Skip to main content

Advertisement

Log in

Vaccine therapies for patients with glioblastoma

  • Topic Review
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Glioblastoma (GBM) is a high-grade glial tumor with an extremely aggressive clinical course and a median overall survival of only 14.6 months following maximum surgical resection and adjuvant chemoradiotherapy. A central feature of this disease is local and systemic immunosuppression, and defects in patient immune systems are closely associated with tumor progression. Immunotherapy has emerged as an important adjuvant in the therapeutic armamentarium of clinicians caring for patients with GBM. The fundamental aim of immunotherapy is to augment the host antitumor immune response. Active immunotherapy utilizes vaccines to stimulate adaptive immunity against tumor-associated antigens. A vast array of vaccine strategies have advanced from preclinical study to active clinical trials in patients with recurrent or newly diagnosed GBM, including those that employ peptides, heat shock proteins, autologous tumor cells, and dendritic cells. In this review, the rationale for glioma immunotherapy is outlined, and the prevailing forms of vaccine therapy are described.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330

    PubMed  CAS  Google Scholar 

  2. Selznick LA, Shamji MF, Fecci P, Gromeier M, Friedman AH, Sampson J (2008) Molecular strategies for the treatment of malignant glioma–genes, viruses, and vaccines. Neurosurg Rev 31:141–155. doi:10.1007/s10143-008-0121-0 discussion 155

    PubMed  PubMed Central  Google Scholar 

  3. Jackson C, Ruzevick J, Brem H, Lim M (2013) Vaccine strategies for glioblastoma: progress and future directions. Immunotherapy 5:155–167. doi:10.2217/imt.12.155

    PubMed  CAS  PubMed Central  Google Scholar 

  4. Tanaka S, Louis DN, Curry WT, Batchelor TT, Dietrich J (2013) Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat Rev Clin Oncol 10:14–26. doi:10.1038/nrclinonc.2012.204

    PubMed  CAS  Google Scholar 

  5. Ji J, Black KL, Yu JS (2010) Glioma stem cell research for the development of immunotherapy. Neurosurg Clin N Am 21:159–166. doi:10.1016/j.nec.2009.08.006

    PubMed  PubMed Central  Google Scholar 

  6. Dunn GP, Fecci PE, Curry WT (2012) Cancer immunoediting in malignant glioma. Neurosurgery 71:201–222. doi:10.1227/NEU.0b013e31824f840d discussion 222–203

    PubMed  Google Scholar 

  7. Bloch O, Crane CA, Kaur R, Safaee M, Rutkowski MJ, Parsa AT (2013) Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin Cancer Res 19:3165–3175. doi:10.1158/1078-0432.ccr-12-3314

    PubMed  CAS  PubMed Central  Google Scholar 

  8. Ullen H, Blom U, Blomgren H, von Holst H (1986) Blood lymphocyte subsets in patients with primary intracranial tumours. Correlation to histological tumour type and anatomical site. Acta Neurochir (Wien) 81:100–105

    CAS  Google Scholar 

  9. Bodmer S, Strommer K, Frei K, Siepl C, de Tribolet N, Heid I, Fontana A (1989) Immunosuppression and transforming growth factor-beta in glioblastoma. Preferential production of transforming growth factor-beta 2. J Immunol 143:3222–3229

    PubMed  CAS  Google Scholar 

  10. Dix AR, Brooks WH, Roszman TL, Morford LA (1999) Immune defects observed in patients with primary malignant brain tumors. J Neuroimmunol 100:216–232

    PubMed  CAS  Google Scholar 

  11. Morford LA, Dix AR, Brooks WH, Roszman TL (1999) Apoptotic elimination of peripheral T lymphocytes in patients with primary intracranial tumors. J Neurosurg 91:935–946. doi:10.3171/jns.1999.91.6.0935

    PubMed  CAS  Google Scholar 

  12. Zou JP, Morford LA, Chougnet C, Dix AR, Brooks AG, Torres N, Shuman JD, Coligan JE, Brooks WH, Roszman TL, Shearer GM (1999) Human glioma-induced immunosuppression involves soluble factor(s) that alters monocyte cytokine profile and surface markers. J Immunol 162:4882–4892

    PubMed  CAS  Google Scholar 

  13. Roszman TL, Brooks WH, Elliott LH (1987) Inhibition of lymphocyte responsiveness by a glial tumor cell-derived suppressive factor. J Neurosurg 67:874–879. doi:10.3171/jns.1987.67.6.0874

