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Biomarkers for glioma immunotherapy: the next generation

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Abstract

The term “biomarker” historically refers to a single parameter, such as the expression level of a gene or a radiographic pattern, used to indicate a broader biological state. Molecular indicators have been applied to several aspects of cancer therapy: to describe the genotypic and phenotypic state of neoplastic tissue for prognosis, to predict susceptibility to anti-proliferative agents, to validate the presence of specific drug targets, and to evaluate responsiveness to therapy. For glioblastoma (GBM), immunohistochemical and radiographic biomarkers accessible to the clinical lab have informed traditional regimens, but while immunotherapies have emerged as potentially disruptive weapons against this diffusely infiltrating, heterogeneous tumor, biomarkers with strong predictive power have not been fully established. The cancer immunotherapy field, through the recently accelerated expansion of trials, is currently leveraging this wealth of clinical and biological data to define and revise the use of biomarkers for improving prognostic accuracy, personalization of therapy, and evaluation of responses across the wide variety of tumors. Technological advancements in DNA sequencing, cytometry, and microscopy have facilitated the exploration of more integrated, high-dimensional profiling of the disease system—incorporating both immune and tumor parameters—rather than single metrics, as biomarkers for therapeutic sensitivity. Here we discuss the utility of traditional GBM biomarkers in immunotherapy and how the impending transformation of the biomarker paradigm—from single markers to integrated profiles—may offer the key to bringing predictive, personalized immunotherapy to GBM patients.

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References

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

  2. Moskwa P, Zinn PO, Choi YE, Shukla SA, Fendler W, Chen CC, Lu J, Golub TR, Hjelmeland A, Chowdhury D (2014) A functional screen identifies miRs that induce radioresistance in glioblastomas. Mol Cancer Res. doi:10.1158/1541-7786.MCR-14-0268

    PubMed Central  PubMed  Google Scholar 

  3. Xiao S, Yang Z, Lv R, Zhao J, Wu M, Liao Y, Liu Q (2014) miR-135b contributes to the radioresistance by targeting GSK3beta in human glioblastoma multiforme cells. PLoS ONE 9:e108810. doi:10.1371/journal.pone.0108810

    PubMed Central  PubMed  Google Scholar 

  4. Wu L, Yang L, Xiong Y, Guo H, Shen X, Cheng Z, Zhang Y, Gao Z, Zhu X (2014) Annexin A5 promotes invasion and chemoresistance to temozolomide in glioblastoma multiforme cells. Tumour Biol. doi:10.1007/s13277-014-2545-1

    Google Scholar 

  5. Garrido W, Rocha JD, Jaramillo C, Fernandez K, Oyarzun C, Martin RS, Quezada C (2014) Chemoresistance in high-grade gliomas: relevance of adenosine signalling in stem-like cells of glioblastoma multiforme. Curr Drug Targets 15:931–942

    CAS  PubMed  Google Scholar 

  6. Brada M, Stenning S, Gabe R, Thompson LC, Levy D, Rampling R, Erridge S, Saran F, Gattamaneni R, Hopkins K, Beall S, Collins VP, Lee SM (2010) Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin oncology : official journal of the American Society of Clinical Oncol 28:4601–4608. doi:10.1200/JCO.2009.27.1932

    CAS  Google Scholar 

  7. Ch’en IL, Tsau JS, Molkentin JD, Komatsu M, Hedrick SM (2011) Mechanisms of necroptosis in T cells. J Exp Med 208:633–641. doi:10.1084/jem.20110251

    PubMed Central  PubMed  Google Scholar 

  8. Gaiha GD, Brass AL (2014) Immunology. The fiery side of HIV-induced T cell death. Science 343:383–384. doi:10.1126/science.1250175

    CAS  PubMed  Google Scholar 

  9. Ohlen C, Kalos M, Hong DJ, Shur AC, Greenberg PD (2001) Expression of a tolerizing tumor antigen in peripheral tissue does not preclude recovery of high-affinity CD8+ T cells or CTL immunotherapy of tumors expressing the antigen. Journal of immunology 166:2863–2870

    CAS  Google Scholar 

  10. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, Ahmed R (1998) Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188:2205–2213

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Wherry EJ (2011) T cell exhaustion. Nature immunology 12:492–499

    CAS  Google Scholar 

  12. Yang I, Kremen TJ, Giovannone AJ, Paik E, Odesa SK, Prins RM, Liau LM (2004) Modulation of major histocompatibility complex Class I molecules and major histocompatibility complex-bound immunogenic peptides induced by interferon-alpha and interferon-gamma treatment of human glioblastoma multiforme. J Neurosurg 100:310–319. doi:10.3171/jns.2004.100.2.0310

    CAS  PubMed  Google Scholar 

  13. Mahindra AK, Grossman SA (2003) Pneumocystis carinii pneumonia in HIV negative patients with primary brain tumors. J Neurooncol 63:263–270

    PubMed  Google Scholar 

  14. Grossman SA, Ye X, Lesser G, Sloan A, Carraway H, Desideri S, Piantadosi S, Consortium NC (2011) Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 17:5473–5480. doi:10.1158/1078-0432.CCR-11-0774

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Jacobs SK, Wilson DJ, Kornblith PL, Grimm EA (1986) Interleukin-2 and autologous lymphokine-activated killer cells in the treatment of malignant glioma. Preliminary report. J Neurosurg 64:743–749. doi:10.3171/jns.1986.64.5.0743

    CAS  PubMed  Google Scholar 

  16. Merchant RE, Grant AJ, Merchant LH, Young HF (1988) Adoptive immunotherapy for recurrent glioblastoma-multiforme using lymphokine activated killer cells and recombinant interleukin-2. Cancer 62:665–671. doi:10.1002/1097-0142(19880815)62:4<665:Aid-Cncr2820620403>3.0.Co;2-O

    CAS  PubMed  Google Scholar 

  17. Yoshida S, Tanaka R, Takai N, Ono K (1988) Local administration of autologous lymphokine-activated killer cells and recombinant interleukin 2 to patients with malignant brain tumors. Cancer Res 48:5011–5016

    CAS  PubMed  Google Scholar 

  18. Barba D, Saris SC, Holder C, Rosenberg SA, Oldfield EH (1989) Intratumoral LAK cell and interleukin-2 therapy of human gliomas. J Neurosurg 70:175–182. doi:10.3171/jns.1989.70.2.0175

    CAS  PubMed  Google Scholar 

  19. Lillehei KO, Mitchell DH, Johnson SD, McCleary EL, Kruse CA (1991) Long-term follow-up of patients with recurrent malignant gliomas treated with adjuvant adoptive immunotherapy. Neurosurgery 28:16–23

