Recent advances and future of immunotherapy for glioblastoma

References

• Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007 Aug;114(2):97–109.
   PubMed Web of Science ®Google Scholar
• Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med. 2015 Jun 25;372(26):2499–2508.
   PubMed Web of Science ®Google Scholar
• Suzuki H, Aoki K, Chiba K, et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet. 2015 May;47(5):458–468.
   PubMed Web of Science ®Google Scholar
• Paulus W. Pathology, molecular mechanisms and markers of gliomas: new insight and new challenges. Acta Neuropathol. 2015 Jun;129(6):773.
   PubMed Web of Science ®Google Scholar
• Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009 Feb 19;360(8):765–773.
   PubMed Web of Science ®Google Scholar
• Jiao Y, Killela PJ, Reitman ZJ, et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget. 2012 Jul;3(7):709–722.
   PubMed Web of Science ®Google Scholar
• Chamberlain MC, Born D. Prognostic significance of relative 1p/19q codeletion in oligodendroglial tumors. J Neuro Oncol. 2015 Nov;125(2):249–251.
   PubMed Web of Science ®Google Scholar
• Koschmann C, Calinescu AA, Nunez FJ, et al. ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Sci Transl Med. 2016 Mar 2;8(328):328ra28.
   PubMed Web of Science ®Google Scholar
• Verhaak RG, Hoadley KA, Purdom E, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010 Jan 19;17(1):98–110.
   PubMed Web of Science ®Google Scholar
• Van Meir EG, Hadjipanayis CG, Norden AD, et al. Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin. 2010 May–Jun;60(3):166–193.
   PubMed Web of Science ®Google Scholar
• Jha P, Suri V, Singh G, et al. Characterization of molecular genetic alterations in GBMs highlights a distinctive molecular profile in young adults. Diagnostic Mol Pathol. 2011 Dec;20(4):225–232.
   PubMedGoogle Scholar
• Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res. 2013 Feb 15;19(4):764–772.
   PubMed Web of Science ®Google Scholar
• Fontebasso AM, Liu XY, Sturm D, et al. Chromatin remodeling defects in pediatric and young adult glioblastoma: a tale of a variant histone 3 tail. Brain Pathol. 2013 Mar;23(2):210–216.
   PubMed Web of Science ®Google Scholar
• Sturm D, Witt H, Hovestadt V, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012 Oct 16;22(4):425–437.
   PubMed Web of Science ®Google Scholar
• Lindroth AM, Plass C. Recurrent H3.3 alterations in childhood tumors. Nat Genet. 2013 Dec;45(12):1413–1414.
   PubMed Web of Science ®Google Scholar
• Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987–996.
   PubMed Web of Science ®Google Scholar
• Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001 Aug;95(2):190–198.
   PubMed Web of Science ®Google Scholar
• Smith JS, Chang EF, Lamborn KR, et al. Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol. 2008 Mar 10;26(8):1338–1345.
   PubMed Web of Science ®Google Scholar
• Abhinav K, Yeh FC, Mansouri A, et al. High-definition fiber tractography for the evaluation of perilesional white matter tracts in high-grade glioma surgery. Neuro Oncol. 2015 Sep;17(9):1199–1209.
   PubMed Web of Science ®Google Scholar
• Chan MD. Recent technical advances and indications for radiation therapy in low-grade glioma. Semin Radiat Oncol. 2015 Jul;25(3):189–196.
   PubMed Web of Science ®Google Scholar
• van den Bent MJ, Dubbink HJ, Sanson M, et al. MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. J Clin Oncol. 2009 Dec 10;27(35):5881–5886.
   PubMed Web of Science ®Google Scholar
• Agarwal S, Manchanda P, Vogelbaum MA, et al. Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma. Drug Metab Dispos. 2013 Jan;41(1):33–39.
   PubMed Web of Science ®Google Scholar
• Jackson CM, Lim M, Drake CG. Immunotherapy for brain cancer: recent progress and future promise. Clin Cancer Res. 2014 Jul 15;20(14):3651–3659.
   PubMed Web of Science ®Google Scholar
• Calinescu AA, Kamran N, Baker G, et al. Overview of current immunotherapeutic strategies for glioma. Immunotherapy. 2015;7(10):1073–1104.
   PubMed Web of Science ®Google Scholar
• Reardon DA, Freeman G, Wu C, et al. Immunotherapy advances for glioblastoma. Neuro Oncol. 2014 Nov;16(11):1441–1458.
   PubMed Web of Science ®Google Scholar
• Kim ES, Kim JE, Patel MA, et al. Immune checkpoint modulators: an emerging antiglioma armamentarium. J Immunol Res. 2016;2016:4683607.
   PubMed Web of Science ®Google Scholar
• Galon J, Angell HK, Bedognetti D, et al. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity. 2013 Jul 25;39(1):11–26.
   PubMed Web of Science ®Google Scholar
• Gajewski TF, Woo SR, Zha Y, et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol. 2013 Apr;25(2):268–276.
   PubMed Web of Science ®Google Scholar
• Kim JE, Lim M. The role of checkpoints in the treatment of GBM. J Neuro Oncol. 2015 Jul;123(3):413–423.
   PubMed Web of Science ®Google Scholar
• Goldmann J, Kwidzinski E, Brandt C, et al. T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol. 2006 Oct;80(4):797–801.
   PubMed Web of Science ®Google Scholar
• Cserr HF, Harling-Berg CJ, Knopf PM. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol. 1992 Oct;2(4):269–276.
   PubMed Web of Science ®Google Scholar
• Davies DC. Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat. 2002 Jun;200(6):639–646.
   PubMed Web of Science ®Google Scholar
• 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 Aug 1;11(15):5515–5525.
   PubMed Web of Science ®Google Scholar
• 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 Mar;13(3):324–333.
   PubMed Web of Science ®Google Scholar
• Heimberger AB, Kong LY, Abou-Ghazal M, et al. The role of tregs in human glioma patients and their inhibition with a novel STAT-3 inhibitor. Clin Neurosurg. 2009;56:98–106.
   PubMedGoogle Scholar
• Zhang JG, Kruse CA, Driggers L, et al. Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy. J Neuro Oncol. 2008 May;88(1):65–76.
   PubMed Web of Science ®Google Scholar
• Grossman SA, Ye X, Lesser G, et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res. 2011 Aug 15;17(16):5473–5480.
   PubMed Web of Science ®Google Scholar
• Razavi SM, Lee KE, Jin BE, et al. Immune evasion strategies of glioblastoma. Front Surg. 2016;3:11.
   PubMed Web of Science ®Google Scholar
• Jordan JT, Sun W, Hussain SF, et al. Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. Cancer Immunol Immunother. 2008 Jan;57(1):123–131.
