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Glioblastoma Multiforme –  a Review of Pathogenesis, Biomarkers and Therapeutic Perspectives


Authors: J. Polívka 1;  J. Polívka Jr 2,3;  V. Rohan 1;  O. Topolčan 4
Authors‘ workplace: Neurologická klinika LF UK a FN Plzeň 1;  Ústav histologie a embryologie, LF UK v Plzni 2;  Biomedicínské centrum, LF UK v Plzni 3;  Imunoanalytická laboratoř, Oddělení nukleární medicíny, FN Plzeň 4
Published in: Cesk Slov Neurol N 2013; 76/109(5): 575-583
Category: Review Article

Podpořeno MZ ČR –  RVO (Fakultní nemocnice Plzeň –  FNPl, 00669806). Podpořeno projektem ED2.1.00/ 03.0076 Evropského fondu pro regionální

Overview

Glioblastoma multiforme is the most malignant primary brain tumor in adults with high mortality. Standard glioblastoma therapy consists of surgery, radiotherapy and chemotherapy with temozolomide. However, the overall survival is still very low. Further understanding of the cancerogenetic processes and implementation of novel prognostic and predictive biomarkers as well as targeted cancer therapy and cancer immunotherapy could improve this unsatisfactory situation. This review summarizes current understanding of glioblastoma cancerogenesis as well as the role of novel prognostic and predictive biomarkers (Isocitrate dehydrogenases 1 and 2 mutations, glioma cytosine-guanine island methylator phenotype, promoter methylation status of the MGMT gene). New targeted therapeutic approaches, such as growth factor inhibitors and their receptors, inhibitors of intracellular signaling pathways, inhibitors of pathological angiogenesis and tumor immunotherapy are briefly discussed. Novel glioblastoma treatment options are summarized in the context of predictive and personalised medicine.

Key words:
glioblastoma multiforme – biomarkers –molecular genetics – targeted therapy – personalized medicine

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manu­script met the ICMJE “uniform requirements” for biomedical papers.


Sources

1. National Comprehensive Cancer Network clinical practice guidelines in oncology‑ central nervous system cancers. v.1.2010 [on-line]. Available from URL: http:/ / www.nccn.org/  professionals/ physician_gls/ PDF/ cns.pdf.

2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987– 996.

3. Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M et al. Long‑term survival with glioblastoma multiforme. Brain 2007; 130(Pt 10): 2596– 2606.

4. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Dia­gnosed in the United States in 2004– 2007 [on-line]. Available from URL: www.cbtrus.org/ reports/ reports.html. Accessed August 19, 2011.

5. Burger PC, Vogel FS, Green SB, Strike TA. Glioblastoma multiforme and anaplastic astrocytoma pathologic criteria and prognostic implications. Cancer 1985; 56(5):1106– 1111.

6. Kleihues P, Ohgaki H. Primary and secondary glioblastomas: from concept to clinical dia­gnosis. Neuro Oncol 1999; 1(1): 44– 51.

7. Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007; 170(5): 1445– 1453.

8. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321(5897): 1807– 1812.

9. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455(7216): 1061– 1068.

10. Rao SK, Edwards J, Joshi AD, Siu IM, Riggins GJ. A survey of glioblastoma genomic amplifications and deletions. J Neurooncol 2010; 96(2):169– 179.

11. Verhaak RG, Hoadley KA, Purdom E, Wang V,Qi Y, Wilkerson MD 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.

12. Raimundo N, Baysal BE, Shadel GS. Revisiting the TCA cycle: signaling to tumor formation. Trends Mol Med 2011; 17(11): 641– 649.

13. Capper D, Weissert S, Balss J, Habel A, Meyer J,Jäger D et al. Characterization of R132H mutation‑ specific IDH1 antibody binding in brain tumors. Brain Pathol 2010; 20(1): 245– 254.

14. Frezza C, Tennant DA, Gottlieb E. IDH1 Mutations in Gliomas: When an Enzyme Loses Its Grip. Cancer Cell 2010; 17(1): 7– 9.

15. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360(8): 765– 773.

16. Hartmann C, Meyer J, Balss J, Capper D, Mueller W,Christians A et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 2009; 118(4): 469– 474.

17. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. Cancer‑associated IDH1 mutations produce 2- hydroxyglutarate. Nature 2010; 465(7300): 966.

18. Loenarz C, Schofield CJ. Expanding chemical bio­logy of 2- oxoglutarate oxygenases. Nat Chem Biol 2008; 4(3): 152– 156.

19. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel‑ Wahab O et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012; 483(7390): 474– 478.

20. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH et al. Oncometabolite 2- hydroxyglutarate is a competitive inhibitor of a‑ ketoglutarate‑ dependent dioxygenases. Cancer Cell 2011; 19(1): 17– 30.

21. Dunn GP, Andronesi OC, Cahill DP. From genomics to the clinic: bio­logical and translational insights of mutant IDH1/ 2 in glioma. Neurosurg Focus 2013; 34(2): E2.

22. Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J,Ducray F et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic bio­marker in gliomas. J Clin Oncol 2009; 27(25): 4150– 4154.

23. Hartmann C, Hentschel B, Wick W, Capper D, Felsberg J, Simon M et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1- mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol 2010; 120(6): 707– 718.

24. Takano S, Tian W, Matsuda M, Yamamoto T, Ishikawa E, Kaneko MK et al. Detection of IDH1 mutation in human gliomas: comparison of immunohistochemistry and sequencing. Brain Tumor Pathol 2011; 28(2): 115– 123.

