaichana , H Zaidi , C Pendleton , et al. The efficacy of carmustine wafers for older patients with glioblastoma multiforme: prolonging survival. Neurol Res. 2011;33:759-764.

8. MJ McGirt , KD Than , JD Weingart , et al. Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg. 2009;110:583-588.

9. DT Nagasawa , F Chow , A Yew , W Kim , N Cremer , I Yang . Temozolomide and other potential agents for the treatment of glioblastoma multiforme. Neurosurg Clin N Am. 2012;23:307-322.

11. M Preusser , M Lim , DA Hafler , DA Reardon , JH Sampson . Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol. 2015, Sep;11(9):504–14.

12. CG Drake . Prostate cancer as a model for tumour immunotherapy. Nat Rev Immunol. 2010;10:580-593.

13. EJ Lipson , CG Drake . Ipilimumab: an anti-CTLA-4 anti-body for metastatic melanoma. Clin Cancer Res. 2011;17:6958-6962.

14. MA Patel , DM Pardoll . Concepts of immunotherapy for glioma. J Neurooncol. 2015;123:323-330.

16. RH Schwartz . T cell anergy. Annu Rev Immunol. 2003;21:305-334.

17. DJ Irvine , MA Purbhoo , M Krogsgaard , MM Davis . Direct observation of ligand recognition by T cells. Nature. 2002;419:845-849.

18. I Stefanova , JR Dorfman , RN Germain . Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature. 2002;420:429-434.

19. MM Davis , M Krogsgaard , JB Huppa , et al. Dynamics of cell surface molecules during T cell recognition. Annu Rev Biochem. 2003;72:717-742.

20. PR Walker , T Calzascia , PY Dietrich . All in the head: obstacles for immune rejection of brain tumours. Immunology. 2002;107:28-38.

21. R Hohlfeld , H Wekerle . Immunological update on multiple sclerosis. Curr Opin Neurol. 2001;14:299-304.

23. HG Fischer , U Bonifas , G Reichmann . Phenotype and functions of brain dendritic cells emerging during chronic infection of mice with Toxoplasma gondii. J Immunol. 2000;164:4826-4834.

24. LL Rubin , JM Staddon . The cell biology of the blood–brain barrier. Annu Rev Neurosci. 1999;22:11-28.

25. M Harris . Monoclonal antibodies as therapeutic agents for cancer. Lancet Oncol. 2004;5:292-302.

26. I Zafir-Lavie , Y Michaeli , Y Reiter . Novel antibodies as anticancer agents. Oncogene. 2007;26:3714-3733.

27. ID Davis . An overview of cancer immunotherapy. Immunol Cell Biol. 2000;78:179-195.

29. G Liu , H Ying , G Zeng , CJ Wheeler , KL Black , JS Yu . HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res. 2004;64:4980-4986.

30. JG Zhang , J Eguchi , CA Kruse , et al. Antigenic profiling of glioma cells to generate allogeneic vaccines or dendritic cell-based therapeutics. Clin Cancer Res. 2007;13:566-575.

31. S Saikali , T Avril , B Collet , et al. Expression of nine tumour antigens in a series of human glioblastoma multiforme: interest of EGFRvIII, IL-13Ralpha2, gp100 and TRP-2 for immunotherapy. J Neurooncol. 2007;81:139-148.

33. DL Silbergeld , RC Rostomily , EC Alvord Jr. The cause of death in patients with glioblastoma is multifactorial: clinical factors and autopsyfindings in 117 cases of supratentorial glioblastoma in adults. J Neurooncol. 1991;10:179-185.

34. MK Aghi , TT Batchelor , DN Louis , FG Barker , WT Curry Jr. Decreased rate of infection in glioblastoma patients with allelic loss of chromosome 10q. J Neurooncol. 2009;93:115-120.

35. AT Parsa , JS Waldron , A Panner , et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84-88.

37. PE Fecci , DA Mitchell , JF Whitesides , et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 2006;66:3294-3302.

39. AP See , JJ Parker , A Waziri . The role of regulatory T cells and microglia in Glioblastoma-associated immunosuppression. J Neurooncol. 2015;123:405-412.

42. DN Louis , EC Holland , JG Cairncross . Glioma classification: a molecular reappraisal. Am J Pathol. 2001;159:779-786.

44. V Pistoia , F Morandi , X Wang , S Ferrone . Soluble HLA-G: Are they clinically relevant? Semin Cancer Biol. 2007;17:469-479.

