Advertisement

From Molecular to Clinical Radiation Biology of Glioblastoma

  • Nadia PasinettiEmail author
  • Luigi Pirtoli
  • Michela Buglione
  • Luca Triggiani
  • Paolo Borghetti
  • Paolo Tini
  • Stefano Maria Magrini
Chapter
  • 618 Downloads
Part of the Current Clinical Pathology book series (CCPATH)

Abstract

For a long time, the radiobiological subject of the well-known radiation resistance of glioblastoma (GB) was studied through mathematical models (MMs), not differently from other cancers. Recently, some peculiarities of the IR-surviving fraction’s curves in GB, diverging from LQ model at various doses, have been attributed to different cell-death pathways and/or repair mechanisms of damage to critical molecular targets, requiring more sophisticated formalisms. Accordingly, novel perspectives in GB treatment derive from experimental studies of targeted therapies, either alone or combined with traditional RT and CHT. However, clinical trials had not yet yielded significant results in terms of patient survival improvement, in spite of substantial improvements in knowledge of the biology of this disease and of technological advances and medical procedure refinements. GB is a largely heterogeneous cancer, which partly justifies failure of treatment. Recent molecular and genetic studies have revealed a plethora of potential new therapeutic targets for GB. In this chapter, we review up-to-date clinical trials of GBM treatments with more therapeutic effect than conventional therapies that are ongoing or are about to launch in clinical settings and discuss future perspectives.

Keywords

Malignant Glioma Vascular Endothelial Growth Factor Receptor Oncolytic Virus Cytokine Therapy Passive Immunotherapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Gerweck LE, Komblith PL, Burlett P, et al. Radiation sensitivity of cultured glioblastoma cells. Radiology. 1977;125:231–4.CrossRefPubMedGoogle Scholar
  2. 2.
    Fowler JF. A review: the linear quadratic formula and progress in fractionated radiotherapy. Br J Radiol. 1989;62:679–94.CrossRefPubMedGoogle Scholar
  3. 3.
    Williams JR, Gridley DS, Slater JB. Radiobiology of resistant glioblastoma cells. www.intechopen 2011;3–22.
  4. 4.
    Joiner MC, Marples B, Lamblin P. Low-dose hypersensitivity: current status and possible mechanism. Int J Radiat Oncol Biol Phys. 2001;49:379–89.CrossRefPubMedGoogle Scholar
  5. 5.
    Palumbo S, Pirtoli L, Tini P, et al. Different involvement of autophagy in human malignant glioma cell lines undergoing irradiation and temozolomide combined treatment. J Cell Biochem. 2012;113:2308–18.CrossRefPubMedGoogle Scholar
  6. 6.
    Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.CrossRefPubMedGoogle Scholar
  7. 7.
    Pedicini P, Fiorentino A, Simeon V, et al. Clinical radiobiology of glioblastoma multiforme. Estimation of tumor control probability from various radiotherapy fractionation schemes. Strahlenther Onkol. 2014;190:925–32.CrossRefPubMedGoogle Scholar
  8. 8.
    Otomo T, Hishii M, Arai H, et al. Microarray analysis of temporal gene responses to ionizing radiation in two glioblastoma cell lines: up-regulation of DNA repair genes. J Radiat Res. 2004;45:53–60.CrossRefPubMedGoogle Scholar
  9. 9.
    Veliz I, Loo Y, Castillo O, et al. Advances and challenges in the molecular biology and treatment of glioblastoma—is there any hope for the future? Ann Transl Med. 2015;3(1):7.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Hatampaa KJ, Burma S, Zhao D, Habib AA. Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance. Neoplasia. 2010;12:675–84.CrossRefGoogle Scholar
  11. 11.
    Verhaak RGW, Hoadley KA, Purdom E, et al. An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1. Cancer Cell. 2010;17(1):98–110. doi: 10.1016/J.ccr2009.12.020.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Verhaak RGW, 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;17(1):98–110.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ohka F, Natsume A, Wakabayashi T. Current trends in targeted therapies for glioblastoma multiforme. Neurol Res Int. 2012;2012:878425.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Mrugala MM. Advances and challenges in the treatment of glioblastoma: a clinician’s perspective. Discov Med. 2013;15(83):221–30.PubMedGoogle Scholar
  15. 15.