   PubMed Web of Science ®Google Scholar
• Bloch O, Crane CA, Kaur R, et al. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin Cancer Res. 2013 Jun 15;19(12):3165–3175.
   PubMed Web of Science ®Google Scholar
• Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009 Mar;9(3):162–174.
   PubMed Web of Science ®Google Scholar
• Facoetti A, Nano R, Zelini P, et al. Human leukocyte antigen and antigen processing machinery component defects in astrocytic tumors. Clin Cancer Res. 2005 Dec 1;11(23):8304–8311.
   PubMed Web of Science ®Google Scholar
• Kren L, Slaby O, Muckova K, et al. Expression of immune-modulatory molecules HLA-G and HLA-E by tumor cells in glioblastomas: an unexpected prognostic significance? Neuropathology. 2011 Apr;31(2):129–134.
   PubMed Web of Science ®Google Scholar
• Wastowski IJ, Simoes RT, Yaghi L, et al. Human leukocyte antigen-G is frequently expressed in glioblastoma and may be induced in vitro by combined 5-aza-2ʹ-deoxycytidine and interferon-gamma treatments: results from a multicentric study. Am J Pathol. 2013 Feb;182(2):540–552.
   PubMed Web of Science ®Google Scholar
• Xu LW, Chow KK, Lim M, et al. Current vaccine trials in glioblastoma: a review. J Immunol Res. 2014;2014:796856.
   PubMed Web of Science ®Google Scholar
• Badie B, Schartner J, Prabakaran S, et al. Expression of Fas ligand by microglia: possible role in glioma immune evasion. J Neuroimmunol. 2001 Nov 1;120(1–2):19–24.
   PubMed Web of Science ®Google Scholar
• Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol. 2002 Jul;3(7):611–618.
   PubMed Web of Science ®Google Scholar
• Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009 Aug 3;206(8):1717–1725.
   PubMed Web of Science ®Google Scholar
• Tarhini AA, Kirkwood JM. CTLA-4-blocking immunotherapy with ipilimumab for advanced melanoma. Oncology (Williston Park). 2010 Dec;24(14):1302, 04.
   Google Scholar
• Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Apr;12(4):252–264.
   PubMed Web of Science ®Google Scholar
• Grosso JF, Kelleher CC, Harris TJ, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007 Nov;117(11):3383–3392.
   PubMed Web of Science ®Google Scholar
• Berghoff AS, Kiesel B, Widhalm G, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol. 2015 Aug;17(8):1064–1075.
   PubMed Web of Science ®Google Scholar
• Liu Z, Han H, He X, et al. Expression of the galectin-9-Tim-3 pathway in glioma tissues is associated with the clinical manifestations of glioma. Oncol Lett. 2016 Mar;11(3):1829–1834.
   PubMed Web of Science ®Google Scholar
• Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013 Jul 25;39(1):1–10.
   PubMed Web of Science ®Google Scholar
• Driessens G, Kline J, Gajewski TF. Costimulatory and coinhibitory receptors in anti-tumor immunity. Immunol Rev. 2009 May;229(1):126–144.
   PubMed Web of Science ®Google Scholar
• Jackson C, Ruzevick J, Phallen J, et al. Challenges in immunotherapy presented by the glioblastoma multiforme microenvironment. Clin Dev Immunol. 2011;2011:732413.
   PubMedGoogle Scholar
• Saikali S, Avril T, Collet B, et al. Expression of nine tumour antigens in a series of human glioblastoma multiforme: interest of EGFRvIII, IL-13Ralpha2, gp100 and TRP-2 for immunotherapy. J Neuro Oncol. 2007 Jan;81(2):139–148.
   PubMed Web of Science ®Google Scholar
• Bakdash G, Sittig SP, van Dijk T, et al. The nature of activatory and tolerogenic dendritic cell-derived signal II. Front Immunol. 2013;4:53.
   PubMed Web of Science ®Google Scholar
• Joller N, Hafler JP, Brynedal B, et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol. 2011 Feb 1;186(3):1338–1342.
   PubMed Web of Science ®Google Scholar
• Hastings WD, Anderson DE, Kassam N, et al. TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. Eur J Immunol. 2009 Sep;39(9):2492–2501.
   PubMed Web of Science ®Google Scholar
• Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065–1068.
   PubMed Web of Science ®Google Scholar
• Linsley PS, Greene JL, Brady W, et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity. 1994 Dec;1(9):793–801.
   PubMed Web of Science ®Google Scholar
• Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711–723.
   PubMed Web of Science ®Google Scholar
• Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459–465.
   PubMed Web of Science ®Google Scholar
• Queirolo P, Spagnolo F, Ascierto PA, et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neuro Oncol. 2014 May;118(1):109–116.
   PubMed Web of Science ®Google Scholar
• Company B-MS. Yervoy (ipilimumab) [prescribing information]. [ cited 2013]. Available from: http://www.yervoy.com.
   Google Scholar
• Fecci PE, Ochiai H, Mitchell DA, et al. Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clin Cancer Res. 2007 Apr 1;13(7):2158–2167.
   PubMed Web of Science ®Google Scholar
• Vom Berg J, Vrohlings M, Haller S, et al. Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection. J Exp Med. 2013 Dec 16;210(13):2803–2811.
   PubMed Web of Science ®Google Scholar
• Agarwalla P, Barnard Z, Fecci P, et al. Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors. J Immunother. 2012 Jun;35(5):385–389.
   PubMed Web of Science ®Google Scholar
• 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 Jun 28;366(26):2443–2454.
   PubMed Web of Science ®Google Scholar
• Eppihimer MJ, Gunn J, Freeman GJ, et al. Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation. 2002 Apr;9(2):133–145.
   PubMed Web of Science ®Google Scholar
• Liu Y, Carlsson R, Ambjorn M, et al. PD-L1 expression by neurons nearby tumors indicates better prognosis in glioblastoma patients. J Neurosci. 2013 Aug 28;33(35):14231–14245.
   PubMed Web of Science ®Google Scholar
• Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122–133.
   PubMed Web of Science ®Google Scholar
• Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311–4318.
   PubMed Web of Science ®Google Scholar
• Company B-MS. Opdivo (nivolumab) [prescribing information]. [ cited 2014]. Available from: http://www.opdivo.bmscustomerconnect.com/gateway.
   Google Scholar
• Merck & Co. I. Keytruda (pembrolizumab) [prescribing information]. [ cited 2015]. Available from: http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf.
   Google Scholar
• Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015 Jan 22;372(4):311–319.
   PubMed Web of Science ®Google Scholar
• Scott JA. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: Interim phase I results. J Clin Oncol. 2016 Jun 27. pii:JCO669861. [Epub ahead of print].
   Google Scholar
• Preusser M, Lim M, Hafler DA, et al. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol. 2015 Sep;11(9):504–514.
