, Volume 14, Issue 2, pp 345–357 | Cite as

Tumor Vaccines for Malignant Gliomas

  • Visish M. Srinivasan
  • Sherise D. Ferguson
  • Sungho Lee
  • Shiao-Pei Weathers
  • Brittany C. Parker Kerrigan
  • Amy B. Heimberger


Despite continued research efforts, glioblastoma multiforme (GBM) remains the deadliest brain tumor. Immunotherapy offers a novel way to treat this disease, the genetic signature of which is not completely elucidated. Additionally, these tumors are known to induce immunosuppression in the surrounding tumor microenvironment via an array of mechanisms, making effective treatment all the more difficult. The immunotherapeutic strategy of using tumor vaccines offers a way to harness the activity of the host immune system to potentially control tumor progression. GBM vaccines can react to a variety of tumor-specific antigens, which can be harvested from the patient’s unique pathological condition using selected immunotherapy techniques. This article reviews the rationale behind and development of GBM vaccines, the relevant clinical trials, and the challenges involved in this treatment strategy.


Glioma Glioblastoma Tumor vaccine Rindopepimut Dendritic cells 

Supplementary material

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  1. 1.
    Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987-996.PubMedCrossRefGoogle Scholar
  2. 2.
    Batich KA, Swartz AM, Sampson JH. Enhancing dendritic cell-based vaccination for highly aggressive glioblastoma. Expert Opin Biol Ther 2015;15(1):79-94.PubMedCrossRefGoogle Scholar
  3. 3.
    Klebanoff CA, Gattinoni L, Torabi-Parizi P, et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci U S A 2005;102(27):9571-9576.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 2004;64(14):4973-4979.PubMedCrossRefGoogle Scholar
  5. 5.
    Sampson JH, Heimberger AB, Archer GE, 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(31):4722-4729.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Purcell AW, McCluskey J, Rossjohn J. More than one reason to rethink the use of peptides in vaccine design. Nat Rev Drug Discov 2007;6(5):404-414.PubMedCrossRefGoogle Scholar
  7. 7.
    Swartz AM, Batich KA, Fecci PE, Sampson JH. Peptide vaccines for the treatment of glioblastoma. J Neurooncol 2015;123(3):433-440.PubMedCrossRefGoogle Scholar
  8. 8.
    Mohme M, Neidert MC, Regli L, Weller M, Martin R. Immunological challenges for peptide-based immunotherapy in glioblastoma. Cancer Treat Rev 2014;40:248-258.PubMedCrossRefGoogle Scholar
  9. 9.
    Xu LW, Chow KK, Lim M, Li G. Current vaccine trials in glioblastoma: a review. J Immunol Res 2014;2014:796856.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Hodges TR, Ferguson SD, Caruso HG, et al. Prioritization schema for immunotherapy clinical trials in glioblastoma. Oncoimmunology 2016;5(6):e1145332.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Heimberger AB, Crotty LE, Archer GE, et al. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin Cancer Res 2003;9(11):4247-4254.PubMedGoogle Scholar
  12. 12.
    Patel R, Leung HY. Targeting the EGFR-family for therapy: biological challenges and clinical perspective. Curr Pharm Des 2012;18(19):2672-2679.PubMedCrossRefGoogle Scholar
  13. 13.
    Prigent SA, Nagane M, Lin H, et al. Enhanced tumorigenic behavior of glioblastoma cells expressing a truncated epidermal growth factor receptor is mediated through the Ras-Shc-Grb2 pathway. J Biol Chem 1996;271(41):25639-25645.PubMedCrossRefGoogle Scholar
  14. 14.
    Bigner SH, Humphrey PA, Wong AJ, et al. Characterization of the epidermal growth factor receptor in human glioma cell lines and xenografts. Cancer Res 1990;50(24):8017-8022.PubMedGoogle Scholar
  15. 15.
    Humphrey PA, Wong AJ, Vogelstein B, 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):4207-4211.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Heimberger AB, Hlatky R, Suki D, et al. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res 2005;11:1462-1466.PubMedCrossRefGoogle Scholar
  17. 17.
    Huang HS, Nagane M, Klingbeil CK, et al. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem 1997;272(5):2927-2935.PubMedCrossRefGoogle Scholar
  18. 18.
    Pelloski CE, Ballman KV, Furth AF, et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol 2007;25(16):2288-2294.PubMedCrossRefGoogle Scholar
  19. 19.
    Schuster J, Lai RK, Recht LD, et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol 2015;17(6):854-861.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Del Vecchio CA, Giacomini CP, Vogel H, et al. EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms. Oncogene 2013;32(21):2670-2681.PubMedCrossRefGoogle Scholar
  21. 21.