    PubMed  CAS  Google Scholar 

  14. Elliott LH, Brooks WH, Roszman TL (1984) Cytokinetic basis for the impaired activation of lymphocytes from patients with primary intracranial tumors. J Immunol 132:1208–1215

    PubMed  CAS  Google Scholar 

  15. Elliott LH, Brooks WH, Roszman TL (1992) Suppression of high affinity IL-2 receptors on mitogen activated lymphocytes by glioma-derived suppressor factor. J Neurooncol 14:1–7

    PubMed  CAS  Google Scholar 

  16. Kohanbash G, McKaveney K, Sakaki M, Ueda R, Mintz AH, Amankulor N, Fujita M, Ohlfest JR, Okada H (2013) GM-CSF promotes the immunosuppressive activity of glioma-infiltrating myeloid cells through interleukin-4 receptor-alpha. Cancer Res 73:6413–6423. doi:10.1158/0008-5472.can-12-4124

    PubMed  CAS  Google Scholar 

  17. Yang T, Witham TF, Villa L, Erff M, Attanucci J, Watkins S, Kondziolka D, Okada H, Pollack IF, Chambers WH (2002) Glioma-associated hyaluronan induces apoptosis in dendritic cells via inducible nitric oxide synthase: implications for the use of dendritic cells for therapy of gliomas. Cancer Res 62:2583–2591

    PubMed  CAS  Google Scholar 

  18. Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, Herndon JE 2nd, Bigner DD, Dranoff G, Sampson JH (2006) Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 66:3294–3302. doi:10.1158/0008-5472.can-05-3773

    PubMed  CAS  Google Scholar 

  19. Pellegatta S, Cuppini L, Finocchiaro G (2011) Brain cancer immunoediting: novel examples provided by immunotherapy of malignant gliomas. Expert Rev Anticancer Ther 11:1759–1774. doi:10.1586/era.11.102

    PubMed  CAS  Google Scholar 

  20. Burnet FM (1970) The concept of immunological surveillance. Prog Exp Tumor Res 13:1–27

    PubMed  CAS  Google Scholar 

  21. Dunn GP, Koebel CM, Schreiber RD (2006) Interferons, immunity and cancer immunoediting. Nat Rev Immunol 6:836–848

    PubMed  CAS  Google Scholar 

  22. Bullard DE, Gillespie GY, Mahaley MS, Bigner DD (1986) Immunobiology of human gliomas. Semin Oncol 13:94–109

    PubMed  CAS  Google Scholar 

  23. Colombo F, Barzon L, Franchin E, Pacenti M, Pinna V, Danieli D, Zanusso M, Palu G (2005) Combined HSV-TK/IL-2 gene therapy in patients with recurrent glioblastoma multiforme: biological and clinical results. Cancer Gene Ther 12:835–848. doi:10.1038/sj.cgt.7700851

    PubMed  CAS  Google Scholar 

  24. Medawar PB (1948) Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 29:58–69

    PubMed  CAS  PubMed Central  Google Scholar 

  25. Stevens A, Kloter I, Roggendorf W (1988) Inflammatory infiltrates and natural killer cell presence in human brain tumors. Cancer 61:738–743

    PubMed  CAS  Google Scholar 

  26. Knopf PM, Cserr HF, Nolan SC, Wu TY, Harling-Berg CJ (1995) Physiology and immunology of lymphatic drainage of interstitial and cerebrospinal fluid from the brain. Neuropathol Appl Neurobiol 21:175–180

    PubMed  CAS  Google Scholar 

  27. Jackson C, Ruzevick J, Phallen J, Belcaid Z, Lim M (2011) Challenges in immunotherapy presented by the glioblastoma multiforme microenvironment. Clin Dev Immunol 2011:732413. doi:10.1155/2011/732413

    PubMed  PubMed Central  Google Scholar 

  28. Zuber P, Kuppner MC, De Tribolet N (1988) Transforming growth factor-beta 2 down-regulates HLA-DR antigen expression on human malignant glioma cells. Eur J Immunol 18:1623–1626. doi:10.1002/eji.1830181023

    PubMed  CAS  Google Scholar 

  29. Mehling M, Simon P, Mittelbronn M, Meyermann R, Ferrone S, Weller M, Wiendl H (2007) WHO grade associated downregulation of MHC class I antigen-processing machinery components in human astrocytomas: does it reflect a potential immune escape mechanism? Acta Neuropathol 114:111–119. doi:10.1007/s00401-007-0231-8