   PubMed Web of Science ®Google Scholar
• Hafler DA, Kuchroo V. TIMs: central regulators of immune responses. J Exp Med. 2008 Nov 24;205(12):2699–2701.
   PubMed Web of Science ®Google Scholar
• Anderson AC. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res. 2014 May;2(5):393–398.
   PubMed Web of Science ®Google Scholar
• Han S, Feng S, Xu L, et al. Tim-3 on peripheral CD4(+) and CD8(+) T cells is involved in the development of glioma. DNA Cell Biol. 2014 Apr;33(4):245–250.
   PubMed Web of Science ®Google Scholar
• Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013 Jun 1;86(2):343–349.
   PubMed Web of Science ®Google Scholar
• Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003 Oct;9(10):1269–1274.
   PubMed Web of Science ®Google Scholar
• Wainwright DA, Balyasnikova IV, Chang AL, et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res. 2012 Nov 15;18(22):6110–6121.
   PubMed Web of Science ®Google Scholar
• Wainwright DA, Chang AL, Dey M, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res. 2014 Oct 15;20(20):5290–5301.
   PubMed Web of Science ®Google Scholar
• Baixeras E, Huard B, Miossec C, et al. Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J Exp Med. 1992 Aug 1;176(2):327–337.
   PubMed Web of Science ®Google Scholar
• Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012 Feb 15;72(4):917–927.
   PubMed Web of Science ®Google Scholar
• Grossauer S, Koeck K, Petritsch C. Immunecheckpoint blockage - a promising strategy to overcome glioma stem cell therapy-resistance. Insights Neurosurg. 2016;1(1):1.
   Google Scholar
• Castro MG, Candolfi M, Wilson TJ, et al. Adenoviral vector-mediated gene therapy for gliomas: coming of age. Expert Opin Biol Ther. 2014 Sep;14(9):1241–1257.
   PubMed Web of Science ®Google Scholar
• Kane JR, Miska J, Young JS, et al. Sui generis: gene therapy and delivery systems for the treatment of glioblastoma. Neuro Oncol. 2015 Mar;17(Suppl 2):ii24–ii36.
   PubMed Web of Science ®Google Scholar
• Workenhe ST, Mossman KL. Oncolytic virotherapy and immunogenic cancer cell death: sharpening the sword for improved cancer treatment strategies. Mol Ther. 2014 Feb;22(2):251–256.
   PubMed Web of Science ®Google Scholar
• Krysko DV, Garg AD, Kaczmarek A, et al. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer. 2012 Dec;12(12):860–875.
   PubMed Web of Science ®Google Scholar
• Curtin JF, Liu N, Candolfi M, et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med. 2009 Jan 13;6(1):e10.
   PubMed Web of Science ®Google Scholar
• Duarte S, Carle G, Faneca H, et al. Suicide gene therapy in cancer: where do we stand now? Cancer Lett. 2012 Nov 28;324(2):160–170.
   PubMed Web of Science ®Google Scholar
• Okura H, Smith C, Rutka J. Gene therapy for malignant glioma. Mol Cell Ther. 2014;2(1):1–19. Epub 2014 Jul 08.
   Google Scholar
• Tobias A, Ahmed A, Moon KS, et al. The art of gene therapy for glioma: a review of the challenging road to the bedside. J Neurol Neurosurg Psychiatry. 2013 Feb;84(2):213–222.
   PubMed Web of Science ®Google Scholar
• Prados MD, McDermott M, Chang SM, et al. Treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration: a phase I/II multi-institutional trial. J Neuro Oncol. 2003 Dec;65(3):269–278.
   PubMed Web of Science ®Google Scholar
• Germano IM, Emdad L, Qadeer ZA, et al. Embryonic stem cell (ESC)-mediated transgene delivery induces growth suppression, apoptosis and radiosensitization, and overcomes temozolomide resistance in malignant gliomas. Cancer Gene Ther. 2010 Sep;17(9):664–674.
   PubMed Web of Science ®Google Scholar
• Rainov NG. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther. 2000 Nov 20;11(17):2389–2401.
   PubMed Web of Science ®Google Scholar
• Maraskovsky E, Brasel K, Teepe M, et al. Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J Exp Med. 1996 Nov 1;184(5):1953–1962.
   PubMed Web of Science ®Google Scholar
• Ali S, Curtin JF, Zirger JM, et al. Inflammatory and anti-glioma effects of an adenovirus expressing human soluble Fms-like tyrosine kinase 3 ligand (hsFlt3L): treatment with hsFlt3L inhibits intracranial glioma progression. Mol Ther. 2004 Dec;10(6):1071–1084.
   PubMed Web of Science ®Google Scholar
• Ali S, King GD, Curtin JF, et al. Combined immunostimulation and conditional cytotoxic gene therapy provide long-term survival in a large glioma model. Cancer Res. 2005 Aug 15;65(16):7194–7204.
   PubMed Web of Science ®Google Scholar
• Candolfi M, Curtin JF, Yagiz K, et al. B cells are critical to T-cell-mediated antitumor immunity induced by a combined immune-stimulatory/conditionally cytotoxic therapy for glioblastoma. Neoplasia. 2011 Oct;13(10):947–960.
   PubMed Web of Science ®Google Scholar
• King GD, Muhammad AK, Curtin JF, et al. Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model. Neuro Oncol. 2008 Feb;10(1):19–31.
   PubMed Web of Science ®Google Scholar
• King GD, Muhammad AK, Larocque D, et al. Combined Flt3L/TK gene therapy induces immunological surveillance which mediates an immune response against a surrogate brain tumor neoantigen. Mol Ther. 2011 Oct;19(10):1793–1801.
   PubMed Web of Science ®Google Scholar
• Aghi M, Martuza RL. Oncolytic viral therapies - the clinical experience. Oncogene. 2005 Nov 21;24(52):7802–7816.
   PubMed Web of Science ®Google Scholar
• Cassady KA, Parker JN. Herpesvirus vectors for therapy of brain tumors. Open Virol J. 2010;4:103–108.
   PubMedGoogle Scholar
• Myers R, Harvey M, Kaufmann TJ, et al. Toxicology study of repeat intracerebral administration of a measles virus derivative producing carcinoembryonic antigen in rhesus macaques in support of a phase I/II clinical trial for patients with recurrent gliomas. Hum Gene Ther. 2008 Jul;19(7):690–698.
   PubMed Web of Science ®Google Scholar
• Forsyth P, Roldan G, George D, et al. A phase I trial of intratumoral administration of reovirus in patients with histologically confirmed recurrent malignant gliomas. Mol Ther. 2008 Mar;16(3):627–632.
   PubMed Web of Science ®Google Scholar
• Kim JW, Kane JR, Young JS, et al. A genetically modified adenoviral vector with a phage display-derived peptide incorporated into fiber fibritin chimera prolongs survival in experimental glioma. Hum Gene Ther. 2015 Sep;26(9):635–646.