    Cloughesy TF, Cavenee WK, Mischel PS. Glioblastoma: from molecular pathology to targeted treatment. Annu Rev Pathol. 2014;9:1–25.CrossRefPubMedGoogle Scholar
  16. 16.
    Brennan CW, Verhaak RG, McKenna A, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462–77.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–17.CrossRefPubMedGoogle Scholar
  18. 18.
    Bastien JI, McNeill KA, Fine HA. Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date. Cancer. 2015;121(4):502–16.CrossRefPubMedGoogle Scholar
  19. 19.
    Rao SK, Edwards J, Joshi AD, Siu IM, Riggins GJ. A survey of glioblastoma genomic amplifications and deletions. J Neurooncol. 2010;96:169–79.CrossRefPubMedGoogle Scholar
  20. 20.
    Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group study. J Clin Oncol. 2005;23:5294–304.CrossRefPubMedGoogle Scholar
  21. 21.
    Chang SM, Wen P, Cloughesy T, et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs. 2005;23:357–61.CrossRefPubMedGoogle Scholar
  22. 22.
    Cloughesy T, Raizer J, Drappatz J, et al. A phase II trial of everolimus in patients with recurrent glioblastoma multiforme. Neuro Oncol. 2011;13 suppl 3:42–3.Google Scholar
  23. 23.
    Kreisl TN, Lassman AB, Mischel PS, et al. A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J Neurooncol. 2009;92:99–105.CrossRefPubMedGoogle Scholar
  24. 24.
    Lee EQ, Kuhn J, Lamborn KR, et al. Phase I/II study of sorafenibin combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02. Neuro Oncol. 2012;14:1511–8.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kreisl TN, Kim L, Moore K, et al. Phase II trial of single agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5):740–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Tanaka K, Babic I, Nathanson D, et al. Oncogenic EGFR signaling activates an mTORC2-NF-jB pathway that promotes chemotherapy resistance. Cancer Discov. 2011;1:524–38.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Sami A, Karsy M. Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding. Tumour Biol. 2013;34:1991–2002.CrossRefPubMedGoogle Scholar
  28. 28.
    Vredenburgh JJ, Desjardins A, Herndon JE, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25(30):4722–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709–22.CrossRefPubMedGoogle Scholar
  30. 30.
    Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699–708.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Fine HA. Bevacizumab in glioblastoma—still much to learn. N Engl J Med. 2014;370:764–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Kreisl TN, Smith P, Sul J, Salgado C, Iwamoto FM, Shih JH, Fine HA. Continuous daily sunitinib for recurrent glioblastoma. J Neurooncol. 2013;111(1):41–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Reardon DA, Vredenburgh JJ, Desjardins A, et al. Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma. J Neurooncol. 2011;101:57–66.CrossRefPubMedGoogle Scholar
  34. 34.
    Thiessen B, Stewart C, Tsao M, et al. A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation. Cancer Chemother Pharmacol. 2010;65:353–61.CrossRefPubMedGoogle Scholar
  35. 35.
    Raizer JJ, Abrey LE, Lassman AB, et al. A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas. Neuro Oncol. 2010;12:87–94.CrossRefPubMedGoogle Scholar
  36. 36.
    Uhm JH, Ballman KV, Wu W, et al. Phase II evaluation of gefitinib in patients with newly diagnosed grade 4 astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074. Int J Radiat Oncol Biol Phys. 2011;80:347–53.CrossRefPubMedGoogle Scholar
  37. 37.
    Raizer JJ, Abrey LE, Lassman AB, et al. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol. 2010;12:95–103.CrossRefPubMedGoogle Scholar
  38. 38.
    Fuller GN, Bigner SH. Amplified cellular oncogenes in neoplasms of the human central nervous system. Mutat Res. 1992;276:299–306.CrossRefPubMedGoogle Scholar
  39. 39.
    Frattini V, Trifonov V, Chan JM, et al. The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet. 2013;4510:1141–9.CrossRefGoogle Scholar
  40. 40.
    Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353:2012–24.CrossRefPubMedGoogle Scholar
  41. 41.