    Inda MM, Bonavia R, Mukasa A, et al. Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev 2010;24(16):1731-1745.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Sampson JH, Aldape KD, Archer GE, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol 2011;13(3):324-333.PubMedCrossRefGoogle Scholar
  23. 23.
    Malkki H. Trial Watch: Glioblastoma vaccine therapy disappointment in Phase III trial. Nat Rev Neurol 2016;12(4):190.PubMedCrossRefGoogle Scholar
  24. 24.
    Cebon J, Knights A, Ebert L, Jackson H, Chen W. Evaluation of cellular immune responses in cancer vaccine recipients: lessons from NY-ESO-1. Expert Rev Vaccines 2010;9(6):617-629.PubMedCrossRefGoogle Scholar
  25. 25.
    Nicholaou T, Ebert L, Davis ID, et al. Directions in the immune targeting of cancer: lessons learned from the cancer-testis Ag NY-ESO-1. Immunol Cell Biol 2006;84(3):303-317.PubMedCrossRefGoogle Scholar
  26. 26.
    Nicholaou T, Ebert LM, Davis ID, et al. Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma. Clin Cancer Res 2009;15(6):2166-2173.PubMedCrossRefGoogle Scholar
  27. 27.
    Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen YT. Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev 2002;188:22-32.PubMedCrossRefGoogle Scholar
  28. 28.
    Altieri DC. Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 2003;22(53):8581-8589.PubMedCrossRefGoogle Scholar
  29. 29.
    Garg H, Suri P, Gupta JC, Talwar GP, Dubey S. Survivin: a unique target for tumor therapy. Cancer Cell Int 2016;16:49.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Chakravarti A, Noll E, Black PM, et al. Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol 2002;20(4):1063-1068.PubMedCrossRefGoogle Scholar
  31. 31.
    Kajiwara Y, Yamasaki F, Hama S, et al. Expression of survivin in astrocytic tumors: correlation with malignant grade and prognosis. Cancer 2003;97(4):1077-1083.PubMedCrossRefGoogle Scholar
  32. 32.
    Ciesielski MJ, Ahluwalia MS, Munich SA, et al. Antitumor cytotoxic T-cell response induced by a survivin peptide mimic. Cancer Immunol Immunother 2010;59(8):1211-1221.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 2009;27(25):4150-4154.PubMedCrossRefGoogle Scholar
  34. 34.
    Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009;360(8):765-773.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Schumacher T, Bunse L, Pusch S, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 2014;512(7514):324-327.PubMedCrossRefGoogle Scholar
  36. 36.
    Platten M, Bunse L, Wick W, Bunse T. Concepts in glioma immunotherapy. Cancer Immunol Immunother 2016;65(10):1269-1275.PubMedCrossRefGoogle Scholar
  37. 37.
    Nishida S, Hosen N, Shirakata T, et al. AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1. Blood 2006;107(8):3303-3312.PubMedCrossRefGoogle Scholar
  38. 38.
    Oka Y, Udaka K, Tsuboi A, et al. Cancer immunotherapy targeting Wilms' tumor gene WT1 product. J Immunol 2000;164(4):1873-1880.PubMedCrossRefGoogle Scholar
  39. 39.
    Sugiyama H. Wilms' tumor gene WT1: its oncogenic function and clinical application. Int J Hematol 2001;73(2):177-187.PubMedCrossRefGoogle Scholar
  40. 40.
    Algar EM, Khromykh T, Smith SI, Blackburn DM, Bryson GJ, Smith PJ. A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in myeloid leukaemia cell lines. Oncogene 1996;12(5):1005-1014.PubMedGoogle Scholar
  41. 41.
    Kijima N, Hosen N, Kagawa N, et al. Wilms' tumor 1 is involved in tumorigenicity of glioblastoma by regulating cell proliferation and apoptosis. Anticancer Res 2014;34(1):61-67.PubMedGoogle Scholar
  42. 42.
    Oji Y, Ogawa H, Tamaki H, et al. Expression of the Wilms' tumor gene WT1 in solid tumors and its involvement in tumor cell growth. Jpn J Cancer Res 1999;90(2):194-204.PubMedCrossRefGoogle Scholar
  43. 43.
    Tuna M, Chavez-Reyes A, Tari AM. HER2/neu increases the expression of Wilms' Tumor 1 (WT1) protein to stimulate S-phase proliferation and inhibit apoptosis in breast cancer cells. Oncogene 2005;24(9):1648-1652.PubMedCrossRefGoogle Scholar
  44. 44.
