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Vaccine Therapies in Malignant Glioma

  • Neuro-Oncology (LE Abrey, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

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.

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References

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

  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. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Suto R, Srivastava PK. A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science. 1995;269(5230):1585–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  35. Cohn L, Delamarre L. Dendritic cell-targeted vaccines. Front Immunol. 2014;5:255. doi:10.3389/fimmu.2014.00255.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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/j.nec.2009.08.012.

    Article  PubMed Central  PubMed  Google Scholar 

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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.

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  1. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 676 N. St. Clair Street, Suite 2210, Chicago, IL, 60611-2911, USA

    Taemin Oh, Eli T. Sayegh, Shayan Fakurnejad, Daniel Oyon, Jonathan Balquiedra Lamano, Joseph David DiDomenico, Orin Bloch & Andrew T. Parsa

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  1. Taemin Oh
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Correspondence to Andrew T. Parsa.

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Oh, T., Sayegh, E.T., Fakurnejad, S. et al. Vaccine Therapies in Malignant Glioma. Curr Neurol Neurosci Rep 15, 508 (2015). https://doi.org/10.1007/s11910-014-0508-y

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