Vaccine Therapies in Malignant Glioma

  • Taemin Oh
  • Eli T. Sayegh
  • Shayan Fakurnejad
  • Daniel Oyon
  • Jonathan Balquiedra Lamano
  • Joseph David DiDomenico
  • Orin Bloch
  • Andrew T. Parsa
Neuro-Oncology (LE Abrey, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Neuro-Oncology


Glioblastoma is a grade IV astrocytoma that is widely accepted in clinical neurosurgery as being an extremely lethal diagnosis. Long-term survival rates remain dismal, and even when tumors undergo gross resection with confirmation of total removal on neuroimaging, they invariably recur with even greater virulence. Standard therapeutic modalities as well as more contemporary treatments have largely resulted in disappointing improvements. However, the therapeutic potential of vaccine immunotherapy for malignant glioma should not be underestimated. In contrast to many of the available treatments, vaccine immunotherapy is unique because it offers the means of delivering treatment that is highly specific to both the patient and the tumor. Peptide, heat-shock proteins, and dendritic cell vaccines collectively encapsulate the majority of research efforts involving vaccine-based treatment modalities. In this review, important recent findings for these vaccine types are discussed in the context of ongoing clinical trials. Broad challenges to immunotherapy are also considered.


Glioma Glioblastoma Immunotherapy Vaccine 


Compliance with Ethics Guidelines

Conflict of Interest

Taemin Oh, Eli T. Sayegh, Shayan Fakurnejad, Daniel Oyon, Jonathan Balquiedra Lamano, Joseph David DiDomenico, Orin Bloch, and Andrew T. Parsa declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.••
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. doi: 10.1056/NEJMoa043330. Establishes the current standard-of-care for treatment of glioblastoma.
  2. 2.
    Selznick LA, Shamji MF, Fecci P, Gromeier M, Friedman AH, Sampson J. Molecular strategies for the treatment of malignant glioma–genes, viruses, and vaccines. Neurosurg Rev. 2008;31(2):141–55. doi: 10.1007/s10143-008-0121-0. discussion 55.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Vartanian A, Singh SK, Agnihotri S, Jalali S, Burrell K, Aldape KD, et al. GBM’s multifaceted landscape: highlighting regional and microenvironmental heterogeneity. Neuro Oncol. 2014;16(9):1167–75. doi: 10.1093/neuonc/nou035.PubMedCrossRefGoogle Scholar
  4. 4.
    Schonberg DL, Lubelski D, Miller TE, Rich JN. Brain tumor stem cells: molecular characteristics and their impact on therapy. Mol Aspects Med. 2013. doi: 10.1016/j.mam.2013.06.004.PubMedGoogle Scholar
  5. 5.
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110. doi: 10.1016/j.ccr.2009.12.020.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Aguilar LK, Arvizu M, Aguilar-Cordova E, Chiocca EA. The spectrum of vaccine therapies for patients with glioblastoma multiforme. Curr Treat Options Oncol. 2012;13(4):437–50. doi: 10.1007/s11864-012-0208-2.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Tanaka S, Louis DN, Curry WT, Batchelor TT, Dietrich J. Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat Rev Clin Oncol. 2012;10(1):14–26. doi: 10.1038/nrclinonc.2012.204.PubMedCrossRefGoogle Scholar
  8. 8.
    Liao W, Lin JX, Leonard WJ. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr Opin Immunol. 2011;23(5):598–604. doi: 10.1016/j.coi.2011.08.003.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Tanaka S, Louis DN, Curry WT, Batchelor TT, Dietrich J. Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat Rev Clin Oncol. 2013;10(1):14–26. doi: 10.1038/nrclinonc.2012.204.PubMedCrossRefGoogle Scholar
  10. 10.
    Mohme M, Neidert MC, Regli L, Weller M, Martin R. Immunological challenges for peptide-based immunotherapy in glioblastoma. Cancer Treat Rev. 2014;40(2):248–58. doi: 10.1016/j.ctrv.2013.08.008.PubMedCrossRefGoogle Scholar