    Van den Bent MJ, Brandes AA, Rampling R, et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC Brain Tumor Group Study 26034. J Clin Oncol. 2009;27:1268–74.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Yung WK, Vredenburgh JJ, Cloughesy TF, et al. Safety and efficacy of erlotinib in first-relapse glioblastoma: a phase II open-label study. Neuro Oncol. 2010;12:1061–70.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Mao H, Lebrun DG, Yang J, Zhu VF, Li M. Deregulated signaling pathways in glioblastoma multiforme: molecular mechanisms and therapeutic targets. Cancer Invest. 2012;30:48–56.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Snuderl M, Fazlollahi L, Le LP, et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell. 2011;20:810–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Szerlip NJ, Pedraza A, Chakravarty D, et al. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci U S A. 2012;109:3041–6.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Inda MM, Bonavia R, Mukasa A, et al. Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev. 2010;24:1731–45.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang S, Berger MS, McDermott MW, Kunwar SM, Junck LR, Chandler W, Zwiebel JA, Kaplan RS, Yung WK. Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol. 2003;21:2508–18.CrossRefPubMedGoogle Scholar
  48. 48.
    ClinicalTrials.gov. Gene therapy in treating patients with recurrent malignant gliomas. http://clinicaltrials.gov/ct2/show/NCT00004041. Accessed June 2014.
  49. 49.
    ClinicalTrials.gov. Gene therapy in treating patients with recurrent or progressive brain tumors. http://clinicaltrials.gov/ct2/show/NCT00004080. Accessed June 2014.
  50. 50.
    ClinicalTrials.gov. A study of PD 0332991 in patients with recurrent Rb positive glioblastoma. http://clinicaltrials.gov/ct2/show/NCT01227434.
  51. 51.
    Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60.CrossRefPubMedGoogle Scholar
  52. 52.
    Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol. 2011;29:4828–36.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Waziri A. Glioblastoma-derived mechanisms of systemic immunosuppression. Neurosurg Clin N Am. 2010;21(1):31–42.CrossRefPubMedGoogle Scholar
  54. 54.
    Lampson LA. Brain tumor immunotherapy: seeing the brain in the body. Drug Discov Today. 2013;18(7–8):399–406.CrossRefPubMedGoogle Scholar
  55. 55.
    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;19(12):3165–75.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Bloch O, Kaur T, Aghi M, et al. Progression-free survival in a trial of immunotherapy for glioblastoma (abstract). In: Proceedings of the 81st Annual Meetings of the American Association of Neurological Surgeons; 2013 April 28–May 1, New Orleans, LA: J Neurosurgery 2013;119. p. A565. Abstract no. 801.Google Scholar
  57. 57.
    Lampson LA. Monoclonal antibodies in neuro-oncology: getting past the blood–brain barrier. MAbs. 2011;3:153–60.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Wolfl M, et al. Primed tumor-reactive multifunctional CD62L1 human CD81 T cells for immunotherapy. Cancer Immunol Immunother. 2011;60:173–86.CrossRefPubMedGoogle Scholar
  59. 59.
    Tatum AM, et al. CD81 T cells targeting a single immunodominant epitope are sufficient for elimination of established SV40T antigen-induced brain tumors. J Immunol. 2008;181:4406–17.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Dietrich PY, et al. T-cell immunotherapy for malignant glioma: toward a combined approach. Curr Opin Oncol. 2010;22:604–10.CrossRefPubMedGoogle Scholar
  61. 61.
    Mellman I, et al. Cancer immunotherapy comes of age. Nature. 2011;480:480–9.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 2004;64:4973–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH, Nelson SF, Liau LM. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res. 2011;17:1603–15.CrossRefPubMedGoogle Scholar
  64. 64.
    Sampson JH, Aldape KD, Archer GE, Coan A, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13(3):324–33.CrossRefPubMedGoogle Scholar
  65. 65.
    Jackson CM, Lim M, Drake CG. Immunotherapy for brain cancer: recent progress and future promise. Clin Cancer Res. 2014;20(14):3651–9.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Lim M. Immunotherapy for glioblastoma: are we finally getting closer? Neuro Oncol. 2015;17(6):771–2.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    ClinicalTrials.gov. Dendritic cell vaccine for patients with brain tumors. https://clinicaltrials.gov/ct2/show/NCT01204684.
  68. 68.
    Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.CrossRefPubMedGoogle Scholar
  69. 69.