    CAS  PubMed  Google Scholar 

  20. Tsurushima H, Liu SQ, Tuboi K, Matsumura A, Yoshii Y, Nose T, Saijo K, Ohno T (1999) Reduction of end-stage malignant glioma by injection with autologous cytotoxic T lymphocytes. Jpn J Cancer Res 90:536–545

    CAS  PubMed  Google Scholar 

  21. Dillman RO, Duma CM, Ellis RA, Cornforth AN, Schiltz PM, Sharp SL, DePriest MC (2009) Intralesional lymphokine-activated killer cells as adjuvant therapy for primary glioblastoma. J Immunother 32:914–919. doi:10.1097/CJI.0b013e3181b2910f

    PubMed  Google Scholar 

  22. Dillman RO, Duma CM, Schiltz PM, DePriest C, Ellis RA, Okamoto K, Beutel LD, De Leon C, Chico S (2004) Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma. J Immunother 27:398–404

    PubMed  Google Scholar 

  23. Saris SC, Spiess P, Lieberman DM, Lin S, Walbridge S, Oldfield EH (1992) Treatment of murine primary brain tumors with systemic interleukin-2 and tumor-infiltrating lymphocytes. J Neurosurg 76:513–519. doi:10.3171/jns.1992.76.3.0513

    CAS  PubMed  Google Scholar 

  24. Holladay FP, Heitz T, Chen YL, Chiga M, Wood GW (1992) Successful treatment of a malignant rat glioma with cytotoxic T lymphocytes. Neurosurgery 31:528–533

    CAS  PubMed  Google Scholar 

  25. Holladay FP, Heitz-Turner T, Bayer WL, Wood GW (1996) Autologous tumor cell vaccination combined with adoptive cellular immunotherapy in patients with grade III/IV astrocytoma. J Neurooncol 27:179–189

    CAS  PubMed  Google Scholar 

  26. Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD, Reap EA, Feldman SA, Chinnasamy N, Kuan CT, Song H, Zhang W, Fine HA, Rosenberg SA (2012) Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther 23:1043–1053. doi:10.1089/hum.2012.041

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Miao H, Choi BD, Suryadevara CM, Sanchez-Perez L, Yang S, De Leon G, Sayour EJ, McLendon R, Herndon JE 2nd, Healy P, Archer GE, Bigner DD, Johnson LA, Sampson JH (2014) EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. PLoS ONE 9:e94281. doi:10.1371/journal.pone.0094281

    PubMed Central  PubMed  Google Scholar 

  28. Sampson JH, Choi BD, Sanchez-Perez L, Suryadevara CM, Snyder DJ, Flores CT, Schmittling RJ, Nair SK, Reap EA, Norberg PK, Herndon JE 2nd, Kuan CT, Morgan RA, Rosenberg SA, Johnson LA (2014) EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res 20:972–984. doi:10.1158/1078-0432.CCR-13-0709

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR, McGettigan SE, Nace AK, Dentchev T, Thekkat P, Loew A, Boesteanu AC, Cogdill AP, Chen T, Fraietta JA, Kloss CC, Posey AD Jr, Engels B, Singh R, Ezell T, Idamakanti N, Ramones MH, Li N, Zhou L, Plesa G, Seykora JT, Okada H, June CH, Brogdon JL, Maus MV (2015) Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med 7(275):275ra22. doi:10.1126/scitranslmed.aaa4963

  30. Faulkner C, Palmer A, Williams H, Wragg C, Haynes HR, White P, DeSouza RM, Williams M, Hopkins K, Kurian KM (2014) EGFR and EGFRvIII analysis in glioblastoma as therapeutic biomarkers. Br J Neurosurg. doi:10.3109/02688697.2014.950631

    PubMed  Google Scholar 

  31. Ahmed N, Salsman VS, Kew Y, Shaffer D, Powell S, Zhang YJ, Grossman RG, Heslop HE, Gottschalk S (2010) HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res 16:474–485. doi:10.1158/1078-0432.CCR-09-1322

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Chow KK, Naik S, Kakarla S, Brawley VS, Shaffer DR, Yi Z, Rainusso N, Wu MF, Liu H, Kew Y, Grossman RG, Powell S, Lee D, Ahmed N, Gottschalk S (2013) T cells redirected to EphA2 for the immunotherapy of glioblastoma. Mol Ther 21:629–637. doi:10.1038/mt.2012.210

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JAR (2008) Long-term effects of Aβ42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223. doi:10.1016/s0140-6736(08)61075-2

    CAS  PubMed  Google Scholar 

  34. Chianese-Bullock KA, Pressley J, Garbee C, Hibbitts S, Murphy C, Yamshchikov G, Petroni GR, Bissonette EA, Neese PY, Grosh WW, Merrill P, Fink R, Woodson EMH, Wiernasz CJ, Patterson JW, Slingluff CL (2005) MAGE-A1-, MAGE-A10-, and gp100-derived peptides are immunogenic when combined with granulocyte-macrophage colony-stimulating factor and montanide ISA-51 adjuvant and administered as part of a multipeptide vaccine for melanoma. J Immunol 174:3080–3086. doi:10.4049/jimmunol.174.5.3080

    CAS  PubMed  Google Scholar 

  35. Slingluff CL Jr (2011) The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination? Cancer J 17:343–350. doi:10.1097/PPO.0b013e318233e5b2

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Akiyama Y, Oshita C, Kume A, Iizuka A, Miyata H, Komiyama M, Ashizawa T, Yagoto M, Abe Y, Mitsuya K, Watanabe R, Sugino T, Yamaguchi K, Nakasu Y (2012) alpha-type-1 polarized dendritic cell-based vaccination in recurrent high-grade glioma: a phase I clinical trial. BMC Cancer 12:623. doi:10.1186/1471-2407-12-623

    CAS  PubMed Central  PubMed  Google Scholar 

  37. 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 (2013) 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 19:205–214. doi:10.1158/1078-0432.CCR-11-3358

    CAS  PubMed  Google Scholar 

  38. Kobayashi T, Yamanaka R, Homma J, Tsuchiya N, Yajima N, Yoshida S, Tanaka R (2003) Tumor mRNA-loaded dendritic cells elicit tumor-specific CD8(+) cytotoxic T cells in patients with malignant glioma. Cancer Immunol Immunother 52:632–637. doi:10.1007/s00262-003-0408-5

    CAS  PubMed  Google Scholar 

  39. Chang CN, Huang YC, Yang DM, Kikuta K, Wei KJ, Kubota T, Yang WK (2011) A phase I/II clinical trial investigating the adverse and therapeutic effects of a postoperative autologous dendritic cell tumor vaccine in patients with malignant glioma. J Clin Neurosci 18:1048–1054. doi:10.1016/j.jocn.2010.11.034