   PubMed Web of Science ®Google Scholar
• Nandi S, Ulasov IV, Tyler MA, et al. Low-dose radiation enhances survivin-mediated virotherapy against malignant glioma stem cells. Cancer Res. 2008 Jul 15;68(14):5778–5784.
   PubMed Web of Science ®Google Scholar
• Kirn D, Hermiston T, McCormick F. ONYX-015: clinical data are encouraging. Nat Med. 1998 Dec;4(12):1341–1342.
   PubMed Web of Science ®Google Scholar
• Chiocca EA, Abbed KM, Tatter S, et al. A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther. 2004 Nov;10(5):958–966.
   PubMed Web of Science ®Google Scholar
• Lang FF, Conrad C, Gomez-Manzano C, et al. First-in-human phase I clinical trial of oncolytic delta-24-RGD (DNX-2401) with biological endpoints: implications for viro- immunotherapy. Neuro Oncol. 2014 July 1;16(suppl3):iii39.
   Web of Science ®Google Scholar
• Jacobs SK, Wilson DJ, Kornblith PL, et al. Interleukin-2 or autologous lymphokine-activated killer cell treatment of malignant glioma: phase I trial. Cancer Res. 1986 Apr;46(4 Pt 2):2101–2104.
   PubMed Web of Science ®Google Scholar
• Holladay FP, Heitz-Turner T, Bayer WL, et al. Autologous tumor cell vaccination combined with adoptive cellular immunotherapy in patients with grade III/IV astrocytoma. J Neuro Oncol. 1996 Feb;27(2):179–189.
   PubMed Web of Science ®Google Scholar
• Colombo F, Barzon L, Franchin E, et al. Combined HSV-TK/IL-2 gene therapy in patients with recurrent glioblastoma multiforme: biological and clinical results. Cancer Gene Ther. 2005 Oct;12(10):835–848.
   PubMed Web of Science ®Google Scholar
• Okada H, Giezeman-Smits KM, Tahara H, et al. Effective cytokine gene therapy against an intracranial glioma using a retrovirally transduced IL-4 plus HSVtk tumor vaccine. Gene Ther. 1999 Feb;6(2):219–226.
   PubMed Web of Science ®Google Scholar
• Okada H, Pollack IF, Lotze MT, et al. 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. 2000 Mar 1;11(4):637–653.
   PubMed Web of Science ®Google Scholar
• Natsume A, Ishii D, Wakabayashi T, et al. IFN-beta down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide. Cancer Res. 2005 Sep 1;65(17):7573–7579.
   PubMed Web of Science ®Google Scholar
• Natsume A, Wakabayashi T, Ishii D, et al. A combination of IFN-beta and temozolomide in human glioma xenograft models: implication of p53-mediated MGMT downregulation. Cancer Chemother Pharmacol. 2008 Apr;61(4):653–659.
   PubMed Web of Science ®Google Scholar
• Wakabayashi T, Natsume A, Hashizume Y, et al. A phase I clinical trial of interferon-beta gene therapy for high-grade glioma: novel findings from gene expression profiling and autopsy. J Gene Med. 2008 Apr;10(4):329–339.
   PubMed Web of Science ®Google Scholar
• Chiocca EA, Smith KM, McKinney B, et al. A phase I trial of Ad.hIFN-beta gene therapy for glioma. Mol Ther. 2008 Mar;16(3):618–626.
   PubMed Web of Science ®Google Scholar
• Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015 Apr 3;348(6230):69–74.
   PubMed Web of Science ®Google Scholar
• Heemskerk B, Kvistborg P, Schumacher TN. The cancer antigenome. EMBO J. 2013 Jan 23;32(2):194–203.
   PubMed Web of Science ®Google Scholar
• Heimberger AB, Suki D, Yang D, et al. The natural history of EGFR and EGFRvIII in glioblastoma patients. J Transl Med. 2005 Oct;19(3):38.
   Web of Science ®Google Scholar
• Liu G, Yuan X, Zeng Z, et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer. 2006;5:67.
   PubMed Web of Science ®Google Scholar
• 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 Jan;62(1):125–135.
   PubMed Web of Science ®Google Scholar
• Liu G, Yu JS, Zeng G, et al. AIM-2: a novel tumor antigen is expressed and presented by human glioma cells. J Immunother. 2004 May-Jun;27(3):220–226.
   PubMed Web of Science ®Google Scholar
• Zhang JG, Eguchi J, Kruse CA, et al. Antigenic profiling of glioma cells to generate allogeneic vaccines or dendritic cell-based therapeutics. Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):566–575.
   PubMed Web of Science ®Google Scholar
• Sareddy GR, Panigrahi M, Challa S, et al. Activation of Wnt/beta-catenin/Tcf signaling pathway in human astrocytomas. Neurochem Int. 2009 Sep;55(5):307–317.
   PubMed Web of Science ®Google Scholar
• Liu C, Tu Y, Sun X, et al. Wnt/beta-Catenin pathway in human glioma: expression pattern and clinical/prognostic correlations. Clin Exp Med. 2011 Jun;11(2):105–112.
   PubMed Web of Science ®Google Scholar
• Cenci T, Martini M, Montano N, et al. Prognostic relevance of c-Myc and BMI1 expression in patients with glioblastoma. Am J Clin Pathol. 2012 Sep;138(3):390–396.
   PubMed Web of Science ®Google Scholar
• Leung C, Lingbeek M, Shakhova O, et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature. 2004 Mar 18;428(6980):337–341.
   PubMed Web of Science ®Google Scholar
• Zakrzewska M, Zakrzewski K, Gresner SM, et al. Polycomb genes expression as a predictor of poor clinical outcome in children with medulloblastoma. Child’s Nerv Syst. 2011 Jan;27(1):79–86.
   PubMed Web of Science ®Google Scholar
• Allan K, Jordan RC, Ang LC, et al. Overexpression of cyclin A and cyclin B1 proteins in astrocytomas. Arch Pathol Lab Med. 2000 Feb;124(2):216–220.
   PubMed Web of Science ®Google Scholar
• Rempel SA, Rosenblum ML, Mikkelsen T, et al. Cathepsin B expression and localization in glioma progression and invasion. Cancer Res. 1994 Dec 1;54(23):6027–6031.
   PubMed Web of Science ®Google Scholar
• Gopinath S, Malla R, Alapati K, et al. Cathepsin B and uPAR regulate self-renewal of glioma-initiating cells through GLI-regulated Sox2 and Bmi1 expression. Carcinogenesis. 2013 Mar;34(3):550–559.
   PubMed Web of Science ®Google Scholar
• Sivaparvathi M, Sawaya R, Wang SW, et al. Overexpression and localization of cathepsin B during the progression of human gliomas. Clin Exp Metastasis. 1995 Jan;13(1):49–56.