    PubMed  CAS  Google Scholar 

  30. El Andaloussi A, Lesniak MS (2006) An increase in CD4+ CD25+ FOXP3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme. Neuro Oncol 8:234–243. doi:10.1215/15228517-2006-006

    PubMed  PubMed Central  Google Scholar 

  31. Jacobs JF, Idema AJ, Bol KF, Nierkens S, Grauer OM, Wesseling P, Grotenhuis JA, Hoogerbrugge PM, de Vries IJ, Adema GJ (2009) Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors. Neuro Oncol 11:394–402. doi:10.1215/15228517-2008-104

    PubMed  CAS  PubMed Central  Google Scholar 

  32. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO (2007) Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13:84–88. doi:10.1038/nm1517

    PubMed  CAS  Google Scholar 

  33. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800. doi:10.1038/nm730

    PubMed  CAS  Google Scholar 

  34. Zisakis A, Piperi C, Themistocleous MS, Korkolopoulou P, Boviatsis EI, Sakas DE, Patsouris E, Lea RW, Kalofoutis A (2007) Comparative analysis of peripheral and localised cytokine secretion in glioblastoma patients. Cytokine 39:99–105. doi:10.1016/j.cyto.2007.05.012

    PubMed  CAS  Google Scholar 

  35. Joseph JV, Balasubramaniyan V, Walenkamp A, Kruyt FA (2013) TGF-beta as a therapeutic target in high grade gliomas: promises and challenges. Biochem Pharmacol 85:478–485. doi:10.1016/j.bcp.2012.11.005

    PubMed  CAS  Google Scholar 

  36. Lalier L, Cartron PF, Pedelaborde F, Olivier C, Loussouarn D, Martin SA, Meflah K, Menanteau J, Vallette FM (2007) Increase in PGE2 biosynthesis induces a Bax dependent apoptosis correlated to patients’ survival in glioblastoma multiforme. Oncogene 26:4999–5009. doi:10.1038/sj.onc.1210303

    PubMed  CAS  Google Scholar 

  37. Kong LY, Abou-Ghazal MK, Wei J, Chakraborty A, Sun W, Qiao W, Fuller GN, Fokt I, Grimm EA, Schmittling RJ, Archer GE Jr, Sampson JH, Priebe W, Heimberger AB (2008) A novel inhibitor of signal transducers and activators of transcription 3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells. Clin Cancer Res 14:5759–5768. doi:10.1158/1078-0432.ccr-08-0377

    PubMed  CAS  PubMed Central  Google Scholar 

  38. Garner JM, Fan M, Yang CH, Du Z, Sims M, Davidoff AM, Pfeffer LM (2013) Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappaB signaling in glioblastoma cancer stem cells regulates the Notch pathway. J Biol Chem 288:26167–26176. doi:10.1074/jbc.M113.477950

    PubMed  CAS  PubMed Central  Google Scholar 

  39. Liang Q, Ma C, Zhao Y, Gao G, Ma J (2013) Inhibition of STAT3 reduces astrocytoma cell invasion and constitutive activation of STAT3 predicts poor prognosis in human astrocytoma. PLoS One 8:e84723. doi:10.1371/journal.pone.0084723

    PubMed  PubMed Central  Google Scholar 

  40. Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, Pilozzi E, Larocca LM, Peschle C, De Maria R (2006) Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ 13:1238–1241. doi:10.1038/sj.cdd.4401872

    PubMed  CAS  Google Scholar 

  41. Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, Lichter P, Unterberg A, Radlwimmer B, Herold-Mende CC (2008) Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14:123–129. doi:10.1158/1078-0432.ccr-07-0932

    PubMed  CAS  Google Scholar 

  42. Learn CA, Fecci PE, Schmittling RJ, Xie W, Karikari I, Mitchell DA, Archer GE, Wei Z, Dressman H, Sampson JH (2006) Profiling of CD4+, CD8+, and CD4+ CD25+ CD45RO+ FoxP3+ T cells in patients with malignant glioma reveals differential expression of the immunologic transcriptome compared with T cells from healthy volunteers. Clin Cancer Res 12:7306–7315. doi:10.1158/1078-0432.ccr-06-1727