    CAS  PubMed  Google Scholar 

  40. Marsh JC, Goldfarb J, Shafman TD, Diaz AZ (2013) Current status of immunotherapy and gene therapy for high-grade gliomas. Cancer Control 20:43–48

    PubMed  Google Scholar 

  41. Yu JS, Wheeler CJ, Zeltzer PM, Ying H, Finger DN, Lee PK, Yong WH, Incardona F, Thompson RC, Riedinger MS, Zhang W, Prins RM, Black KL (2001) Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res 61:842–847

    CAS  PubMed  Google Scholar 

  42. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ (2004) Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 64:4973–4979. doi:10.1158/0008-5472.CAN-03-3505

    CAS  PubMed  Google Scholar 

  43. Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ, Lin JW, Chute DJ, Mischel PS, Cloughesy TF, Roth MD (2005) 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 11:5515–5525. doi:10.1158/1078-0432.CCR-05-0464

    CAS  PubMed  Google Scholar 

  44. Jie X, Hua L, Jiang W, Feng F, Feng G, Hua Z (2012) Clinical application of a dendritic cell vaccine raised against heat-shocked glioblastoma. Cell Biochem Biophys 62:91–99. doi:10.1007/s12013-011-9265-6

    CAS  PubMed  Google Scholar 

  45. Everson RG, Jin RM, Wang X, Safaee M, Scharnweber R, Lisiero DN, Soto H, Liau LM, Prins RM (2014) Cytokine responsiveness of CD8(+) T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients. J Immunother Cancer 2:10. doi:10.1186/2051-1426-2-10

    PubMed Central  PubMed  Google Scholar 

  46. Fecci PE, Sweeney AE, Grossi PM, Nair SK, Learn CA, Mitchell DA, Cui X, Cummings TJ, Bigner DD, Gilboa E, Sampson JH (2006) Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells. Clin Cancer Res 12:4294–4305. doi:10.1158/1078-0432.CCR-06-0053

    CAS  PubMed  Google Scholar 

  47. Poirier MD, Haban H, El Andaloussi A (2009) A combination of systemic and intracranial anti-CD25 immunotherapy elicits a long-time survival in murine model of glioma. J Oncol 2009:963037. doi:10.1155/2009/963037

    PubMed Central  PubMed  Google Scholar 

  48. Maes W, Rosas GG, Verbinnen B, Boon L, De Vleeschouwer S, Ceuppens JL, Van Gool SW (2009) DC vaccination with anti-CD25 treatment leads to long-term immunity against experimental glioma. Neuro Oncol 11:529–542. doi:10.1215/15228517-2009-004

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Clark PA, Iida M, Treisman DM, Kalluri H, Ezhilan S, Zorniak M, Wheeler DL, Kuo JS (2012) Activation of multiple ERBB family receptors mediates glioblastoma cancer stem-like cell resistance to EGFR-targeted inhibition. Neoplasia 14(5):420–428

  50. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au H-J, Langer C, Moore MJ, Zalcberg JR (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765. doi:10.1056/NEJMoa0804385

  51. Zhu X, Fujita M, Snyder LA, Okada H (2011) Systemic delivery of neutralizing antibody targeting CCL2 for glioma therapy. J Neurooncol 104:83–92. doi:10.1007/s11060-010-0473-5

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Vom Berg J, Vrohlings M, Haller S, Haimovici A, Kulig P, Sledzinska A, Weller M, Becher B (2013) Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection. J Exp Med 210:2803–2811. doi:10.1084/jem.20130678

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Dunn GP, Dunn IF, Curry WT (2007) Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human glioma. Cancer Immun 7:12

    PubMed Central  PubMed  Google Scholar 

  55. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723. doi:10.1056/NEJMoa1003466

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Pedicord VA, Montalvo W, Leiner IM, Allison JP (2011) Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci USA 108:266–271. doi:10.1073/pnas.1016791108

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Curran MA, Montalvo W, Yagita H, Allison JP (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci USA 107:4275–4280. doi:10.1073/pnas.0915174107

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Zubairi S, Sanos SL, Hill S, Kaye PM (2004) Immunotherapy with OX40L-Fc or anti-CTLA-4 enhances local tissue responses and killing of Leishmania donovani. Eur J Immunol 34:1433–1440. doi:10.1002/eji.200324021

    CAS  PubMed  Google Scholar 

  60. Korman AJ, Peggs KS, Allison JP (2006) Checkpoint blockade in cancer immunotherapy. Adv Immunol 90:297–339. doi:10.1016/S0065-2776(06)90008-X

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Drake CG, Lipson EJ, Brahmer JR (2014) Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat Rev Clin Oncol 11:24–37. doi:10.1038/nrclinonc.2013.208

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. doi:10.1126/scitranslmed.3002842

    PubMed Central  Google Scholar 

  63. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518. doi:10.1056/NEJMoa1215134

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Duraiswamy J, Freeman GJ, Coukos G (2014) Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors–response. Cancer Res 74:633–634. doi:10.1158/0008-5472.CAN-13-2752 (discussion 635)

    CAS  PubMed  Google Scholar 

  65. Gregor PD, Wolchok JD, Ferrone CR, Buchinshky H, Guevara-Patino JA, Perales MA, Mortazavi F, Bacich D, Heston W, Latouche JB, Sadelain M, Allison JP, Scher HI, Houghton AN (2004) CTLA-4 blockade in combination with xenogeneic DNA vaccines enhances T-cell responses, tumor immunity and autoimmunity to self antigens in animal and cellular model systems. Vaccine 22:1700–1708. doi:10.1016/j.vaccine.2003.10.048

    CAS  PubMed  Google Scholar 

  66. Fox BA, Schendel DJ, Butterfield LH, Aamdal S, Allison JP, Ascierto PA, Atkins MB, Bartunkova J, Bergmann L, Berinstein N, Bonorino CC, Borden E, Bramson JL, Britten CM, Cao X, Carson WE, Chang AE, Characiejus D, Choudhury AR, Coukos G, de Gruijl T, Dillman RO, Dolstra H, Dranoff G, Durrant LG, Finke JH, Galon J, Gollob JA, Gouttefangeas C, Grizzi F, Guida M, Hakansson L, Hege K, Herberman RB, Hodi FS, Hoos A, Huber C, Hwu P, Imai K, Jaffee EM, Janetzki S, June CH, Kalinski P, Kaufman HL, Kawakami K, Kawakami Y, Keilholtz U, Khleif SN, Kiessling R, Kotlan B, Kroemer G, Lapointe R, Levitsky HI, Lotze MT, Maccalli C, Maio M, Marschner JP, Mastrangelo MJ, Masucci G, Melero I, Melief C, Murphy WJ, Nelson B, Nicolini A, Nishimura MI, Odunsi K, Ohashi PS, O’Donnell-Tormey J, Old LJ, Ottensmeier C, Papamichail M, Parmiani G, Pawelec G, Proietti E, Qin S, Rees R, Ribas A, Ridolfi R, Ritter G, Rivoltini L, Romero PJ, Salem ML, Scheper RJ, Seliger B, Sharma P, Shiku H, Singh-Jasuja H, Song W, Straten PT, Tahara H, Tian Z, van Der Burg SH, von Hoegen P, Wang E, Welters MJ, Winter H, Withington T, Wolchok JD, Xiao W, Zitvogel L, Zwierzina H, Marincola FM, Gajewski TF, Wigginton JM, Disis ML (2011) Defining the critical hurdles in cancer immunotherapy. J Transl Med 9:214. doi:10.1186/1479-5876-9-214