   PubMed Web of Science ®Google Scholar
• Barresi V, Buttarelli FR, Vitarelli EE, et al. Caveolin-1 expression in diffuse gliomas: correlation with the proliferation index, epidermal growth factor receptor, p53, and 1p/19q status. Hum Pathol. 2009 Dec;40(12):1738–1746.
   PubMed Web of Science ®Google Scholar
• Senetta R, Miracco C, Lanzafame S, et al. Epidermal growth factor receptor and caveolin-1 coexpression identifies adult supratentorial ependymomas with rapid unfavorable outcomes. Neuro Oncol. 2011 Feb;13(2):176–183.
   PubMed Web of Science ®Google Scholar
• Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003 Sep 15;63(18):5821–5828.
   PubMed Web of Science ®Google Scholar
• Emlet DR, Gupta P, Holgado-Madruga M, et al. Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III. Cancer Res. 2014 Feb 15;74(4):1238–1249.
   PubMed Web of Science ®Google Scholar
• Dahlrot RH, Hansen S, Jensen SS, et al. Clinical value of CD133 and nestin in patients with glioma: a population-based study. Int J Clin Exp Pathol. 2014;7(7):3739–3751.
   PubMed Web of Science ®Google Scholar
• Zhang M, Song T, Yang L, et al. Nestin and CD133: valuable stem cell-specific markers for determining clinical outcome of glioma patients. J Exp Clin Cancer Res. 2008;27:85.
   PubMed Web of Science ®Google Scholar
• Kitange GJ, Carlson BL, Schroeder MA, et al. Expression of CD74 in high grade gliomas: a potential role in temozolomide resistance. J Neuro Oncol. 2010 Nov;100(2):177–186.
   PubMed Web of Science ®Google Scholar
• Baron N, Deuster O, Noelker C, et al. Role of macrophage migration inhibitory factor in primary glioblastoma multiforme cells. J Neurosci Res. 2011 May;89(5):711–717.
   PubMed Web of Science ®Google Scholar
• Shono T, Tofilon PJ, Bruner JM, et al. Cyclooxygenase-2 expression in human gliomas: prognostic significance and molecular correlations. Cancer Res. 2001 Jun 1;61(11):4375–4381.
   PubMed Web of Science ®Google Scholar
• Penas-Prado M, Hess KR, Fisch MJ, et al. Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma. Neuro Oncol. 2015 Feb;17(2):266–273.
   PubMed Web of Science ®Google Scholar
• Eberstal S, Badn W, Fritzell S, et al. Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors. Cancer Immunol Immunother. 2012 Aug;61(8):1191–1199.
   PubMed Web of Science ®Google Scholar
• Lewis-Tuffin LJ, Rodriguez F, Giannini C, et al. Misregulated E-cadherin expression associated with an aggressive brain tumor phenotype. Plos One. 2010;5(10):e13665.
   PubMed Web of Science ®Google Scholar
• Wu W, Tian Y, Wan H, et al. Expression of beta-catenin and E- and N-cadherin in human brainstem gliomas and clinicopathological correlations. Int J Neurosci. 2013 May;123(5):318–323.
   PubMed Web of Science ®Google Scholar
• 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 Nov 1;28(31):4722–4729.
   PubMed Web of Science ®Google Scholar
• Babu R, Adamson DC. Rindopepimut: an evidence-based review of its therapeutic potential in the treatment of EGFRvIII-positive glioblastoma. Core Evid. 2012;7:93–103.
   PubMedGoogle Scholar
• 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 Jan;17(6):854–861.
   PubMed Web of Science ®Google Scholar
• Heimberger AB, Sampson JH. The PEPvIII-KLH (CDX-110) vaccine in glioblastoma multiforme patients. Expert Opin Biol Ther. 2009 Aug;9(8):1087–1098.
   PubMed Web of Science ®Google Scholar
• Okada H, Kalinski P, Ueda R, 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. 2011 Jan 20;29(3):330–336.
   PubMed Web of Science ®Google Scholar
• Wykosky J, Gibo DM, Stanton C, et al. Interleukin-13 receptor alpha 2, EphA2, and Fos-related antigen 1 as molecular denominators of high-grade astrocytomas and specific targets for combinatorial therapy. Clin Cancer Res. 2008 Jan 1;14(1):199–208.
   PubMed Web of Science ®Google Scholar
• Okada H, Kohanbash G, Zhu X, et al. Immunotherapeutic approaches for glioma. Crit Rev Immunol. 2009;29(1):1–42.
   PubMed Web of Science ®Google Scholar
• Driggers L, Zhang JG, Newcomb EW, et al. Immunotherapy of pediatric brain tumor patients should include an immunoprevention strategy: a medical hypothesis paper. J Neuro Oncol. 2010 Apr;97(2):159–169.
   PubMed Web of Science ®Google Scholar
• Ueda R, Low KL, Zhu X, et al. Spontaneous immune responses against glioma-associated antigens in a long term survivor with malignant glioma. J Transl Med. 2007;5:68.
   PubMed Web of Science ®Google Scholar
• Pollack IF, Jakacki RI, Butterfield LH, et al. Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas. J Clin Oncol. 2014 Jul 1;32(19):2050–2058.
   PubMed Web of Science ®Google Scholar
• Orzan F, Pellegatta S, Poliani PL, et al. Enhancer of Zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells. Neuropathol Appl Neurobiol. 2011 Jun;37(4):381–394.
   PubMed Web of Science ®Google Scholar
• Scarcella DL, Chow CW, Gonzales MF, et al. Expression of MAGE and GAGE in high-grade brain tumors: a potential target for specific immunotherapy and diagnostic markers. Clin Cancer Res. 1999 Feb;5(2):335–341.
   PubMed Web of Science ®Google Scholar
• Mennel HD, Lell B. Ganglioside (GD2) expression and intermediary filaments in astrocytic tumors. Clin Neuropathol. 2005 Jan-Feb;24(1):13–18.
   PubMed Web of Science ®Google Scholar
• Schulz G, Cheresh DA, Varki NM, et al. Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients. Cancer Res. 1984 Dec;44(12 Pt 1):5914–5920.
   PubMed Web of Science ®Google Scholar
• Finocchiaro G, Pellegatta S. Immunotherapy with dendritic cells loaded with glioblastoma stem cells: from preclinical to clinical studies. Cancer Immunol Immunother. 2016 Jan;65(1):101–109.
   PubMed Web of Science ®Google Scholar
• Cantini G, Pisati F, Pessina S, et al. Immunotherapy against the radial glia marker GLAST effectively triggers specific antitumor effectors without autoimmunity. Oncoimmunology. 2012 Sep 1;1(6):884–893.