  11. 11.
    Sayegh ET, Oh T, Fakurnejad S, Bloch O, Parsa AT. Vaccine therapies for patients with glioblastoma. J Neurooncol. 2014. doi: 10.1007/s11060-014-1502-6.PubMedGoogle Scholar
  12. 12.
    Jackson C, Ruzevick J, Brem H, Lim M. Vaccine strategies for glioblastoma: progress and future directions. Immunotherapy. 2013;5(2):155–67. doi: 10.2217/imt.12.155.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H, Nuno MA, et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immuno Immun. 2013;62(1):125–35. doi: 10.1007/s00262-012-1319-0.CrossRefGoogle Scholar
  14. 14.
    Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A. 1992;89(7):2965–9.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Humphrey PA, Wong AJ, Vogelstein B, Friedman HS, Werner MH, Bigner DD, et al. Amplification and expression of the epidermal growth factor receptor gene in human glioma xenografts. Cancer Res. 1988;48(8):2231–8.PubMedGoogle Scholar
  16. 16.
    Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuller GN, Archer GE, et al. Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci U S A. 1990;87(11):4207–11.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Kuan CT, Wikstrand CJ, Bigner DD. EGF mutant receptor vIII as a molecular target in cancer therapy. Endocr Relat Cancer. 2001;8(2):83–96.PubMedCrossRefGoogle Scholar
  18. 18.••
    Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, 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 Offic J Am Soc Clin Oncol. 2010;28(31):4722–9. doi: 10.1200/JCO.2010.28.6963. Provides evidence supporting immunological escape following immunotherapy, highlighting a demanding challenge to current immunotherapeutic approaches.
  19. 19.
    Del Vecchio CA, Li G, Wong AJ. 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.PubMedCrossRefGoogle Scholar
  20. 20.
    Heimberger AB, Crotty LE, Archer GE, Hess KR, Wikstrand CJ, Friedman AH, et al. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin Cancer Res Offic J Am Assoc Cancer Res. 2003;9(11):4247–54.Google Scholar
  21. 21.
    Neidert MC, Schoor O, Trautwein C, Trautwein N, Christ L, Melms A, et al. Natural HLA class I ligands from glioblastoma: extending the options for immunotherapy. J Neurooncol. 2013;111(3):285–94. doi: 10.1007/s11060-012-1028-8.PubMedCrossRefGoogle Scholar
  22. 22.
    Agashe VR, Hartl FU. Roles of molecular chaperones in cytoplasmic protein folding. Semin Cell Dev Biol. 2000;11(1):15–25. doi: 10.1006/scdb.1999.0347.PubMedCrossRefGoogle Scholar
  23. 23.
    Nishikawa M, Takemoto S, Takakura Y. Heat shock protein derivatives for delivery of antigens to antigen presenting cells. Int J Pharm. 2008;354(1–2):23–7. doi: 10.1016/j.ijpharm.2007.09.030.PubMedCrossRefGoogle Scholar
  24. 24.
    Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. 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. 2000;12(11):1539–46.PubMedCrossRefGoogle Scholar
  25. 25.
    Pawaria S, Binder RJ. CD91-dependent programming of T-helper cell responses following heat shock protein immunization. Nat Commun. 2011;2:521. doi: 10.1038/ncomms1524.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem. 2002;277(17):15028–34. doi: 10.1074/jbc.M200497200.PubMedCrossRefGoogle Scholar
  27. 27.
    Basu S, Binder RJ, Ramalingam T, Srivastava PK. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity. 2001;14(3):303–13.PubMedCrossRefGoogle Scholar
  28. 28.
    Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med. 2000;6(4):435–42. doi: 10.1038/74697.PubMedCrossRefGoogle Scholar
  29. 29.
    Singh-Jasuja H, Toes RE, Spee P, Munz C, Hilf N, Schoenberger SP, et al. Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor-mediated endocytosis. J Exp Med. 2000;191(11):1965–74.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Suto R, Srivastava PK. A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science. 1995;269(5230):1585–8.PubMedCrossRefGoogle Scholar