    Heimberger AB, Sampson JH. PEP-3-KLH (CDX-110) vaccine in glioblastoma multiforme patients. Expert Opin Biol Ther. 2009;9(8):1087–98.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Schuster J, Lai RK, Recht LD, et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. 2015;17(6):854–61.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    ClinicalTrials.gov. Anti PD1 antibody in diffuse intrinsic pontine glioma and relapsed glioblastoma multiforme. https://clinicaltrials.gov/show/NCT01952769.
  72. 72.
    Fewkes NM, Mackall CL. Novel gamma-chain cytokines as candidate immune modulators in immune therapies for cancer. Cancer J. 2010;16:392–8.CrossRefPubMedGoogle Scholar
  73. 73.
    DiMeco F, Rhines LD, Hanes J, Tyler BM, Brat D, Torchiana E, Guarnieri M, Colombo MP, Pardoll DM, Finocchiaro G, et al. Paracrine delivery of IL-12 against intracranial 9L gliosarcoma in rats. J Neurosurg. 2000;92:419–27.CrossRefPubMedGoogle Scholar
  74. 74.
    ClinicalTrials.gov. A study of Ad-RTS-hIL-12 WITH Veledimex in subjects with glioblastoma or malignant glioma. http://clinicaltrials.gov/ct2/show/NCT02026271.
  75. 75.
    Patel MA, Kim JE, Ruzevick J, Li G, Lim M. The future of glioblastoma therapy: synergism of standard of care and immunotherapy. Cancers (Basel). 2014;6(4):1953–85.CrossRefGoogle Scholar
  76. 76.
    Carlsson SK, Brothers SP, Wahlestedt C. Emerging treatment strategies for glioblastoma multiforme. EMBO Mol Med. 2014;6(11):1359–70.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Roth JC, Cassady KA, Cody JJ, Parker JN, Price KH, Coleman JM, Peggins JO, Noker PE, Powers NW, Grimes SD, et al. Evaluation of the safety and biodistribution of M032, an attenuated herpes simplex virus type 1 expressing hIL-12, after intracerebral administration to aotus nonhuman primates. Hum Gene Ther Clin Dev. 2014;25:16–27.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    ClinicalTrials.gov. Genetically engineered HSV-1 Phase 1 Study (M032-HSV-1) http://clinicaltrials.gov/ct2/show/NCT02062827.
  79. 79.
    Fueyo J, Alemany R, Gomez-Manzano C, Fuller GN, Khan A, Conrad CA, Liu TJ, Jiang H, Lemoine MG, Suzuki K, et al. Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway. J Natl Cancer Inst. 2003;95:652–60.CrossRefPubMedGoogle Scholar
  80. 80.
    Pol JG, Marguerie M, Arulanandam R, Bell JC, Lichty BD. Panorama from the oncolytic virotherapy summit. Mol Ther. 2013;21:1814–8.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Prins RM, Odesa SK, Liau LM. Immunotherapeutic targeting of shared melanoma-associated antigens in a murine glioma model. Cancer Res. 2003;63:8487–91.PubMedGoogle Scholar
  82. 82.
    Lake RA, Robinson BWS. Immunotherapy and chemotherapy—a practical partnership. Nat Rev Cancer. 2005;5:397–405.CrossRefPubMedGoogle Scholar
  83. 83.
    Haynes NM, Van der Most RG, Lake RA, Smyth MJ. Immunogenic anti-cancer chemotherapy as an emerging concept. 2008. Curr Opin Immunol.Google Scholar
  84. 84.
    ClinicalTrials.gov. Phase III STUDY of Rindopepimut/GM-CSF in patients with newly diagnosed glioblastoma (ACT IV). https://clinicaltrials.gov/ct2/show/NCT01480479.
  85. 85.
    ClinicalTrials.gov. A study of Rindopepimut/GM-CSF in patients with relapsed EGFRvIII-positive glioblastoma (ReACT). https://clinicaltrials.gov/ct2/show/NCT01498328.
  86. 86.
    ClinicalTrials.gov. Study of a Drug [DCVax®-L] to treat newly diagnosed gbm brain cancer (ReACT). https://clinicaltrials.gov/ct2/show/NCT00045968.
  87. 87.
    Alizadeh D, Larmonier N. Chemotherapeutic targeting of cancer-induced immunosuppressive cells. Cancer Res. 2014;74(10):2663–8.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Gough MJ, Crittenden MR. Combination approaches to immunotherapy: the radiotherapy example. Immunotherapy. 2009;1:1025–37.CrossRefPubMedGoogle Scholar
  89. 89.
    Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105(4):256–65.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Garnett-Benson C, Hodge JW, Gameiro SR. Combination regimens of radiation therapy and therapeutic cancer vaccines: mechanisms and opportunities. Semin Radiat Oncol. 2015;25(1):46–53.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    ClinicalTrials.gov. Phase 1b Study of AdV-tk + Valacyclovir combined with radiation therapy for malignant gliomas (BrTK01). https://clinicaltrials.gov/ct2/show/NCT00751270.
  92. 92.
    Zagzag D, Salnikow K, Chiriboga L, Yee H, Lan L, Ali MA, Garcia R, Demaria S, Newcomb EW. Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain. Lab Invest. 2005;85(3):328–41.CrossRefPubMedGoogle Scholar
  93. 93.
    Newcomb EW, Demaria S, Lukyanov Y, Shao Y, Schnee T, Kawashima N, Lan L, Dewyngaert JK, Zagzag D, McBride WH, Formenti SC. The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas. Clin Cancer Res. 2006;12(15):4730–7.CrossRefPubMedGoogle Scholar
  94. 94.
    Pellegatta S, Poliani PL, Stucchi E, et al. Intra-tumoral dendritic cells increase efficacy of peripheral vaccination by modulation of glioma microenvironment. Neuro Oncol. 2010;12(4):377–88.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Yamanaka R, Homma J, Yajima N, et al. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res. 2005;11(11):4160–7.CrossRefPubMedGoogle Scholar
  96. 96.
    Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28(31):4722–9.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Soukup K, Wang X. Radiation meets immunotherapy—a perfect match in the era of combination therapy? Int J Radiat Biol. 2015;91(4):299–305.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Debus J, Abdollahi A. For the next trick: new discoveries in radiobiology applied to glioblastoma. Am Soc Clin Oncol Educ Book. 2014:e95-9. doi:10.14694/EdBook_AM.2014.34.e95, Review.Google Scholar
  99. 99.
    Mizoe JE, Tsujii H, Hasegawa A, et al. Phase I/II clinical trial of carbon ion radiotherapy for malignant gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy. Int J Radiat Oncol Biol Phys. 2007;69(2):390–6.CrossRefPubMedGoogle Scholar
  100. 100.
    Combs SE, Bruckner T, Mizoe JE, Kamada T, Tsujii H, Kieser M, Debus J. Comparison of carbon ion radiotherapy to photon radiation alone or in combination with temozolomide in patients with high-grade gliomas: explorative hypothesis-generating retrospective analysis. Radiother Oncol. 2013;108(1):132–5.CrossRefPubMedGoogle Scholar
  101. 101.
    Combs SE, Kieser M, Rieken S, et al. Randomized phase II study evaluating a carbon ion boost applied after combined radiochemotherapy with temozolomide versus a proton boost after radiochemotherapy with temozolomide in patients with primary glioblastoma: the CLEOPATRA trial. BMC Cancer. 2010;10:478.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    McLendon R, Friedman A, Bigner D, et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8.CrossRefGoogle Scholar
  103. 103.
    Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Kalbasi A, June CH, Haas N, Vapiwala N. Radiation and immunotherapy: a synergistic combination. J Clin Invest. 2013;123:2756–63.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Nadia Pasinetti
    • 1
    Email author
  • Luigi Pirtoli
    • 2
    • 3
  • Michela Buglione
    • 1
  • Luca Triggiani
    • 1
  • Paolo Borghetti
    • 1
  • Paolo Tini
    • 2
    • 4
  • Stefano Maria Magrini
    • 5
  1. 1.Radiation Oncology DepartmentUniversity andSpedali Civili - BresciaBresciaItaly
  2. 2.Tuscany Tumor InstituteFlorenceItaly
  3. 3.Unit of Radiation Oncology, Department of Medicine, Surgery and NeurosciencesUniversity of SienaSienaItaly
  4. 4.Unit of Radiation OncologyUniversity Hospital of Siena (Azienda Ospedaliera Universitaria Senese), Istituto Toscano TumoriSienaItaly
  5. 5.Radiation Oncology DepartmentUniversity and Spedali Civili - Brescia BresciaBresciaItaly

Personalised recommendations