   PubMed Web of Science ®Google Scholar
• Jimeno A, Weiss GJ, Miller WH Jr., et al. Phase I study of the hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin Cancer Res. 2013 May 15;19(10):2766–2774.
   PubMed Web of Science ®Google Scholar
• Cui D, Xu Q, Wang K, et al. Gli1 is a potential target for alleviating multidrug resistance of gliomas. J Neurol Sci. 2010 Jan 15;288(1–2):156–166.
   PubMed Web of Science ®Google Scholar
• Rossi M, Magnoni L, Miracco C, et al. beta-catenin and Gli1 are prognostic markers in glioblastoma. Cancer Biol Ther. 2011 Apr 15;11(8):753–761.
   PubMed Web of Science ®Google Scholar
• Yamamoto H, Swoger J, Greene S, et al. Beta1,6-N-acetylglucosamine-bearing N-glycans in human gliomas: implications for a role in regulating invasivity. Cancer Res. 2000 Jan 1;60(1):134–142.
   PubMed Web of Science ®Google Scholar
• Akiyama Y, Oshita C, Kume A, et al. Alpha-type-1 polarized dendritic cell-based vaccination in recurrent high-grade glioma: a phase I clinical trial. BMC Cancer. 2012;12:623.
   PubMed Web of Science ®Google Scholar
• Liu G, Ying H, Zeng G, et al. HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res. 2004 Jul 15;64(14):4980–4986.
   PubMed Web of Science ®Google Scholar
• Xu Q, Liu G, Yuan X, et al. Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens. Stem Cells. 2009 Aug;27(8):1734–1740.
   PubMed Web of Science ®Google Scholar
• Waitkus MS, Diplas BH, Yan H. Isocitrate dehydrogenase mutations in gliomas. Neuro Oncol. 2016 Jan;18(1):16–26.
   PubMed Web of Science ®Google Scholar
• Mitchell DA, Cui X, Schmittling RJ, et al. Monoclonal antibody blockade of IL-2 receptor alpha during lymphopenia selectively depletes regulatory T cells in mice and humans. Blood. 2011 Sep 15;118(11):3003–3012.
   PubMed Web of Science ®Google Scholar
• Mintz A, Gibo DM, Slagle-Webb B, et al. IL-13Ralpha2 is a glioma-restricted receptor for interleukin-13. Neoplasia. 2002 Sep-Oct;4(5):388–399.
   PubMed Web of Science ®Google Scholar
• Kogiku M, Ohsawa I, Matsumoto K, et al. Prognosis of glioma patients by combined immunostaining for survivin, Ki-67 and epidermal growth factor receptor. J Clin Neurosci. 2008 Nov;15(11):1198–1203.
   PubMed Web of Science ®Google Scholar
• Persson O, Salford LG, Fransson J, et al. Distribution, cellular localization, and therapeutic potential of the tumor-associated antigen Ku70/80 in glioblastoma multiforme. J Neuro Oncol. 2010 Apr;97(2):207–215.
   PubMed Web of Science ®Google Scholar
• Bao S, Wu Q, Li Z, et al. Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res. 2008 Aug 1;68(15):6043–6048.
   PubMed Web of Science ®Google Scholar
• Cheng L, Wu Q, Huang Z, et al. L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1. EMBO J. 2011 Mar 2;30(5):800–813.
   PubMed Web of Science ®Google Scholar
• Bao L, Dunham K, Lucas K. MAGE-A1, MAGE-A3, and NY-ESO-1 can be upregulated on neuroblastoma cells to facilitate cytotoxic T lymphocyte-mediated tumor cell killing. Cancer Immunol Immunother. 2011 Sep;60(9):1299–1307.
   PubMed Web of Science ®Google Scholar
• Kuan CT, Srivastava N, McLendon RE, et al. Recombinant single-chain variable fragment antibodies against extracellular epitopes of human multidrug resistance protein MRP3 for targeting malignant gliomas. Int J Cancer. 2010 Aug 1;127(3):598–611.
   PubMed Web of Science ®Google Scholar
• Terasaki M, Shibui S, Narita Y, et al. Phase I trial of a personalized peptide vaccine for patients positive for human leukocyte antigen–A24 with recurrent or progressive glioblastoma multiforme. J Clin Oncol. 2011 January 20;29(3):337–344.
   PubMed Web of Science ®Google Scholar
• Ishiwata T, Teduka K, Yamamoto T, et al. Neuroepithelial stem cell marker nestin regulates the migration, invasion and growth of human gliomas. Oncol Rep. 2011 Jul;26(1):91–99.
   PubMed Web of Science ®Google Scholar
• Dhodapkar MV, Sznol M, Zhao B, et al. Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205. Sci Transl Med. 2014 Apr 16;6(232):232–251.
   Web of Science ®Google Scholar
• Rousseau A, Nutt CL, Betensky RA, et al. Expression of oligodendroglial and astrocytic lineage markers in diffuse gliomas: use of YKL-40, ApoE, ASCL1, and NKX2-2. J Neuropathol Exp Neurol. 2006 Dec;65(12):1149–1156.
   PubMed Web of Science ®Google Scholar
• Ligon KL, Huillard E, Mehta S, et al. Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron. 2007 Feb 15;53(4):503–517.
   PubMed Web of Science ®Google Scholar
• Ligon KL, Alberta JA, Kho AT, et al. The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas. J Neuropathol Exp Neurol. 2004 May;63(5):499–509.
   PubMed Web of Science ®Google Scholar
• Elsir T, Eriksson A, Orrego A, et al. Expression of PROX1 Is a common feature of high-grade malignant astrocytic gliomas. J Neuropathol Exp Neurol. 2010 Feb;69(2):129–138.
   PubMed Web of Science ®Google Scholar
• Geiger KD, Hendruschk S, Rieber EP, et al. The prostate stem cell antigen represents a novel glioma-associated antigen. Oncol Rep. 2011 Jul;26(1):13–21.
   PubMed Web of Science ®Google Scholar
• Schmitz M, Temme A, Senner V, et al. Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy. Br J Cancer. 2007 Apr 23;96(8):1293–1301.
   PubMed Web of Science ®Google Scholar
• Favaro R, Appolloni I, Pellegatta S, et al. Sox2 is required to maintain cancer stem cells in a mouse model of high-grade oligodendroglioma. Cancer Res. 2014 Mar 15;74(6):1833–1844.
   PubMed Web of Science ®Google Scholar
• Ueda R, Ohkusu-Tsukada K, Fusaki N, et al. Identification of HLA-A2- and A24-restricted T-cell epitopes derived from SOX6 expressed in glioma stem cells for immunotherapy. Int J Cancer. 2010 Feb 15;126(4):919–929.
   PubMed Web of Science ®Google Scholar
• Schmitz M, Wehner R, Stevanovic S, et al. Identification of a naturally processed T cell epitope derived from the glioma-associated protein SOX11. Cancer Lett. 2007 Jan 8;245(1–2):331–336.