  31. 31.
    See AP, Pradilla G, Yang I, Han S, Parsa AT, Lim M. Heat shock protein-peptide complex in the treatment of glioblastoma. Expert Rev Vaccines. 2011;10(6):721–31. doi: 10.1586/erv.11.49.PubMedCrossRefGoogle Scholar
  32. 32.
    Crane CA, Han SJ, Ahn B, Oehlke J, Kivett V, Fedoroff A, et al. Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein. Clin Cancer Res Offic J Am Assoc Cancer Res. 2013;19(1):205–14. doi: 10.1158/1078-0432.CCR-11-3358.CrossRefGoogle Scholar
  33. 33.
    Bloch O, Crane CA, Fuks Y, Kaur R, Aghi MK, Berger MS, et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol. 2014;16(2):274–9. doi: 10.1093/neuonc/not203.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Wu ZB, Cai L, Qiu C, Zhang AL, Lin SJ, Yao Y, et al. CTL responses to HSP47 associated with the prolonged survival of patients with glioblastomas. Neurology. 2014;82(14):1261–5. doi: 10.1212/WNL.0000000000000290.PubMedCrossRefGoogle Scholar
  35. 35.
    Cohn L, Delamarre L. Dendritic cell-targeted vaccines. Front Immunol. 2014;5:255. doi: 10.3389/fimmu.2014.00255.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014;15(7):e257–67. doi: 10.1016/S1470-2045(13)70585-0.PubMedCrossRefGoogle Scholar
  37. 37.
    De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J, et al. Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res Offic J Am Assoc Cancer Res. 2008;14(10):3098–104. doi: 10.1158/1078-0432.CCR-07-4875.CrossRefGoogle Scholar
  38. 38.
    Kikuchi T, Akasaki Y, Abe T, Fukuda T, Saotome H, Ryan JL, et al. Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12. J Immunother. 2004;27(6):452–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Liau LM, Black KL, Martin NA, Sykes SN, Bronstein JM, Jouben-Steele L, et al. Treatment of a patient by vaccination with autologous dendritic cells pulsed with allogeneic major histocompatibility complex class I-matched tumor peptides. Case Report Neurosur Foc. 2000;9(6):e8.Google Scholar
  40. 40.
    Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res Offic J Am Assoc Cancer Res. 2005;11(15):5515–25. doi: 10.1158/1078-0432.CCR-05-0464.CrossRefGoogle Scholar
  41. 41.
    Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol Offic J Am Soc Clin Oncol. 2011;29(3):330–6. doi: 10.1200/JCO.2010.30.7744.CrossRefGoogle Scholar
  42. 42.
    Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon 2nd JE, Lally-Goss D, et al. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther. 2009;8(10):2773–9. doi: 10.1158/1535-7163.MCT-09-0124.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH, et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res Offic J Am Assoc Cancer Res. 2011;17(6):1603–15. doi: 10.1158/1078-0432.CCR-10-2563.CrossRefGoogle Scholar
  44. 44.
    Prins RM, Wang X, Soto H, Young E, Lisiero DN, Fong B, et al. Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. J Immunother. 2013;36(2):152–7. doi: 10.1097/CJI.0b013e3182811ae4.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Everson RG, Jin RM, Wang X, Safaee M, Scharnweber R, Lisiero DN, et al. Cytokine responsiveness of CD8(+) T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients. J Immunother Cancer. 2014;2:10. doi: 10.1186/2051-1426-2-10.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Fong B, Jin R, Wang X, Safaee M, Lisiero DN, Yang I, et al. 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. 2012;7(4):e32614. doi: 10.1371/journal.pone.0032614.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Jackson C, Ruzevick J, Phallen J, Belcaid Z, Lim M. Challenges in immunotherapy presented by the glioblastoma multiforme microenvironment. Clin Dev Immunol. 2011;2011:732413. doi: 10.1155/2011/732413.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Yamanaka R. Cell- and peptide-based immunotherapeutic approaches for glioma. Trends Mol Med. 2008;14(5):228–35. doi: 10.1016/j.molmed.2008.03.003.PubMedCrossRefGoogle Scholar