45. H Wiendl , M Mitsdoerffer , M Weller . Hide-and-seek in the brain: a role for HLA-G mediating immune privilege for glioma cells. Semin Cancer Biol. 2003;13:343-351.

46. A Das , WL Tan , J Teo , DR Smith . Expression of survivin in primary glioblastomas. J Cancer Res Clin Oncol. 2002;128:302-306.

48. A Zisakis , C Piperi , MS Themistocleous , et al. Comparative analysis of peripheral and localised cytokine secretion in glioblastoma patients. Cytokine. 2007;39:99-105.

50. Y Muragaki , T Maruyama , H Iseki , et al. Phase I/IIa trial of autologous formalin-fixed tumor vaccine concomitant with fractionated radiotherapy for newly diagnosed glioblastoma: clinical article. J Neurosurg. 2011;115:248-255.

51. G Palu , A Cavaggioni , P Calvi , et al. Gene therapy of glioblastoma multiforme via combined expression of suicide and cytokine genes: a pilot study in humans. Gene Ther. 1999;6:330-337.

52. RE Merchant , AJ Grant , LH Merchant , HF Young . Adoptive immunotherapy for recurrent glioblastoma multiforme using lymphokine activated killer cells and recombinant interleukin-2. Cancer. 1988;62:665-671.

54. L Ampie , W Choy , JB Lamano , S Fakurnejad , O Bloch , AT Parsa . Heat shock protein vaccines against glioblastoma: from bench to bedside. J Neurooncol. 2015;123:441-448.

55. SL Topalian , FS Hodi , JR Brahmer , et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.

56. JD Wolchok , H Kluger , MK Callahan , et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133.

57. SM Ansell , AM Lesokhin , I Borrello , et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311-319.

58. RJ Motzer , BI Rini , DF McDermott , et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015;33:1430-1437.

59. NA Rizvi , J Mazières , D Planchard , et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16:257-265.

62. AV Krauze , SD Myrehaug , MG Chang , et al. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma. Int J Radiat Oncol Biol Phys. 2015;92:986-992.

63. DA Wainwright , AL Chang , M Dey , et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res. 2014;20:5290-5301.

64. MG Castro , GJ Baker , PR Lowenstein . Blocking immunosuppressive checkpoints for glioma therapy: the more the Merrier! Clin Cancer Res. 2014;20:5147-5149.

66. G Denkberg , CJ Cohen , A Lev , P Chames , HR Hoogenboom , Y Reiter . Direct visualization of distinct T cell epitopes derived from a melanoma tumor-associated antigen by using human recombinant antibodies with MHC- restricted T cell receptor-like specificity. Proc Natl Acad Sci. 2002;99:9421-9426.

67. CJ Cohen , O Sarig , Y Yamano , U Tomaru , S Jacobson , Y Reiter . Direct phenotypic analysis of human MHC class I antigen presentation: visualization, quantitation, and in situ detection of human viral epitopes using peptide-specific, MHC-restricted human recombinant antibodies. J Immunol. 2003;170:4349-4361.

68. G Denkberg , E Klechevsky , Y Reiter . Modification of a tumor-derived peptide at an HLA-A2 anchor residue can alter the conformation of the MHC-peptide complex: probing with TCR-like recombinant antibodies. J Immunol. 2002;169:4399-4407.

71. LM Liau , RM Prins , SM Kiertscher , et al. Dendritic cell vaccination in glioblastoma patients induces systemic andintracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005;11:5515-5525.

72. JH Sampson , AB Heimberger , GE Archer , et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28:4722-4729.

73. T Schneider , R Gerhards , E Kirches , R Firsching . Preliminary results of active specific immunization with modified tumor cell vaccine in glioblastoma multiforme. J Neuro-Oncol. 2001;53:39-46.

74. HH Steiner , MM Bonsanto , P Beckhove , et al. Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit. J Clin Oncol. 2004;22:4272-4281.

75. E Ishikawa , K Tsuboi , T Yamamoto , et al. Clinical trial of autologous formalin-fixed tumor vaccine for Glioblastoma multiforme patients. Cancer Sci. 2007;98:1226-1233.

76. U Bogdahn , P Hau , G Stockhammer , et al. Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro-Oncol. 2011;13:132-142.