   PubMed Web of Science ®Google Scholar
• Son MJ, Woolard K, Nam DH, et al. SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell. 2009 May 8;4(5):440–452.
   PubMed Web of Science ®Google Scholar
• Tchirkov A, Rolhion C, Kemeny JL, et al. Clinical implications of quantitative real-time RT-PCR analysis of hTERT gene expression in human gliomas. Br J Cancer. 2003 Feb 24;88(4):516–520.
   PubMed Web of Science ®Google Scholar
• Yamamoto M, Sawaya R, Mohanam S, et al. Expression and localization of urokinase-type plasminogen activator receptor in human gliomas. Cancer Res. 1994 Sep 15;54(18):5016–5020.
   PubMed Web of Science ®Google Scholar
• Gondi CS, Lakka SS, Dinh DH, et al. RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas. Oncogene. 2004 Nov 4;23(52):8486–8496.
   PubMed Web of Science ®Google Scholar
• 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 May;108(5):963–971.
   PubMed Web of Science ®Google Scholar
• Morita S, Oka Y, Tsuboi A, et al. A phase I/II trial of a WT1 (Wilms’ tumor gene) peptide vaccine in patients with solid malignancy: safety assessment based on the phase I data. Jpn J Clin Oncol. 2006 Apr;36(4):231–236.
   PubMed Web of Science ®Google Scholar
• Nakahara Y, Okamoto H, Mineta T, et al. Expression of the Wilms’ tumor gene product WT1 in glioblastomas and medulloblastomas. Brain Tumor Pathol. 2004;21(3):113–116.
   PubMedGoogle Scholar
• Shao R, Francescone R, Ngernyuang N, et al. Anti-YKL-40 antibody and ionizing irradiation synergistically inhibit tumor vascularization and malignancy in glioblastoma. Carcinogenesis. 2014 Feb;35(2):373–382.
   PubMed Web of Science ®Google Scholar
• Schumacher T, Bunse L, Pusch S, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature. 2014 Aug 21;512(7514):324–327.
   PubMed Web of Science ®Google Scholar
• Hou Y, Kohanbash G, Okada K, et al. Novel and shared neoantigen for glioma T cell therapy derived from histone 3 variant H3. 3 K27M mutation. J Immunother Cancer. 2015;3(Suppl 2):P445.
   Google Scholar
• Burnet FM. Immunological aspects of malignant disease. Lancet. 1967 Jun 3;1(7501):1171–1174.
   PubMed Web of Science ®Google Scholar
• Baldwin RW, Robins RA. Factors interfering with immunological rejection of tumours. Br Med Bull. 1976 May;32(2):118–123.
   PubMed Web of Science ®Google Scholar
• Doll R, Kinlen L. Immunosurveillance and cancer: epidemiological evidence. Br Med J. 1970 Nov 14;4(5732):420–422.
   PubMed Web of Science ®Google Scholar
• Munn DH, Bronte V. Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol. 2016 Apr;39:1–6.
   PubMed Web of Science ®Google Scholar
• Celldex website. Available from: http://ir.celldex.com/releasedetail.cfm?ReleaseID=959021.
   Google Scholar
• Hadrup SR, Bakker AH, Shu CJ, et al. Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers. Nat Methods. 2009 Jul;6(7):520–526.
   PubMed Web of Science ®Google Scholar
• van Rooij N, van Buuren MM, Philips D, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013 Nov 10;31(32):e439–e442.
   PubMed Web of Science ®Google Scholar
• Carreno BM, Magrini V, Becker-Hapak M, et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science. 2015 May 15;348(6236):803–808.
   PubMed Web of Science ®Google Scholar
• Gandhi SJ, Minn AJ, Vonderheide RH, et al. Awakening the immune system with radiation: optimal dose and fractionation. Cancer Lett. 2015 Nov 28;368(2):185–190.
   PubMed Web of Science ®Google Scholar
• Corso CD, Ali AN, Diaz R. Radiation-induced tumor neoantigens: imaging and therapeutic implications. Am J Cancer Res. 2011;1(3):390–412.
   PubMed Web of Science ®Google Scholar
• Golden EB, Frances D, Pellicciotta I, et al. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology. 2014;3:e28518.
   PubMed Web of Science ®Google Scholar
• Wild-Bode C, Weller M, Rimner A, et al. Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. Cancer Res. 2001 Mar 15;61(6):2744–2750.
   PubMed Web of Science ®Google Scholar
• Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013 Jun 1;86(2):343–349.
   PubMed Web of Science ®Google Scholar
• Tinhofer I, Niehr F, Konschak R, et al. Next-generation sequencing: hype and hope for development of personalized radiation therapy? Radiat Oncol. 2015;10:183.
   PubMed Web of Science ®Google Scholar
• Prins RM, Soto H, Konkankit V, et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res. 2011 Mar 15;17(6):1603–1615.
   PubMed Web of Science ®Google Scholar
• Mitchell DA, Batich KA, Gunn MD, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature. 2015 Mar 19;519(7543):366–369.
   PubMed Web of Science ®Google Scholar
• Cobbs CS, Harkins L, Samanta M, et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 2002 Jun 15;62(12):3347–3350.
   PubMed Web of Science ®Google Scholar
• Dos Santos CJ, Stangherlin LM, Figueiredo EG, et al. High prevalence of HCMV and viral load in tumor tissues and peripheral blood of glioblastoma multiforme patients. J Med Virol. 2014 Nov;86(11):1953–1961.
   PubMed Web of Science ®Google Scholar
• Libard S, Popova SN, Amini RM, et al. Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade. Plos One. 2014;9(9):e108861.
   PubMed Web of Science ®Google Scholar
• Lucas KG, Bao L, Bruggeman R, et al. The detection of CMV pp65 and IE1 in glioblastoma multiforme. J Neuro Oncol. 2011 Jun;103(2):231–238.
   PubMed Web of Science ®Google Scholar
• Mitchell DA, Xie W, Schmittling R, et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol. 2008 Feb;10(1):10–18.
   PubMed Web of Science ®Google Scholar
• Shamran HA, Kadhim HS, Hussain AR, et al. Detection of human cytomegalovirus in different histopathological types of glioma in Iraqi patients. Biomed Res Int. 2015;2015:642652.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMedGoogle Scholar
• Choi Y, Chang J. Viral vectors for vaccine applications. Clin Exp Vaccine Res. 2013 Jul;2(2):97–105.
   PubMedGoogle Scholar
• Fan Y, Moon JJ. Nanoparticle drug delivery systems designed to improve cancer vaccines and immunotherapy. Vaccines. 2015;3(3):662–685.