    PubMed  CAS  Google Scholar 

  43. Sampson JH, Schmittling RJ, Archer GE, Congdon KL, Nair SK, Reap EA, Desjardins A, Friedman AH, Friedman HS, Herndon JE 2nd, Coan A, McLendon RE, Reardon DA, Vredenburgh JJ, Bigner DD, Mitchell DA (2012) A pilot study of IL-2Ralpha blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma. PLoS One 7:e31046. doi:10.1371/journal.pone.0031046

    PubMed  CAS  PubMed Central  Google Scholar 

  44. Komohara Y, Ohnishi K, Kuratsu J, Takeya M (2008) Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 216:15–24. doi:10.1002/path.2370

    PubMed  CAS  Google Scholar 

  45. Prosniak M, Harshyne LA, Andrews DW, Kenyon LC, Bedelbaeva K, Apanasovich TV, Heber-Katz E, Curtis MT, Cotzia P, Hooper DC (2013) Glioma grade is associated with the accumulation and activity of cells bearing M2 monocyte markers. Clin Cancer Res 19:3776–3786. doi:10.1158/1078-0432.ccr-12-1940

    PubMed  CAS  Google Scholar 

  46. Wainwright DA, Sengupta S, Han Y, Ulasov IV, Lesniak MS (2010) The presence of IL-17A and T helper 17 cells in experimental mouse brain tumors and human glioma. PLoS One 5:e15390. doi:10.1371/journal.pone.0015390

    PubMed  PubMed Central  Google Scholar 

  47. Rock KL, Shen L (2005) Cross-presentation: underlying mechanisms and role in immune surveillance. Immunol Rev 207:166–183. doi:10.1111/j.0105-2896.2005.00301.x

    PubMed  CAS  Google Scholar 

  48. Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, Mellman I, Prindiville SA, Viner JL, Weiner LM, Matrisian LM (2009) The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res 15:5323–5337. doi:10.1158/1078-0432.ccr-09-0737

    PubMed  Google Scholar 

  49. Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H, Nuno MA, Richardson JE, Fan X, Ji J, Chu RM, Bender JG, Hawkins ES, Patil CG, Black KL, Yu JS (2013) Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother 62:125–135. doi:10.1007/s00262-012-1319-0

    PubMed  CAS  PubMed Central  Google Scholar 

  50. Neidert MC, Schoor O, Trautwein C, Trautwein N, Christ L, Melms A, Honegger J, Rammensee HG, Herold-Mende C, Dietrich PY, Stevanovic S (2013) Natural HLA class I ligands from glioblastoma: extending the options for immunotherapy. J Neurooncol 111:285–294. doi:10.1007/s11060-012-1028-8

    PubMed  CAS  Google Scholar 

  51. Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 89:2965–2969

    PubMed  CAS  PubMed Central  Google Scholar 

  52. Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuller GN, Archer GE, Friedman HS, Kwatra MM, Bigner SH, Bigner DD (1990) Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci USA 87:4207–4211

    PubMed  CAS  PubMed Central  Google Scholar 

  53. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE 2nd, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD (2010) 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 28:4722–4729. doi:10.1200/jco.2010.28.6963

    PubMed  PubMed Central  Google Scholar 

  54. Mitchell DA, Sampson JH (2009) Toward effective immunotherapy for the treatment of malignant brain tumors. Neurotherapeutics 6:527–538. doi:10.1016/j.nurt.2009.04.003

    PubMed  CAS  PubMed Central  Google Scholar 

  55. Yamanaka R (2009) Dendritic-cell- and peptide-based vaccination strategies for glioma. Neurosurg Rev 32:265–273. doi:10.1007/s10143-009-0189-1 discussion 273

    PubMed  Google Scholar 

  56. Agashe VR, Hartl FU (2000) Roles of molecular chaperones in cytoplasmic protein folding. Semin Cell Dev Biol 11:15–25. doi:10.1006/scdb.1999.0347

    PubMed  CAS  Google Scholar 

  57. Nishikawa M, Takemoto S, Takakura Y (2008) Heat shock protein derivatives for delivery of antigens to antigen presenting cells. Int J Pharm 354:23–27. doi:10.1016/j.ijpharm.2007.09.030

    PubMed  CAS  Google Scholar 

  58. Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 12:1539–1546

    PubMed  CAS  Google Scholar 

  59. Pawaria S, Binder RJ (2011) CD91-dependent programming of T-helper cell responses following heat shock protein immunization. Nat Commun 2:521. doi:10.1038/ncomms1524