    PubMed Central  PubMed  Google Scholar 

  67. Dancey JE, Dodd LE, Ford R, Kaplan R, Mooney M, Rubinstein L, Schwartz LH, Shankar L, Therasse P (2009) Recommendations for the assessment of progression in randomised cancer treatment trials. Eur J Cancer 45:281–289. doi:10.1016/j.ejca.2008.10.042

    CAS  PubMed  Google Scholar 

  68. Keeren K, Friedrich M, Gebuhr I, Philipp S, Sabat R, Sterry W, Brandt C, Meisel C, Grutz G, Volk HD, Sawitzki B (2009) Expression of tolerance associated gene-1, a mitochondrial protein inhibiting T cell activation, can be used to predict response to immune modulating therapies. J Immunol 183:4077–4087. doi:10.4049/jimmunol.0804351

    CAS  PubMed  Google Scholar 

  69. Anderson AC (2012) Tim-3, a negative regulator of anti-tumor immunity. Curr Opin Immunol 24:213–216. doi:10.1016/j.coi.2011.12.005

    CAS  PubMed  Google Scholar 

  70. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, Bettini ML, Gravano DM, Vogel P, Liu CL, Tangsombatvisit S, Grosso JF, Netto G, Smeltzer MP, Chaux A, Utz PJ, Workman CJ, Pardoll DM, Korman AJ, Drake CG, Vignali DA (2012) Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 72:917–927. doi:10.1158/0008-5472.CAN-11-1620

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Hamid O, Carvajal RD (2013) Anti-programmed death-1 and anti-programmed death-ligand 1 antibodies in cancer therapy. Expert Opin Biol Ther 13:847–861. doi:10.1517/14712598.2013.770836

    CAS  PubMed  Google Scholar 

  72. Ascierto PA, Kalos M, Schaer DA, Callahan MK, Wolchok JD (2013) Biomarkers for immunostimulatory monoclonal antibodies in combination strategies for melanoma and other tumor types. Clin Cancer Res 19:1009–1020. doi:10.1158/1078-0432.CCR-12-2982

    CAS  PubMed  Google Scholar 

  73. Ng Tang D, Shen Y, Sun J, Wen S, Wolchok JD, Yuan J, Allison JP, Sharma P (2013) Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol Res 1:229–234. doi:10.1158/2326-6066.CIR-13-0020

    PubMed  Google Scholar 

  74. Li M, Bolduc AR, Hoda MN, Gamble DN, Dolisca SB, Bolduc AK, Hoang K, Ashley C, McCall D, Rojiani AM, Maria BL, Rixe O, MacDonald TJ, Heeger PS, Mellor AL, Munn DH, Johnson TS (2014) The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J Immunother Cancer 2:21. doi:10.1186/2051-1426-2-21

    PubMed Central  PubMed  Google Scholar 

  75. Sippel TR, White J, Nag K, Tsvankin V, Klaassen M, Kleinschmidt-DeMasters BK, Waziri A (2011) Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I. Clin Cancer Res 17:6992–7002. doi:10.1158/1078-0432.CCR-11-1107

    CAS  PubMed  Google Scholar 

  76. Huang JR, Tsai YC, Chang YJ, Wu JC, Hung JT, Lin KH, Wong CH, Yu AL (2014) alpha-Galactosylceramide but not phenyl-glycolipids induced NKT cell anergy and IL-33-mediated myeloid-derived suppressor cell accumulation via upregulation of egr2/3. J Immunol 192:1972–1981. doi:10.4049/jimmunol.1302623

    CAS  PubMed  Google Scholar 

  77. Liang X, De Vera ME, Buchser WJ, de Vivar Romo, Chavez A, Loughran P, Beer Stolz D, Basse P, Wang T, Van Houten B, Zeh HJ 3rd, Lotze MT (2012) Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression. Cancer Res 72:2791–2801. doi:10.1158/0008-5472.CAN-12-0320

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Lotfi R, Lee JJ, Lotze MT (2007) Eosinophilic granulocytes and damage-associated molecular pattern molecules (DAMPs): role in the inflammatory response within tumors. J Immunother 30:16–28. doi:10.1097/01.cji.0000211324.53396.f6

    CAS  PubMed  Google Scholar 

  79. Gustafson MP, Lin Y, LaPlant B, Liwski CJ, Maas ML, League SC, Bauer PR, Abraham RS, Tollefson MK, Kwon ED, Gastineau DA, Dietz AB (2013) Immune monitoring using the predictive power of immune profiles. J Immunother Cancer 1:7. doi:10.1186/2051-1426-1-7

    PubMed Central  PubMed  Google Scholar 

  80. Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, Lugli A, Zlobec I, Hartmann A, Bifulco C, Nagtegaal ID, Palmqvist R, Masucci GV, Botti G, Tatangelo F, Delrio P, Maio M, Laghi L, Grizzi F, Asslaber M, D’Arrigo C, Vidal-Vanaclocha F, Zavadova E, Chouchane L, Ohashi PS, Hafezi-Bakhtiari S, Wouters BG, Roehrl M, Nguyen L, Kawakami Y, Hazama S, Okuno K, Ogino S, Gibbs P, Waring P, Sato N, Torigoe T, Itoh K, Patel PS, Shukla SN, Wang Y, Kopetz S, Sinicrope FA, Scripcariu V, Ascierto PA, Marincola FM, Fox BA, Pages F (2014) Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol 232:199–209. doi:10.1002/path.4287

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL, Fell HP, Ferree S, George RD, Grogan T, James JJ, Maysuria M, Mitton JD, Oliveri P, Osborn JL, Peng T, Ratcliffe AL, Webster PJ, Davidson EH, Hood L, Dimitrov K (2008) Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol 26:317–325. doi:10.1038/nbt1385

    CAS  PubMed  Google Scholar 

  82. Nielsen T, Wallden B, Schaper C, Ferree S, Liu S, Gao D, Barry G, Dowidar N, Maysuria M, Storhoff J (2014) Analytical validation of the PAM50-based Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Analysis System using formalin-fixed paraffin-embedded breast tumor specimens. BMC Cancer 14:177. doi:10.1186/1471-2407-14-177