    Clark AJ, Dos Santos WG, McCready J, et al. Wilms tumor 1 expression in malignant gliomas and correlation of + KTS isoforms with p53 status. J Neurosurg 2007;107:586-592.PubMedCrossRefGoogle Scholar
  45. 45.
    Oji Y, Suzuki T, Nakano Y, et al. Overexpression of the Wilms' tumor gene W T1 in primary astrocytic tumors. Cancer Sci 2004;95(10):822-827.PubMedCrossRefGoogle Scholar
  46. 46.
    Rushing EJ, Sandberg GD, Horkayne-Szakaly I. High-grade astrocytomas show increased Nestin and Wilms's tumor gene (WT1) protein expression. Int J Surg Pathol 2010;18(4):255-259.PubMedCrossRefGoogle Scholar
  47. 47.
    Hashiba T, Izumoto S, Kagawa N, et al. Expression of WT1 protein and correlation with cellular proliferation in glial tumors. Neurol Med Chir (Tokyo) 2007;47(4):165-170.CrossRefGoogle Scholar
  48. 48.
    Rauscher J, Beschorner R, Gierke M, et al. WT1 expression increases with malignancy and indicates unfavourable outcome in astrocytoma. J Clin Pathol 2014;67(7):556-561.PubMedCrossRefGoogle Scholar
  49. 49.
    Hashimoto N, Tsuboi A, Kagawa N, et al. Wilms tumor 1 peptide vaccination combined with temozolomide against newly diagnosed glioblastoma: safety and impact on immunological response. Cancer Immunol Immunother 2015;64(6):707-716.PubMedCrossRefGoogle Scholar
  50. 50.
    Izumoto S, Tsuboi A, Oka Y, et al. Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. J Neurosurg 2008;108(5):963-971.PubMedCrossRefGoogle Scholar
  51. 51.
    Thomas AA, Fisher JL, Ernstoff MS, Fadul CE. Vaccine-based immunotherapy for glioblastoma. CNS Oncol 2013;2(4):331-349.PubMedCrossRefGoogle Scholar
  52. 52.
    Jackson C, Ruzevick J, Brem H, Lim M. Vaccine strategies for glioblastoma: progress and future directions. Immunotherapy 2013;5(2):155-167.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Dutoit V, Herold-Mende C, Hilf N, et al. Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain 2012;135(Pt 4):1042-1054.PubMedCrossRefGoogle Scholar
  54. 54.
    Rampling R, Peoples S, Mulholland PJ, et al. A Cancer Research UK first time in human phase i trial of IMA950 (novel multipeptide therapeutic vaccine) in patients with newly diagnosed glioblastoma. Clin Cancer Res 2016;22(19):4776-4785.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Zhu X, Fallert-Junecko BA, Fujita M, et al. Poly-ICLC promotes the infiltration of effector T cells into intracranial gliomas via induction of CXCL10 in IFN-alpha and IFN-gamma dependent manners. Cancer Immunol Immunother 2010;59(9):1401-1409.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Bota DA, Alexandru-Abrams D, Pretto C, et al. Use of ERC-1671 vaccine in a patient with recurrent glioblastoma multiforme after progression during bevacizumab therapy: first published report. Perm J 2015;19(2):41-46.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Schijns VE, Pretto C, Devillers L, et al. 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 2015;33(23):2690-2696.PubMedCrossRefGoogle Scholar
  58. 58.
    Price DA, Brenchley JM, Ruff LE, et al. Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses. J Exp Med 2005;202(10):1349-1361.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Yee C, Savage PA, Lee PP, Davis MM, Greenberg PD. Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers. J Immunol 1999;162(4):2227-2234.PubMedGoogle Scholar
  60. 60.
    Garber ST, Hashimoto Y, Weathers SP, et al. Immune checkpoint blockade as a potential therapeutic target: surveying CNS malignancies. Neuro Oncol 2016;18(10):1357-1366.PubMedCrossRefGoogle Scholar
  61. 61.
    Daud AI, Loo K, Pauli ML, et al. Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J Clin Invest 2016;126(9):3447-3452.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366(26):2443-2454.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515(7528):568-571.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014;515(7528):577-581.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515(7528):563-567.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-128.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016;387:1909-1920.PubMedCrossRefGoogle Scholar
  68. 68.
    Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014;371(23):2189-2199.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Hodges TR, Ott M, Xiu J, et al. Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro Oncol 2017. In Press.Google Scholar
  70. 70.
    Craig EA, Weissman JS, Horwich AL. Heat shock proteins and molecular chaperones: mediators of protein conformation and turnover in the cell. Cell 1994;78(3):365-372.PubMedCrossRefGoogle Scholar
  71. 71.