77. RE Merchant , DW McVicar , LH Merchant , HF Young . Treatment of recurrent malignant glioma by repeated intracerebral injections of human recombinant interleukin-2 alone or in combination with systemic interferon- α . Results of a phase I clinical trial. J Neuro-Oncol. 1992;12:75-83.

78. D Barba , SC Saris , C Holder , SA Rosenberg , EH. Oldfield LAK Intratumoral cell and interleukin-2 therapy of human gliomas. J Neurosurgery. 1989;70:175-182.

79. F Colombo , L Barzon , E Franchin , et al. Combined HSV-TK/IL-2 gene therapy in patients with recurrent glioblastoma multiforme: biological and clinical results. Cancer Gene Ther. 2005;12:835-848.

80. M Farkkila , J Jaaskelainen , M Kallio , et al. Randomised, controlled study of intratumoral recombinant γ –interferon treatment in newly diagnosed glioblastoma. Br J Cancer. 1994;70:138-141.

81. JE Wolff , S Wagner , C Reinert , et al. Maintenance treatment with interferon-gamma and low-dose cyclophosphamide for pediatric high-grade glioma. J Neuro-Oncol. 2006;79:315-321.

82. J Allen , R Packer , A Bleyer , P Zeltzer , M Prados , A Nirenberg . Recombinant interferon beta: a phase I-II trial in children with recurrent brain tumors. J Clin Oncol. 1991;9:783-788.

83. MR Fetell , EM Housepian , MW Oster , et al. Intratumor administration of beta-interferon in recurrent malignant gliomas. A Phase I clinical and laboratory study. Cancer. 1990;65:78-83.

84. MS Mahaley , EJ Dropcho , L Bertsch , T Tirey , GY Gillespie . Systemic beta-interferon therapy for recurrent gliomas: a brief report. J Neurosurgery. 1989;71:639-641.

85. JC Buckner , LD Brown , JW Kugler , et al. Phase II evaluation of recombinant interferon alpha and BCNU in recurrent glioma. J Neurosurgery. 1995;82:430-435.

86. JC Buckner , PJ Schomberg , WL McGinnis , et al. A Phase III study of radiation therapy plus carmustine with or without recombinant interferon- α in the treatment of patients with newly diagnosed high-grade glioma. Cancer. 2001;92:420-433.

87. JJ Olson , E McKenzie , M Skurski-Martin , Z Zhang , D Brat , S Phuphanich . Phase I analysis of BCNU-impregnated biodegradable polymer wafers followed by systemic interferon alfa-2b in adults with recurrent glioblastoma multiforme. J Neuro-Oncol. 2008;90:293-299.

88. H Okada , FS Lieberman , KA Walter , et al. Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas. J Transl Med. 2007;5:67.

90. T Kikuchi , Y Akasaki , T Abe , et al. Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12. J Immunother. 2004;27:452-459.

92. KO Lillehei , DH Mitchell , SD Johnson , EL McCleary , CA Kruse . Long-term follow-up of patients with recurrent malignant gliomas treated with adjuvant adoptive immunotherapy. Neurosurgery. 1991;28:16-23.

93. RL Hayes , M Koslow , EM Hiesiger , et al. Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma. Cancer. 1995;76:840-852.

94. RO Dillman , CM Duma , PM Schiltz , et al. Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma. J Immunother. 2004;27:398-404.

95. H Tsurushima , SQ Liu , K Tuboi , et al. Reduction of end-stage malignant glioma by injection with autologous cytotoxic T lymphocytes. Jap J Cancer Res. 1999;90:536-545.

97. C Jackson , J Ruzevick , J Phallen , Z Belcaid , M Lim . Challenges in Immunotherapy Presented by the Glioblastoma Multiforme Microenvironment. Clin Dev Immunol. 2011;2011:732413, doi: 10.1155/2011/732413. Epub 2011 Dec 10.

98. JP Caruso , O Cohen-Inbar , MH Bilsky , PC Gerszten , JP Sheehan . Stereotactic radiosurgery and immunotherapy for metastatic spinal melanoma. Neurosurg Focus. 2015;38:E6.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Canadian Journal of Neurological Sciences
  • ISSN: 0317-1671
  • EISSN: 2057-0155
  • URL: /core/journals/canadian-journal-of-neurological-sciences
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 32
Total number of PDF views: 161 *
Loading metrics...

Abstract views

Total abstract views: 527 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 19th October 2017. This data will be updated every 24 hours.