    PubMed Central  PubMed  Google Scholar 

  83. Stricker TP, Morales La Madrid A, Chlenski A, Guerrero L, Salwen HR, Gosiengfiao Y, Perlman EJ, Furman W, Bahrami A, Shohet JM, Zage PE, Hicks MJ, Shimada H, Suganuma R, Park JR, So S, London WB, Pytel P, Maclean KH, Cohn SL (2014) Validation of a prognostic multi-gene signature in high-risk neuroblastoma using the high throughput digital NanoString nCounter system. Mol Oncol 8:669–678. doi:10.1016/j.molonc.2014.01.010

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Veldman-Jones M, Lai Z, Wappett M, Harbron C, Barrett JC, Harrington EA, Thress KS (2014) Reproducible, quantitative and flexible molecular sub-typing of clinical DLBCL samples using the NanoString nCounter system. Clin Cancer Res. doi:10.1158/1078-0432.CCR-14-0357

    PubMed  Google Scholar 

  85. Andorfer CA, Necela BM, Thompson EA, Perez EA (2011) MicroRNA signatures: clinical biomarkers for the diagnosis and treatment of breast cancer. Trends Mol Med 17:313–319. doi:10.1016/j.molmed.2011.01.006

    CAS  PubMed  Google Scholar 

  86. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N (2015) Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160:48–61. doi:10.1016/j.cell.2014.12.033

    CAS  PubMed  Google Scholar 

  87. Spranger S, Gajewski T (2013) Rational combinations of immunotherapeutics that target discrete pathways. J Immunother Cancer 1:16. doi:10.1186/2051-1426-1-16

    PubMed Central  PubMed  Google Scholar 

  88. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570. doi:10.1126/science.1203486

    CAS  PubMed  Google Scholar 

  89. Newell EW, Sigal N, Bendall SC, Nolan GP, Davis MM (2012) Cytometry by time-of-flight shows combinatorial cytokine expression and virus-specific cell niches within a continuum of CD8+ T cell phenotypes. Immunity 36:142–152. doi:10.1016/j.immuni.2012.01.002

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Talmadge JE, Gabrilovich DI (2013) History of myeloid-derived suppressor cells. Nat Rev Cancer 13:739–752. doi:10.1038/nrc3581

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Vahedi G, Takahashi H, Nakayamada S, Sun HW, Sartorelli V, Kanno Y, O’Shea JJ (2012) STATs shape the active enhancer landscape of T cell populations. Cell 151:981–993. doi:10.1016/j.cell.2012.09.044

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Warren RL, Freeman JD, Zeng T, Choe G, Munro S, Moore R, Webb JR, Holt RA (2011) Exhaustive T-cell repertoire sequencing of human peripheral blood samples reveals signatures of antigen selection and a directly measured repertoire size of at least 1 million clonotypes. Genome Res 21:790–797. doi:10.1101/gr.115428.110

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Wang C, Sanders CM, Yang Q, Schroeder HW Jr, Wang E, Babrzadeh F, Gharizadeh B, Myers RM, Hudson JR Jr, Davis RW, Han J (2010) High throughput sequencing reveals a complex pattern of dynamic interrelationships among human T cell subsets. Proc Natl Acad Sci USA 107:1518–1523. doi:10.1073/pnas.0913939107

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Robins HS, Srivastava SK, Campregher PV, Turtle CJ, Andriesen J, Riddell SR, Carlson CS, Warren EH (2010) Overlap and effective size of the human CD8+ T cell receptor repertoire. Sci Transl Med. doi:10.1126/scitranslmed.3001442

    PubMed Central  PubMed  Google Scholar 

  95. Morris H, DeWolf S, Robins H, Sprangers B, LoCascio SA, Shonts BA, Kawai T, Wong W, Yang S, Zuber J, Shen Y, Sykes M (2015) Tracking donor-reactive T cells: evidence for clonal deletion in tolerant kidney transplant patients. Sci Transl Med. doi:10.1126/scitranslmed.3010760

    PubMed Central  Google Scholar 

  96. Robert L, Harview C, Emerson R, Wang X, Mok S, Homet B, Comin-Anduix B, Koya RC, Robins H, Tumeh PC, Ribas A (2014) Distinct immunological mechanisms of CTLA-4 and PD-1 blockade revealed by analyzing TCR usage in blood lymphocytes. Oncoimmunology 3:e29244. doi:10.4161/onci.29244

    PubMed Central  PubMed  Google Scholar 

  97. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571. doi:10.1038/nature13954

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Johnson PL, Kochin BF, McAfee MS, Stromnes IM, Regoes RR, Ahmed R, Blattman JN, Antia R (2011) Vaccination alters the balance between protective immunity, exhaustion, escape, and death in chronic infections. J Virol 85:5565–5570. doi:10.1128/JVI.00166-11

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Blattman JN, Wherry EJ, Ha SJ, van der Most RG, Ahmed R (2009) Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection. J Virol 83:4386–4394. doi:10.1128/JVI.02524-08

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Hess CF, Schaaf JC, Kortmann RD, Schabet M, Bamberg M (1994) Malignant glioma: patterns of failure following individually tailored limited volume irradiation. Radiother Oncol 30:146–149

    CAS  PubMed  Google Scholar 

  101. Hochberg FH, Pruitt A (1980) Assumptions in the radiotherapy of glioblastoma. Neurology 30:907–911

    CAS  PubMed  Google Scholar 

  102. Liang BC, Thornton AF Jr, Sandler HM, Greenberg HS (1991) Malignant astrocytomas: focal tumor recurrence after focal external beam radiation therapy. J Neurosurg 75:559–563. doi:10.3171/jns.1991.75.4.0559

    CAS  PubMed  Google Scholar 

  103. Fujisawa HRR, Nakamura M, Colella S, Yonekawa Y, Kleihues P, Ohgaki H (2000) Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo) than in secondary glioblastomas. Lab Invest 80:65–72

    CAS  PubMed  Google Scholar 

  104. Tada K, Shiraishi S, Kamiryo T, Nakamura H, Hirano H, Kuratsu J, Kochi M, Saya H, Ushio Y (2001) Analysis of loss of heterozygosity on chromosome 10 in patients with malignant astrocytic tumors: correlation with patient age and survival. J Neurosurg 95:651–659. doi:10.3171/jns.2001.95.4.0651

    CAS  PubMed  Google Scholar 

  105. Balesaria SBC, Bower M, Clark J, Nicholson SK, Lewis P, de Sanctis S, Evans H, Peterson D, Mendoza N, Glaser MG, Newlands ES, Fisher RA (1999) Loss of chromosome 10 is an independent prognostic factor in high-grade gliomas. Br J Cancer 81:1371–1377