    Graner MW, Bigner DD. Chaperone proteins and brain tumors: potential targets and possible therapeutics. Neuro Oncol 2005;7(3):260-278.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Ampie L, Choy W, Lamano JB, Fakurnejad S, Bloch O, Parsa AT. Heat shock protein vaccines against glioblastoma: from bench to bedside. J Neurooncol 2015;123(3):441-448.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Asea A, Kraeft SK, Kurt-Jones EA, 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):435-442.PubMedCrossRefGoogle Scholar
  74. 74.
    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):23-27.PubMedCrossRefGoogle Scholar
  75. 75.
    Sayegh ET, Oh T, Fakurnejad S, Bloch O, Parsa AT. Vaccine therapies for patients with glioblastoma. J Neurooncol 2014;119(3):531-546.PubMedCrossRefGoogle Scholar
  76. 76.
    Belli F, Testori A, Rivoltini L, et al. Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings. J Clin Oncol 2002;20(20):4169-4180.PubMedCrossRefGoogle Scholar
  77. 77.
    Srivastava PK. Purification of heat shock protein-peptide complexes for use in vaccination against cancers and intracellular pathogens. Methods 1997;12(2):165-171.PubMedCrossRefGoogle Scholar
  78. 78.
    Crane CA, Han SJ, Ahn B, Oehlke J, Kivett V, Fedoroff A, Butowski N, Chang SM, Clarke J, Berger MS, McDermott MW, Prados MD, Parsa AT. 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 2013;19(1):205–14.Google Scholar
  79. 79.
    Bloch O, Crane CA, Fuks Y, et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol 2014;16(2):274-279.PubMedCrossRefGoogle Scholar
  80. 80.
    Panjwani NN, Popova L, Srivastava PK. Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J Immunol 2002;168(6):2997-3003.PubMedCrossRefGoogle Scholar
  81. 81.
    Srivastava P. Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2002;2(3):185-194.PubMedCrossRefGoogle Scholar
  82. 82.
    Testori A, Richards J, Whitman E, et al. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol 2008;26(6):955-962.PubMedCrossRefGoogle Scholar
  83. 83.
    Wood C, Srivastava P, Bukowski R, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet 2008;372(9633):145-154.PubMedCrossRefGoogle Scholar
  84. 84.
    Steinman RM, Turley S, Mellman I, Inaba K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 2000;191(3):411-416.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Finocchiaro G, Pellegatta S. Immunotherapy with dendritic cells loaded with glioblastoma stem cells: from preclinical to clinical studies. Cancer Immunol Immunother 2016;65(1):101-109.PubMedCrossRefGoogle Scholar
  86. 86.
    Rutkowski S, De Vleeschouwer S, Kaempgen E, et al. Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study. Br J Cancer 2004;91(9):1656-1662.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Wheeler CJ, Das A, Liu G, Yu JS, Black KL. Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination. Clin Cancer Res 2004;10(16):5316-5326.PubMedCrossRefGoogle Scholar
  88. 88.
    Sampson JH, Archer GE, Mitchell DA, 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):2773-2779.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Phuphanich S, Wheeler CJ, Rudnick JD, et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother 2013;62(1):125-135.PubMedCrossRefGoogle Scholar
  90. 90.
    Antonios JP, Everson RG, Liau LM. Dendritic cell immunotherapy for brain tumors. J Neurooncol 2015;123(3):425-432.PubMedCrossRefGoogle Scholar
  91. 91.
    Yamanaka R, Abe T, Yajima N, et al. Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial. Br J Cancer 2003;89(7):1172-1179.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Yamanaka R, Homma J, Yajima N, et al. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res 2005;11(11):4160-4167.PubMedCrossRefGoogle Scholar
  93. 93.
    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.PubMedCrossRefGoogle Scholar
  94. 94.
    Hdeib A, Sloan AE. Dendritic cell immunotherapy for solid tumors: evaluation of the DCVax(R) platform in the treatment of glioblastoma multiforme. CNS Oncol 2015;4(2):63-69.PubMedCrossRefGoogle Scholar
  95. 95.
    Boczkowski D, Nair SK, Nam JH, Lyerly HK, Gilboa E. Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells. Cancer Res 2000;60(4):1028-1034.PubMedGoogle Scholar
  96. 96.
    Parajuli P, Mathupala S, Sloan AE. Systematic comparison of dendritic cell-based immunotherapeutic strategies for malignant gliomas: in vitro induction of cytolytic and natural killer-like T cells. Neurosurgery 2004;55(5):1194-1204.PubMedCrossRefGoogle Scholar
  97. 97.