    PubMed  PubMed Central  Google Scholar 

  60. Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034. doi:10.1074/jbc.M200497200

    PubMed  CAS  Google Scholar 

  61. Basu S, Binder RJ, Ramalingam T, Srivastava PK (2001) CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14:303–313

    PubMed  CAS  Google Scholar 

  62. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:435–442. doi:10.1038/74697

    PubMed  CAS  Google Scholar 

  63. Singh-Jasuja H, Toes RE, Spee P, Munz C, Hilf N, Schoenberger SP, Ricciardi-Castagnoli P, Neefjes J, Rammensee HG, Arnold-Schild D, Schild H (2000) Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor-mediated endocytosis. J Exp Med 191:1965–1974

    PubMed  CAS  PubMed Central  Google Scholar 

  64. Suto R, Srivastava PK (1995) A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 269:1585–1588

    PubMed  CAS  Google Scholar 

  65. Liu SQ, Saijo K, Todoroki T, Ohno T (1995) Induction of human autologous cytotoxic T lymphocytes on formalin-fixed and paraffin-embedded tumour sections. Nat Med 1:267–271

    PubMed  CAS  Google Scholar 

  66. See AP, Pradilla G, Yang I, Han S, Parsa AT, Lim M (2011) Heat shock protein-peptide complex in the treatment of glioblastoma. Expert Rev Vaccines 10:721–731. doi:10.1586/erv.11.49

    PubMed  CAS  Google Scholar 

  67. Bloch O, Crane CA, Fuks Y, Kaur R, Aghi MK, Berger MS, Butowski NA, Chang SM, Clarke JL, McDermott MW, Prados MD, Sloan AE, Bruce JN, Parsa AT (2014) Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol 16:274–279. doi:10.1093/neuonc/not203

    PubMed  CAS  Google Scholar 

  68. Okada H, Lieberman FS, Edington HD, Witham TF, Wargo MJ, Cai Q, Elder EH, Whiteside TL, Schold SC Jr, Pollack IF (2003) Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of recurrent glioblastoma: preliminary observations in a patient with a favorable response to therapy. J Neurooncol 64:13–20

    PubMed  Google Scholar 

  69. Steiner HH, Bonsanto MM, Beckhove P, Brysch M, Geletneky K, Ahmadi R, Schuele-Freyer R, Kremer P, Ranaie G, Matejic D, Bauer H, Kiessling M, Kunze S, Schirrmacher V, Herold-Mende C (2004) Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit. J Clin Oncol 22:4272–4281. doi:10.1200/jco.2004.09.038

    PubMed  Google Scholar 

  70. Wood GW, Holladay FP, Turner T, Wang YY, Chiga M (2000) A pilot study of autologous cancer cell vaccination and cellular immunotherapy using anti-CD3 stimulated lymphocytes in patients with recurrent grade III/IV astrocytoma. J Neurooncol 48:113–120

    PubMed  CAS  Google Scholar 

  71. Okada H, Pollack IF, Lotze MT, Lunsford LD, Kondziolka D, Lieberman F, Schiff D, Attanucci J, Edington H, Chambers W, Robbins P, Baar J, Kinzler D, Whiteside T, Elder E (2000) Gene therapy of malignant gliomas: a phase I study of IL-4-HSV-TK gene-modified autologous tumor to elicit an immune response. Hum Gene Ther 11:637–653. doi:10.1089/10430340050015824

    PubMed  CAS  Google Scholar 

  72. Liu SQ, Shiraiwa H, Kawai K, Hayashi H, Akaza H, Kim BS, Oki A, Nishida M, Kubo T, Hashizaki K, Saijo K, Ohno T (1996) Tumor-specific autologous cytotoxic T lymphocytes from tissue sections. Nat Med 2:1283

    PubMed  CAS  Google Scholar 

  73. Ohno T (2003) Autologous cancer vaccine: a novel formulation. Microbiol Immunol 47:255–263

    PubMed  CAS  Google Scholar 

  74. Ishikawa E, Tsuboi K, Yamamoto T, Muroi A, Takano S, Enomoto T, Matsumura A, Ohno T (2007) Clinical trial of autologous formalin-fixed tumor vaccine for glioblastoma multiforme patients. Cancer Sci 98:1226–1233. doi:10.1111/j.1349-7006.2007.00518.x