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Steck PAPM, Jasser SA, Tung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:362–465

    Google Scholar 

  107. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947

    CAS  PubMed  Google Scholar 

  108. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812. doi:10.1126/science.1164382

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Kim YW, Koul D, Kim SH, Lucio-Eterovic AK, Freire PR, Yao J, Wang J, Almeida JS, Aldape K, Yung WK (2013) Identification of prognostic gene signatures of glioblastoma: a study based on TCGA data analysis. Neuro-oncology 15:829–839. doi:10.1093/neuonc/not024

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Bhat KP, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, Wani K, Heathcock L, James JD, Goodman LD, Conroy S, Long L, Lelic N, Wang S, Gumin J, Raj D, Kodama Y, Raghunathan A, Olar A, Joshi K, Pelloski CE, Heimberger A, Kim SH, Cahill DP, Rao G, Den Dunnen WF, Boddeke HW, Phillips HS, Nakano I, Lang FF, Colman H, Sulman EP, Aldape K (2013) Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma. Cancer Cell 24:331–346. doi:10.1016/j.ccr.2013.08.001

    CAS  PubMed  Google Scholar 

  112. Mischel PS, Shai R, Shi T, Horvath S, Lu KV, Choe G, Seligson D, Kremen TJ, Palotie A, Liau LM, Cloughesy TF, Nelson SF (2003) Identification of molecular subtypes of glioblastoma by gene expression profiling. Oncogene 22:2361–2373. doi:10.1038/sj.onc.1206344

    CAS  PubMed  Google Scholar 

  113. Gan HK, Kaye AH, Luwor RB (2009) The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci 16:748–754. doi:10.1016/j.jocn.2008.12.005

    CAS  PubMed  Google Scholar 

  114. Schlegel J, Merdes A, Stumm G, Albert FK, Forsting M, Hynes N, Kiessling M (1994) Amplification of the epidermal-growth-factor-receptor gene correlates with different growth behaviour in human glioblastoma. Int J Cancer 56:72–77

    CAS  PubMed  Google Scholar 

  115. Wong AJBS, Bigner DD, Kinzler Hamilton SR, Vogelstein B (1987) Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 84:6899–6903

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Humphrey PAWA, Vogelstein B, Zalutsky MR, Fuller GN, Archer GE, Friedman HS, Kwatra MM, Bigner SH, Bidgner DD (1990) Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci USA 97:4207–4211

    Google Scholar 

  118. Shinojima NTK, Shiraishe S, Kamirya T, Kochi M, Nakamura H, Makio K, Saya H, Hirano H, Kuratsu J, Oka K, Ishimaru Y, Ushio Y (2003) Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res 63:6962–6970

    CAS  PubMed  Google Scholar 

  119. Heimberger AB, Hlatky R, Suki D, Yang D, Weinberg J, Gilbert M, Sawaya R, Aldape K (2005) Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res 11:1462–1466. doi:10.1158/1078-0432.CCR-04-1737

    CAS  PubMed  Google Scholar 

  120. Han SJ, Zygourakis C, Lim M, Parsa AT (2012) Immunotherapy for glioma: promises and challenges. Neurosurg Clin N Am 23:357–370. doi:10.1016/j.nec.2012.05.001

    PubMed  Google Scholar 

  121. Stragliotto G, Vega F, Stasiecki P, Gropp P, Poisson M, Delattre JY (1996) Multiple infusions of anti-epidermal growth factor receptor (EGFR) monoclonal antibody (EMD 55,900) in patients with recurrent malignant gliomas. Eur J Cancer 32A:636–640

    CAS  PubMed  Google Scholar 

  122. Snelling L, Miyamoto CT, Bender H, Brady LW, Steplewski Z, Class R, Emrich J, Rackover MA (1995) Epidermal growth factor receptor 425 monoclonal antibodies radiolabeled with iodine-125 in the adjuvant treatment of high-grade astrocytomas. Hybridoma 14:111–114

    CAS  PubMed  Google Scholar 

  123. Katanasaka Y, Kodera Y, Kitamura Y, Morimoto T, Tamura T, Koizumi F (2013) Epidermal growth factor receptor variant type III markedly accelerates angiogenesis and tumor growth via inducing c-myc mediated angiopoietin-like 4 expression in malignant glioma. Mol Cancer 12:31. doi:10.1186/1476-4598-12-31

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Li G, Wong AJ (2008) EGF receptor variant III as a target antigen for tumor immunotherapy. Expert Rev Vaccines 7:977–985. doi:10.1586/14760584.7.7.977

    PubMed  Google Scholar 

  125. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE 2nd, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD (2010) Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 28:4722–4729. doi:10.1200/JCO.2010.28.6963

    PubMed Central  PubMed  Google Scholar 

  126. Heimberger AB, Crotty LE, Archer GE, Hess KR, Wikstrand CJ, Friedman AH, Friedman HS, Bigner DD, Sampson JH (2003) Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin Cancer Res 9:4247–4254

    CAS  PubMed  Google Scholar 

  127. Kaina B, Christmann M, Naumann S, Roos WP (2007) MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair (Amst) 6:1079–1099. doi:10.1016/j.dnarep.2007.03.008

    CAS  Google Scholar 

  128. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. doi:10.1056/NEJMoa043331

    CAS  PubMed  Google Scholar 

  129. Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tonjes M, Sill M, Bender S, Kool M, Zapatka M, Becker N, Zucknick M, Hielscher T, Liu XY, Fontebasso AM, Ryzhova M, Albrecht S, Jacob K, Wolter M, Ebinger M, Schuhmann MU, van Meter T, Fruhwald MC, Hauch H, Pekrun A, Radlwimmer B, Niehues T, von Komorowski G, Durken M, Kulozik AE, Madden J, Donson A, Foreman NK, Drissi R, Fouladi M, Scheurlen W, von Deimling A, Monoranu C, Roggendorf W, Herold-Mende C, Unterberg A, Kramm CM, Felsberg J, Hartmann C, Wiestler B, Wick W, Milde T, Witt O, Lindroth AM, Schwartzentruber J, Faury D, Fleming A, Zakrzewska M, Liberski PP, Zakrzewski K, Hauser P, Garami M, Klekner A, Bognar L, Morrissy S, Cavalli F, Taylor MD, van Sluis P, Koster J, Versteeg R, Volckmann R, Mikkelsen T, Aldape K, Reifenberger G, Collins VP, Majewski J, Korshunov A, Lichter P, Plass C, Jabado N, Pfister SM (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437. doi:10.1016/j.ccr.2012.08.024

    CAS  PubMed  Google Scholar 

  130. Stricker SH, Feber A, Engstrom PG, Caren H, Kurian KM, Takashima Y, Watts C, Way M, Dirks P, Bertone P, Smith A, Beck S, Pollard SM (2013) Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner. Genes Dev 27:654–669. doi:10.1101/gad.212662.112