   PubMed Web of Science ®Google Scholar
• Boudreau JE, Bonehill A, Thielemans K, et al. Engineering dendritic cells to enhance cancer immunotherapy. Mol Ther. 2011 May;19(5):841–853.
   PubMed Web of Science ®Google Scholar
• Caruso DA, Orme LM, Neale AM, et al. Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. Neuro Oncol. 2004 Jul;6(3):236–246.
   PubMed Web of Science ®Google Scholar
• Castro MG, Baker GJ, Lowenstein PR. Blocking immunosuppressive checkpoints for glioma therapy: the more the Merrier! Clin Cancer Res. 2014 Oct 15;20(20):5147–5149.
   PubMed Web of Science ®Google Scholar
• Hunn MK, Bauer E, Wood CE, et al. Dendritic cell vaccination combined with temozolomide retreatment: results of a phase I trial in patients with recurrent glioblastoma multiforme. J Neuro Oncol. 2015 Jan;121(2):319–329.
   PubMed Web of Science ®Google Scholar
• Zussman BM, Engh JA. Outcomes of the ACT III study: rindopepimut (CDX-110) therapy for glioblastoma. Neurosurgery. 2015 Jun;76(6):N17.
   PubMedGoogle Scholar
• Hsu M, Sedighim S, Wang T, et al. TCR sequencing can identify and track glioma-infiltrating T cells after DC vaccination. Cancer Immunol Res. 2016 May;4(5):412–418.
   PubMed Web of Science ®Google Scholar
• Everson RG, Jin RM, Wang X, 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.
   PubMedGoogle Scholar
• Ishikawa E, Muragaki Y, Yamamoto T, et al. Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma. J Neurosurg. 2014 Sep;121(3):543–553.
   PubMed Web of Science ®Google Scholar
• 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 Jan;16(2):274–279.
   PubMed Web of Science ®Google Scholar
• Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010 May;11(5):373–384.
   PubMed Web of Science ®Google Scholar
• Hartman LL, Crawford JR, Makale MT, et al. Pediatric phase II trials of poly-ICLC in the management of newly diagnosed and recurrent brain tumors. J Pediatr Hematol Oncol. 2014 Aug;36(6):451–457.
   PubMed Web of Science ®Google Scholar
• Rosenfeld MR, Chamberlain MC, Grossman SA, et al. A multi-institution phase II study of poly-ICLC and radiotherapy with concurrent and adjuvant temozolomide in adults with newly diagnosed glioblastoma. Neuro Oncol. 2010 Oct;12(10):1071–1077.
   PubMed Web of Science ®Google Scholar
• Carpentier A, Metellus P, Ursu R, et al. Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. Neuro Oncol. 2010 Apr;12(4):401–408.
   PubMed Web of Science ®Google Scholar
• Reardon DA, Wucherpfennig KW, Freeman G, et al. An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma. Expert Rev Vaccines. 2013 Jun;12(6):597–615.
   PubMed Web of Science ®Google Scholar
• Chandramohan V, Mitchell DA, Johnson LA, et al. Antibody, T-cell and dendritic cell immunotherapy for malignant brain tumors. Future Oncol. 2013 Jul;9(7):977–990.
   PubMed Web of Science ®Google Scholar
• Niyazi M, Harter PN, Hattingen E, et al. Bevacizumab and radiotherapy for the treatment of glioblastoma: brothers in arms or unholy alliance? Oncotarget. 2016 Jan 19;7(3):2313–2328.
   PubMed Web of Science ®Google Scholar
• Hegde M, Bielamowicz KJ, Ahmed N. Novel approaches and mechanisms of immunotherapy for glioblastoma. Discov Med. 2014 Mar;17(93):145–154.
   PubMed Web of Science ®Google Scholar
• Massimino M, Biassoni V, Miceli R, et al. Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood. J Neuro Oncol. 2014 Jun;118(2):305–312.
   PubMed Web of Science ®Google Scholar
• Westphal M, Heese O, Steinbach JP, et al. A randomised, open label phase III trial with nimotuzumab, an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma. Eur J Cancer. 2015 Mar;51(4):522–532.
   PubMed Web of Science ®Google Scholar
• Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002 Oct 25;298(5594):850–854.
   PubMed Web of Science ®Google Scholar
• Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006 Oct 6;314(5796):126–129.
   PubMed Web of Science ®Google Scholar
• Schuessler A, Smith C, Beagley L, et al. Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res. 2014 Jul 1;74(13):3466–3476.
   PubMed Web of Science ®Google Scholar
• Ikeda H, Shiku H. Antigen-receptor gene-modified T cells for treatment of glioma. Adv Exp Med Biol. 2012;746:202–215.
   PubMed Web of Science ®Google Scholar
• Kahlon KS, Brown C, Cooper LJ, et al. Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res. 2004 Dec 15;64(24):9160–9166.
   PubMed Web of Science ®Google Scholar
• Brown CE, Badie B, Barish ME, et al. Bioactivity and safety of IL13Ralpha2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin Cancer Res. 2015 Sep 15;21(18):4062–4072.
   PubMed Web of Science ®Google Scholar
• Ahmed N, Salsman VS, Kew Y, et al. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res. 2010 Jan 15;16(2):474–485.
   PubMed Web of Science ®Google Scholar
• Kershaw MH, Westwood JA, Darcy PK. Gene-engineered T cells for cancer therapy. Nat Rev Cancer. 2013 08;13(8):525–541. print.
   PubMed Web of Science ®Google Scholar
• Johnson LA, Scholler J, Ohkuri T, et al. Rational development and characterization of humanized anti–EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med. 2015;7(275):275ra22–75ra22. Epub 2015 Feb 18.
   PubMed Web of Science ®Google Scholar
• Castel D, Philippe C, Calmon R, et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol. 2015;130(6):815–827.
   PubMed Web of Science ®Google Scholar
• Siegal T. Clinical relevance of prognostic and predictive molecular markers in gliomas. In: Schramm J, editor. Advances and technical standards in neurosurgery: volume 43. Cham: Springer International Publishing; 2016. p. 91–108.
   Google Scholar
• Avril T, Saikali S, Vauleon E, et al. Distinct effects of human glioblastoma immunoregulatory molecules programmed cell death ligand-1 (PDL-1) and indoleamine 2,3-dioxygenase (IDO) on tumour-specific T cell functions. J Neuroimmunol. 2010 Aug 25;225(1–2):22–33.
   PubMed Web of Science ®Google Scholar
• Ramirez YP, Weatherbee JL, Wheelhouse RT, et al. Glioblastoma multiforme therapy and mechanisms of resistance. Pharmaceuticals. 2013;6(12):1475–1506.
   Google Scholar
• Zhang RR, Pointer KB, Kuo JS, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Neurosurgery. 2014 Dec;75(6):N9–10.
   PubMed Web of Science ®Google Scholar