    PubMed  CAS  Google Scholar 

  75. Muragaki Y, Maruyama T, Iseki H, Tanaka M, Shinohara C, Takakura K, Tsuboi K, Yamamoto T, Matsumura A, Matsutani M, Karasawa K, Shimada K, Yamaguchi N, Nakazato Y, Sato K, Uemae Y, Ohno T, Okada Y, Hori T (2011) Phase I/IIa trial of autologous formalin-fixed tumor vaccine concomitant with fractionated radiotherapy for newly diagnosed glioblastoma clinical article. J Neurosurg 115:248–255. doi:10.3171/2011.4.JNS10377

    PubMed  Google Scholar 

  76. Vauleon E, Avril T, Collet B, Mosser J, Quillien V (2010) Overview of cellular immunotherapy for patients with glioblastoma. Clin Dev Immunol 2010 doi:10.1155/2010/689171

  77. Cserr HF, DePasquale M, Harling-Berg CJ, Park JT, Knopf PM (1992) Afferent and efferent arms of the humoral immune response to CSF-administered albumins in a rat model with normal blood–brain barrier permeability. J Neuroimmunol 41:195–202

    PubMed  CAS  Google Scholar 

  78. Cserr HF, Harling-Berg CJ, Knopf PM (1992) Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol 2:269–276

    PubMed  CAS  Google Scholar 

  79. Harling-Berg C, Knopf PM, Merriam J, Cserr HF (1989) Role of cervical lymph nodes in the systemic humoral immune response to human serum albumin microinfused into rat cerebrospinal fluid. J Neuroimmunol 25:185–193

    PubMed  CAS  Google Scholar 

  80. Steinman RM, Turley S, Mellman I, Inaba K (2000) The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 191:411–416

    PubMed  CAS  PubMed Central  Google Scholar 

  81. Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE 2nd, Lally-Goss D, McGehee-Norman S, Paolino A, Reardon DA, Friedman AH, Friedman HS, Bigner DD (2009) An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther 8:2773–2779. doi:10.1158/1535-7163.mct-09-0124

    PubMed  CAS  PubMed Central  Google Scholar 

  82. Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH, Nelson SF, Liau LM (2011) Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res 17:1603–1615. doi:10.1158/1078-0432.ccr-10-2563

    PubMed  CAS  PubMed Central  Google Scholar 

  83. Fong B, Jin R, Wang X, Safaee M, Lisiero DN, Yang I, Li G, Liau LM, Prins RM (2012) Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients. PLoS One 7:e32614. doi:10.1371/journal.pone.0032614

    PubMed  CAS  PubMed Central  Google Scholar 

  84. Agarwalla P, Barnard Z, Fecci P, Dranoff G, Curry WT Jr (2012) Sequential immunotherapy by vaccination with GM–CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors. J Immunother 35:385–389. doi:10.1097/CJI.0b013e3182562d59

    PubMed  CAS  PubMed Central  Google Scholar 

  85. (2013) ImmunoCellular Therapeutics phase II study demonstrates that glioblastoma patients live longer without disease progression when treated with ICT-107. http://investors.imuc.com/releasedetail.cfm?ReleaseID=813442

  86. Hickey MJ, Malone CC, Erickson KL, Jadus MR, Prins RM, Liau LM, Kruse CA (2010) Cellular and vaccine therapeutic approaches for gliomas. J Transl Med 8:100. doi:10.1186/1479-5876-8-100

    PubMed  PubMed Central  Google Scholar 

  87. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110. doi:10.1016/j.ccr.2009.12.020

    PubMed  CAS  PubMed Central  Google Scholar 

  88. Miglierini P, Bouchekoua M, Rousseau B, Hieu PD, Malhaire JP, Pradier O (2012) Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: efficacy and toxicity. Clin Neurol Neurosurg 114:1222–1225. doi:10.1016/j.clineuro.2012.02.056

    PubMed  Google Scholar 

  89. Yamanaka R (2008) Cell- and peptide-based immunotherapeutic approaches for glioma. Trends Mol Med 14:228–235. doi:10.1016/j.molmed.2008.03.003

    PubMed  CAS  Google Scholar 

  90. Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, Ozawa T, Holland EC, Huse JT, Jhanwar S, Leversha MA, Mikkelsen T, Brennan CW (2012) Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci USA 109:3041–3046. doi:10.1073/pnas.1114033109