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. doi:10.1056/NEJMoa0808710

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Minniti G, Scaringi C, Arcella A, Lanzetta G, Di Stefano D, Scarpino S, Bozzao A, Pace A, Villani V, Salvati M, Esposito V, Giangaspero F, Enrici RM (2014) IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy. J Neurooncol 118:377–383. doi:10.1007/s11060-014-1443-0

    CAS  PubMed  Google Scholar 

  133. Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, Sulman EP, Anne SL, Doetsch F, Colman H, Lasorella A, Aldape K, Califano A, Iavarone A (2010) The transcriptional network for mesenchymal transformation of brain tumours. Nature 463:318–325. doi:10.1038/nature08712

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Sonabend AM, Bansal M, Guarnieri P, Lei L, Amendolara B, Soderquist C, Leung R, Yun J, Kennedy B, Sisti J, Bruce S, Bruce R, Shakya R, Ludwig T, Rosenfeld S, Sims PA, Bruce JN, Califano A, Canoll P (2014) The transcriptional regulatory network of proneural glioma determines the genetic alterations selected during tumor progression. Cancer Res 74:1440–1451. doi:10.1158/0008-5472.CAN-13-2150

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Allen BK, Stathias V, Maloof ME, Vidovic D, Winterbottom EF, Capobianco AJ, Clarke J, Schurer S, Robbins DJ, Ayad NG (2014) Epigenetic pathways and glioblastoma treatment: insights from signaling cascades. J Cell Biochem. doi:10.1002/jcb.24990

    Google Scholar 

  136. Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, Menn O, Osswald M, Oezen I, Ott M, Keil M, Balss J, Rauschenbach K, Grabowska AK, Vogler I, Diekmann J, Trautwein N, Eichmuller SB, Okun J, Stevanovic S, Riemer AB, Sahin U, Friese MA, Beckhove P, von Deimling A, Wick W, Platten M (2014) A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512:324–327. doi:10.1038/nature13387

    CAS  PubMed  Google Scholar 

  137. Shah N, Lankerovich M, Lee H, Yoon JG, Schroeder B, Foltz G (2013) Exploration of the gene fusion landscape of glioblastoma using transcriptome sequencing and copy number data. BMC Genom 14:818. doi:10.1186/1471-2164-14-818

    CAS  Google Scholar 

  138. Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, Liu EM, Reichel J, Porrati P, Pellegatta S, Qiu K, Gao Z, Ceccarelli M, Riccardi R, Brat DJ, Guha A, Aldape K, Golfinos JG, Zagzag D, Mikkelsen T, Finocchiaro G, Lasorella A, Rabadan R, Iavarone A (2012) Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337:1231–1235. doi:10.1126/science.1220834

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Wikstrand CJ, Grahmann FC, McComb RD, Bigner DD (1985) Antigenic heterogeneity of human anaplastic gliomas and glioma-derived cell lines defined by monoclonal antibodies. J Neuropathol Exp Neurol 44:229–241

    CAS  PubMed  Google Scholar 

  140. Dutoit V, Herold-Mende C, Hilf N, Schoor O, Beckhove P, Bucher J, Dorsch K, Flohr S, Fritsche J, Lewandrowski P, Lohr J, Rammensee HG, Stevanovic S, Trautwein C, Vass V, Walter S, Walker PR, Weinschenk T, Singh-Jasuja H, Dietrich PY (2012) Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain 135:1042–1054. doi:10.1093/brain/aws042

    PubMed  Google Scholar 

  141. Gill BJ, Pisapia DJ, Malone HR, Goldstein H, Lei L, Sonabend A, Yun J, Samanamud J, Sims JS, Banu M, Dovas A, Teich AF, Sheth SA, McKhann GM, Sisti MB, Bruce JN, Sims PA, Canoll P (2014) MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma. Proc Natl Acad Sci USA 111:12550–12555. doi:10.1073/pnas.1405839111

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Joshi BH, Plautz GE, Puri RK (2000) Interleukin-13 receptor alpha chain: a novel tumor-associated transmembrane protein in primary explants of human malignant gliomas. Cancer Res 60:1168–1172

    CAS  PubMed  Google Scholar 

  143. Kawakami KKM, Puri RK (2001) Overexpressed cell surface interleukin-4 receptor molecules can be successfully targeted for antitumor cytotoxin therapy. Crit Rev Immunol 21:299–310

    CAS  PubMed  Google Scholar 

  144. Kunwar S, Prados MD, Chang SM, Berger MS, Lang FF, Piepmeier JM, Sampson JH, Ram Z, Gutin PH, Gibbons RD, Aldape KD, Croteau DJ, Sherman JW, Puri RK, Cintredekin Besudotox Intraparenchymal Study G (2007) Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a report by the Cintredekin Besudotox Intraparenchymal Study Group. J Clin Oncol 25:837–844. doi:10.1200/JCO.2006.08.1117

    CAS  PubMed  Google Scholar 

  145. Weber F, Asher A, Bucholz R, Berger M, Prados M, Chang S, Bruce J, Hall W, Rainov NG, Westphal M, Warnick RE, Rand RW, Floeth F, Rommel F, Pan H, Hingorani VN, Puri RK (2003) Safety, tolerability, and tumor response of IL4-Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. J Neurooncol 64:125–137

    PubMed  Google Scholar 

  146. Sampson JH, Archer G, Pedain C, Wembacher-Schroder E, Westphal M, Kunwar S, Vogelbaum MA, Coan A, Herndon JE, Raghavan R, Brady ML, Reardon DA, Friedman AH, Friedman HS, Rodriguez-Ponce MI, Chang SM, Mittermeyer S, Croteau D, Puri RK, Investigators PT (2010) Poor drug distribution as a possible explanation for the results of the PRECISE trial. J Neurosurg 113:301–309. doi:10.3171/2009.11.JNS091052

    PubMed  Google Scholar 

  147. Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G, Shaffrey M, Ram Z, Piepmeier J, Prados M, Croteau D, Pedain C, Leland P, Husain SR, Joshi BH, Puri RK, Group PS (2010) Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro-oncology 12:871–881. doi:10.1093/neuonc/nop054

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Han J, Yang L, Puri RK (2005) Analysis of target genes induced by IL-13 cytotoxin in human glioblastoma cells. J Neurooncol 72:35–46. doi:10.1007/s11060-004-3119-7

    CAS  PubMed  Google Scholar 

  149. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB, 3rd, Eastern Cooperative Oncology Group Study E (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544. doi:10.1200/JCO.2006.09.6305

    Google Scholar 

  150. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    CAS  PubMed  Google Scholar 