    Chen R, Nishimura MC, Bumbaca SM, et al. A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 2010;17(4):362-375.PubMedCrossRefGoogle Scholar
  98. 98.
    Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444(7120):756-760.PubMedCrossRefGoogle Scholar
  99. 99.
    Fidoamore A, Cristiano L, Antonosante A, et al. Glioblastoma stem cells microenvironment: the paracrine roles of the niche in drug and radioresistance. Stem Cells Int 2016;2016:6809105.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Wei J, Wu A, Kong LY, et al. Hypoxia potentiates glioma-mediated immunosuppression. PLOS ONE 2011;6(1):e16195.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Pellegatta S, Poliani PL, Corno D, et al. Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Res 2006;66(21):10247-10252.PubMedCrossRefGoogle Scholar
  102. 102.
    Vik-Mo EO, Nyakas M, Mikkelsen BV, et al. Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma. Cancer Immunol Immunother 2013;62(9):1499-1509.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Cobbs CS, Harkins L, Samanta M, et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 2002;62(12):3347-3350.PubMedGoogle Scholar
  104. 104.
    Dziurzynski K, Chang SM, Heimberger AB, et al. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol 2012;14(3):246-255.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Varnum SM, Streblow DN, Monroe ME, et al. Identification of proteins in human cytomegalovirus (HCMV) particles: the HCMV proteome. J Virol 2004;78(20):10960-10966.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Mitchell DA, Batich KA, Gunn MD, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 2015;519(7543):366-369.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007;27(1):111-122.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Parsa AT, Waldron JS, Panner A, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 2007;13(1):84-88.PubMedCrossRefGoogle Scholar
  109. 109.
    Antonios JP, Soto H, Everson RG, et al. PD-1 blockade enhances the vaccination-induced immune response in glioma. JCI Insight 2016;1(10).Google Scholar
  110. 110.
    Sakai K, Shimodaira S, Maejima S, et al. Dendritic cell-based immunotherapy targeting Wilms' tumor 1 in patients with recurrent malignant glioma. J Neurosurg 2015;123(4):989-997.PubMedCrossRefGoogle Scholar
  111. 111.
    Schreibelt G, Bol KF, Westdorp H, et al. Effective clinical responses in metastatic melanoma patients after vaccination with primary myeloid dendritic cells. Clin Cancer Res 2016;22(9):2155-2166.PubMedCrossRefGoogle Scholar
  112. 112.
    Gulley JL, Madan RA, Schlom J. Impact of tumour volume on the potential efficacy of therapeutic vaccines. Curr Oncol 2011;18(3):e150-e157.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Widen K, Mozaffari F, Choudhury A, Mellstedt H. Overcoming immunosuppressive mechanisms. Ann Oncol 2008;19(Suppl. 7):vii241-7.Google Scholar
  114. 114.
    Tel J, Aarntzen EH, Baba T, et al. Natural human plasmacytoid dendritic cells induce antigen-specific T-cell responses in melanoma patients. Cancer Res 2013;73(3):1063-1075.PubMedCrossRefGoogle Scholar
  115. 115.
    Wimmers F, Schreibelt G, Skold AE, Figdor CG, De Vries IJ. Paradigm shift in dendritic cell-based immunotherapy: from in vitro generated monocyte-derived DCs to naturally circulating DC subsets. Front Immunol 2014;5:165.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Liau LM, Prins RM, Kiertscher SM, 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 2005;11(15):5515-5525.PubMedCrossRefGoogle Scholar
  117. 117.
    Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004;10(9):909-915.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    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-e267.PubMedCrossRefGoogle Scholar
  119. 119.
    Cho DY, Yang WK, Lee HC, et al. Adjuvant immunotherapy with whole-cell lysate dendritic cells vaccine for glioblastoma multiforme: a phase II clinical trial. World Neurosurg 2012;77(5-6):736-744.PubMedCrossRefGoogle Scholar
  120. 120.
    Oshita C, Takikawa M, Kume A, et al. Dendritic cell-based vaccination in metastatic melanoma patients: phase II clinical trial. Oncol Rep 2012;28(4):1131-1138.PubMedPubMedCentralGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  • Visish M. Srinivasan
    • 1
  • Sherise D. Ferguson
    • 2
  • Sungho Lee
    • 1
  • Shiao-Pei Weathers
    • 2
  • Brittany C. Parker Kerrigan
    • 2
  • Amy B. Heimberger
    • 2
  1. 1.Department of NeurosurgeryBaylor College of MedicineHoustonUSA
  2. 2.Department of NeurosurgeryThe University of Texas MD Anderson Cancer CenterHoustonUSA

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