    PubMed  CAS  PubMed Central  Google Scholar 

  91. Korman AJ, Peggs KS, Allison JP (2006) Checkpoint blockade in cancer immunotherapy. Adv Immunol 90:297–339. doi:10.1016/s0065-2776(06)90008-x

    PubMed  CAS  PubMed Central  Google Scholar 

  92. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465. doi:10.1056/NEJMoa1200694

    PubMed  CAS  PubMed Central  Google Scholar 

  93. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. doi:10.1056/NEJMoa1200690

    PubMed  CAS  PubMed Central  Google Scholar 

  94. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134–144. doi:10.1056/NEJMoa1305133

    PubMed  CAS  PubMed Central  Google Scholar 

  95. Robert C, Thomas L, Bondarenko I, O’Day SJ, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526. doi:10.1056/NEJMoa1104621

    PubMed  CAS  Google Scholar 

  96. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369:122–133. doi:10.1056/NEJMoa1302369

    PubMed  CAS  Google Scholar 

  97. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619. doi:10.1038/nrg1879

    PubMed  CAS  Google Scholar 

  98. Brunner KT, Mauel J, Cerottini JC, Chapuis B (1968) Quantitative assay of the lytic action of immune lymphoid cells on 51-Cr-labelled allogeneic target cells in vitro; inhibition by isoantibody and by drugs. Immunology 14:181–196

    PubMed  CAS  PubMed Central  Google Scholar 

  99. Schmittel A, Keilholz U, Thiel E, Scheibenbogen C (2000) Quantification of tumor-specific T lymphocytes with the ELISPOT assay. J Immunother 23:289–295

    PubMed  CAS  Google Scholar 

  100. Speller SA, Warren AP (2002) Ex vivo detection and enumeration of human antigen-specific CD8+ T lymphocytes using antigen delivery by a recombinant vaccinia expression vector and intracellular cytokine staining. J Immunol Methods 262:167–180

    PubMed  CAS  Google Scholar 

  101. Nomura LE, Walker JM, Maecker HT (2000) Optimization of whole blood antigen-specific cytokine assays for CD4(+) T cells. Cytometry 40:60–68

    PubMed  CAS  Google Scholar 

  102. Suni MA, Picker LJ, Maino VC (1998) Detection of antigen-specific T cell cytokine expression in whole blood by flow cytometry. J Immunol Methods 212:89–98

    PubMed  CAS  Google Scholar 

  103. Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, McMichael AJ, Davis MM (1996) Phenotypic analysis of antigen-specific T lymphocytes. Science 274:94–96

    PubMed  CAS  Google Scholar 

  104. He XS, Rehermann B, Lopez-Labrador FX, Boisvert J, Cheung R, Mumm J, Wedemeyer H, Berenguer M, Wright TL, Davis MM, Greenberg HB (1999) Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers. Proc Natl Acad Sci USA 96:5692–5697

    PubMed  CAS  PubMed Central  Google Scholar 

  105. Hempel DM, Smith KA, Claussen KA, Perricone MA (2002) Analysis of cellular immune responses in the peripheral blood of mice using real-time RT-PCR. J Immunol Methods 259:129–138

    PubMed  CAS  Google Scholar 

  106. Kammula US, Marincola FM, Rosenberg SA (2000) Real-time quantitative polymerase chain reaction assessment of immune reactivity in melanoma patients after tumor peptide vaccination. J Natl Cancer Inst 92:1336–1344

    PubMed  CAS  Google Scholar 

  107. Doucette T, Rao G, Rao A, Shen L, Aldape K, Wei J, Dziurzynski K, Gilbert M, Heimberger AB (2013) Immune heterogeneity of glioblastoma subtypes: extrapolation from the cancer genome atlas. Cancer Immunol Res 1 doi:10.1158/2326-6066.cir-13-0028

Download references

Acknowledgments

The authors have no conflicts of interest to report. This work was supported by grants from the Howard Hughes Medical Institute (ETS), the Reza and Georgianna Khatib Endowed Professor at Northwestern University (OB), and the Michael J. Marchese Professor and Chair at Northwestern University (ATP).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andrew T. Parsa.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sayegh, E.T., Oh, T., Fakurnejad, S. et al. Vaccine therapies for patients with glioblastoma. J Neurooncol 119, 531–546 (2014). https://doi.org/10.1007/s11060-014-1502-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-014-1502-6

Keywords

Navigation