  49. 49.
    Zisakis A, Piperi C, Themistocleous MS, Korkolopoulou P, Boviatsis EI, Sakas DE, et al. Comparative analysis of peripheral and localised cytokine secretion in glioblastoma patients. Cytokine. 2007;39(2):99–105. doi: 10.1016/j.cyto.2007.05.012.PubMedCrossRefGoogle Scholar
  50. 50.
    Kumar R, Kamdar D, Madden L, Hills C, Crooks D, O’Brien D, et al. Th1/Th2 cytokine imbalance in meningioma, anaplastic astrocytoma and glioblastoma multiforme patients. Oncol Rep. 2006;15(6):1513–6.PubMedGoogle Scholar
  51. 51.
    Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limon P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol. 2010;10(8):554–67. doi: 10.1038/nri2808.PubMedCrossRefGoogle Scholar
  52. 52.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800. doi: 10.1038/nm730.PubMedGoogle Scholar
  53. 53.••
    Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13(1):84–8. doi: 10.1038/nm1517. Provides insight into the challenges to immunotherapies, and thus potential improvements for current modalities.PubMedCrossRefGoogle Scholar
  54. 54.
    Grehan JF, Levay-Young BK, Fogelson JL, Francois-Bongarcon V, Benson BA, Dalmasso AP. IL-4 and IL-13 induce protection of porcine endothelial cells from killing by human complement and from apoptosis through activation of a phosphatidylinositide 3-kinase/Akt pathway. J Immunol. 2005;175(3):1903–10.PubMedCrossRefGoogle Scholar
  55. 55.
    Marshall NA, Galvin KC, Corcoran AM, Boon L, Higgs R, Mills KH. Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-gamma + IL-17+ polyfunctional T cells that mediate rejection of murine tumors. Cancer Res. 2012;72(3):581–91. doi: 10.1158/0008-5472.CAN-11-0307.PubMedCrossRefGoogle Scholar
  56. 56.
    Wen PY, Lee EQ, Reardon DA, Ligon KL, Alfred Yung WK. Current clinical development of PI3K pathway inhibitors in glioblastoma. Neuro Oncol. 2012;14(7):819–29. doi: 10.1093/neuonc/nos117.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Oh T, Ivan ME, Sun MZ, Safaee M, Fakurnejad S, Clark AJ, et al. PI3K pathway inhibitors: potential prospects as adjuncts to vaccine immunotherapy for glioblastoma. Immunotherapy. 2014;6(6):737–53.PubMedCrossRefGoogle Scholar
  58. 58.
    Rauch I, Muller M, Decker T. The regulation of inflammation by interferons and their STATs. Jak-Stat. 2013;2(1):e23820. doi: 10.4161/jkst.23820.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Herman SE, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116(12):2078–88. doi: 10.1182/blood-2010-02-271171.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Sgorbissa A, Tomasella A, Potu H, Manini I, Brancolini C. Type I IFNs signaling and apoptosis resistance in glioblastoma cells. Apoptos Int J Programm Cell Death. 2011;16(12):1229–44. doi: 10.1007/s10495-011-0639-4.CrossRefGoogle Scholar
  61. 61.
    Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A. 2008;105(22):7797–802. doi: 10.1073/pnas.0800928105.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Humphries W, Wei J, Sampson JH, Heimberger AB. The role of tregs in glioma-mediated immunosuppression: potential target for intervention. Neurosurg Clin N Am. 2010;21(1):125–37. doi: 10.1016/ Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Taemin Oh
    • 1
  • Eli T. Sayegh
    • 1
  • Shayan Fakurnejad
    • 1
  • Daniel Oyon
    • 1
  • Jonathan Balquiedra Lamano
    • 1
  • Joseph David DiDomenico
    • 1
  • Orin Bloch
    • 1
  • Andrew T. Parsa
    • 1
  1. 1.Department of Neurological Surgery, Feinberg School of MedicineNorthwestern UniversityChicagoUSA

Personalised recommendations