  151. If T (1968) The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 22:259–273

    Google Scholar 

  152. Tannock IF (1970) Population kinetics of carcinoma cells, capillary endothelial cells, and fibroblasts in a transplanted mouse mammary tumor. Cancer Res 30:2470–2476

    CAS  PubMed  Google Scholar 

  153. Maxwell MNS, Wolfe HJ, Hedley-Whyte ET, Galanopoulos T, Neville-Golden J, Antoniades HN (1991) Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression. Cencer Res 51:1345–1351

    CAS  Google Scholar 

  154. Stefanik DF, Fellows WK, Rizkalla LR, Rizkalla WM, Stefanik PP, Deleo AB, Welch WC (2001) Monoclonal antibodies to vascular endothelial growth factor (VEGF) and the VEGF receptor, FLT-1, inhibit the growth of C6 glioma in a mouse xenograft. J Neurooncol 55:91–100

    CAS  PubMed  Google Scholar 

  155. Thompson EM, Frenkel EP, Neuwelt EA (2011) The paradoxical effect of bevacizumab in the therapy of malignant gliomas. Neurology 76:87–93. doi:10.1212/WNL.0b013e318204a3af

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745. doi:10.1200/JCO.2008.16.3055

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740. doi:10.1200/JCO.2008.19.8721

    CAS  PubMed  Google Scholar 

  158. Norden AD, Drappatz J, Muzikansky A, David K, Gerard M, McNamara MB, Phan P, Ross A, Kesari S, Wen PY (2009) An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma. J Neurooncol 92:149–155. doi:10.1007/s11060-008-9745-8

    CAS  PubMed  Google Scholar 

  159. Omuro A, Chan TA, Abrey LE, Khasraw M, Reiner AS, Kaley TJ, Deangelis LM, Lassman AB, Nolan CP, Gavrilovic IT, Hormigo A, Salvant C, Heguy A, Kaufman A, Huse JT, Panageas KS, Hottinger AF, Mellinghoff I (2013) Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma. Neuro-oncology 15:242–250. doi:10.1093/neuonc/nos295

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Zuniga RM, Torcuator R, Jain R, Anderson J, Doyle T, Schultz L, Mikkelsen T (2010) Rebound tumour progression after the cessation of bevacizumab therapy in patients with recurrent high-grade glioma. J Neurooncol 99:237–242. doi:10.1007/s11060-010-0121-0

    CAS  PubMed  Google Scholar 

  161. Kennedy BC, Showers CR, Anderson DE, Anderson L, Canoll P, Bruce JN, Anderson RC (2013) Tumor-associated macrophages in glioma: friend or foe? J Oncol 2013:486912. doi:10.1155/2013/486912

    PubMed Central  PubMed  Google Scholar 

  162. Pello OM, De Pizzol M, Mirolo M, Soucek L, Zammataro L, Amabile A, Doni A, Nebuloni M, Swigart LB, Evan GI, Mantovani A, Locati M (2012) Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood 119:411–421. doi:10.1182/blood-2011-02-339911

    PubMed  Google Scholar 

  163. Moutsopoulos NM, Wen J, Wahl SM (2008) TGF-beta and tumors–an ill-fated alliance. Curr Opin Immunol 20:234–240. doi:10.1016/j.coi.2008.04.003

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Lei L, Sonabend AM, Guarnieri P, Soderquist C, Ludwig T, Rosenfeld S, Bruce JN, Canoll P (2011) Glioblastoma models reveal the connection between adult glial progenitors and the proneural phenotype. PLoS ONE 6:e20041. doi:10.1371/journal.pone.0020041

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Parker JJ, Dionne KR, Massarwa R, Klaassen M, Foreman NK, Niswander L, Canoll P, Kleinschmidt-Demasters BK, Waziri A (2013) Gefitinib selectively inhibits tumor cell migration in EGFR-amplified human glioblastoma. Neuro-oncology 15:1048–1057. doi:10.1093/neuonc/not053

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Vauleon E, Tony A, Hamlat A, Etcheverry A, Chiforeanu DC, Menei P, Mosser J, Quillien V, Aubry M (2012) Immune genes are associated with human glioblastoma pathology and patient survival. BMC Med Genomics 5:41. doi:10.1186/1755-8794-5-41

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H (1996) Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6:217–223 (discussion 223–214)

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  169. Mineo JF, Bordron A, Baroncini M, Maurage CA, Ramirez C, Siminski RM, Berthou C, Dam Hieu P (2007) Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma. J Neurooncol 85:281–287. doi:10.1007/s11060-007-9424-1

    PubMed  Google Scholar 

  170. Mastronardi L, Guiducci A, Puzzilli F, Ruggeri A (1999) Relationship between Ki-67 labeling index and survival in high-grade glioma patients treated after surgery with tamoxifen. J Neurosurg Sci 43:263–270

    CAS  PubMed  Google Scholar 

  171. Liu G, Ying H, Zeng G, Wheeler CJ, Black KL, Yu JS (2004) HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res 64:4980–4986. doi:10.1158/0008-5472.CAN-03-3504

    CAS  PubMed  Google Scholar 

  172. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313:144–147

    CAS  PubMed  Google Scholar 

  173. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186. doi:10.1056/NEJM197111182852108

    CAS  PubMed  Google Scholar 

  174. Eng LF, Vanderhaeghen JJ, Bignami A, Gerstl B (1971) An acidic protein isolated from fibrous astrocytes. Brain Res 28:351–354

    CAS  PubMed  Google Scholar 

  175. Duffy PE, Huang YY, Rapport MM (1982) The relationship of glial fibrillary acidic protein to the shape, motility, and differentiation of human astrocytoma cells. Exp Cell Res 139:145–157

    CAS  PubMed  Google Scholar 

  176. Bigner SH, Mark J, Burger PC, Mahaley MS Jr, Bullard DE, Muhlbaier LH, Bigner DD (1988) Specific chromosomal abnormalities in malignant human gliomas. Cancer Res 48:405–411

    CAS  PubMed  Google Scholar 

  177. Chandramohan V, Bao X, Keir ST, Pegram CN, Szafranski SE, Piao H, Wikstrand CJ, McLendon RE, Kuan CT, Pastan IH, Bigner DD (2013) Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy. Clin Cancer Res 19(17):4717–4727. doi:10.1158/1078-0432.CCR-12-3891

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  1. Department of Neurological Surgery, Columbia University Medical Center, New York, NY, USA

    Jennifer S. Sims, Timothy H. Ung, Justin A. Neira & Jeffrey N. Bruce

  2. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA

    Peter Canoll

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  1. Jennifer S. Sims
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Sims, J.S., Ung, T.H., Neira, J.A. et al. Biomarkers for glioma immunotherapy: the next generation. J Neurooncol 123, 359–372 (2015). https://doi.org/10.1007/s11060-015-1746-9

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