25. Dias‑ Santagata D, Akhavanfard S, David SS, Vernovsky K, Kuhlmann G, Boisvert SL et al. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med 2010; 2(5): 146– 158.

26. MacConaill LE, Campbell CD, Kehoe SM, Bass AJ, Hatton C, Niu L et al. Profiling critical cancer gene mutations in clinical tumor samples. PLoS One 2009; 4(11): e7887.

27. Andronesi OC, Kim GS, Gerstner E, Batchelor T, Tzika AA, Fantin VR et al. Detection of 2- hydroxyglutarate in IDH‑ mutated glioma patients by in vivo spectral‑ editing and 2D correlation magnetic resonance spectroscopy. Sci Transl Med 2012; 4(116): 116ra4.

28. Choi C, Ganji SK, DeBerardinis RJ, Hatanpaa KJ, Rakheja D, Kovacs Z et al. 2– hydroxyglutarate detection by magnetic resonance spectroscopy in IDH‑ mutated patients with gliomas. Nat Med 2012; 18(4): 624– 629.

29. Elkhaled A, Jalbert LE, Phillips JJ, Yoshihara HA, Parvataneni R, Srinivasan R et al. Magnetic resonance of 2- hydroxyglutarate in IDH1– mutated low‑ grade gliomas. Sci Transl Med 2012; 4(116): 116ra5.

30. Pope WB, Prins RM, Thomas MA, Nagarajan R,Yen KE, Bittinger MA et al. Non‑ invasive detection of 2- hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy. J Neurooncol 2012; 107(1): 197– 205.

31. Jones PS, Dunn GP, Barker FG 2nd, Curry WT, Hochberg FH, Cahill DP et al. Molecular genetics of low‑ grade gliomas: genomic alterations guiding dia­gnosis and therapeutic intervention. 11th Annual Frye‑ Halloran Brain Tumor Symposium Meeting Report. Neurosurg Focus 2013; 34(2): E9.

32. Jiao Y, Killela PJ, Reitman ZJ, Rasheed AB, Heaphy CM, de Wilde RF et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 2012; 3(7): 709– 722.

33. Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 2011; 333(6048): 1453– 1455.

34. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science 2011; 333(6041): 425.

35. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010; 17(5): 510– 522.

36. Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012; 483(7390): 479– 483.

37. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al. MGMT gene silencing and benefit from temozolamide in glioblastoma. N Engl J Med 2005; 352(10): 997– 1003.

38. Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP et al. MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol 2010; 12(2): 116– 121.

39. van den Bent MJ, Gravendeel LA, Gorlia T, Kros JM, Lapre L, Wesseling P et al. A hypermethylated phenotype is a better predictor of survival than MGMT methylation in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. Clin Cancer Res 2011; 17(22): 7148– 7155.

40. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5‑year analysis of the EORTC‑ NCIC trial. Lancet Oncol 2009; 10(5): 459– 466.

41. Lakomý R, Fadrus P, Slampa P, Svoboda T, Kren L,Lzicarová E et al. Multimodal treatment of glioblastoma multiforme: results of 86 consecutive patients dia­gnosed in period 2003– 2009. Klin Onkol 2011; 24(2): 112– 120.

42. Pichlmeier U, Bink A, Schackert G, Stummer W; ALA Glioma Study Group. Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. Neuro Oncol 2008; 10(6): 1025– 1034.

43. Senft C, Bink A, Franz K, Vatter H, Gasser T, Seifert V. Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. Lancet Oncol 2011; 12(11): 997– 1003.

44. Bai RY, Staedtke V, Riggins GJ. Molecular targeting of glioblastoma: Drug discovery and therapies. Trends Mol Med 2011; 17(6): 301– 312.

45. Sathornsumetree S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ, Rich JN. Molecularly targeted therapy for malignant glioma. Cancer 2007; 110(1): 13– 24.

46. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004; 22(1): 133– 142.

47. Franceschi E, Cavallo G, Lonardi S, Magrini E, Tosoni A, Grosso D et al. Gefitinib in patients with progressive highgrade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro‑Oncologia (GICNO). Br J Cancer 2007; 96(7): 1047– 1051.

48. Kreisl TN, Lassman AB, Mischel PS, Rosen N, Scher HI, Teruya‑ Feldstein J et al. A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J Neurooncol 2009; 92(1): 99– 105.

49. van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF 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(8): 1268– 1274.

50. de Groot JF, Gilbert MR, Aldape K, Hess KR, Hanna TA, Ictech S et al. Phase II study of carboplatin and erlotinib (Tarceva, OSI‑ 774) in patients with recur­rent glioblastoma. J Neurooncol 2008; 90(1): 89– 97.

51. Sathornsumetee S, Desjardins A, Vredenburgh JJ, McLendon RE, Marcello J, Herndon JE et al. Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol 2010; 12(12): 1300– 1310.

52. Brown PD, Krishnan S, Sarkaria JN, Wu W, Jaeckle KA, Uhm JH et al. Phase I/ II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly dia­gnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol 2008; 26(34): 5603– 5609.

53. Reardon DA, Desjardins A, Vredenburgh JJ, Gururangan S, Friedman AH, Herndon JE 2nd et al. Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. J Neurooncol 2010; 96(2): 219– 230.

54. Karavasilis V, Kotoula V, Pentheroudakis G, Televantou D, Lambaki S, Chrisafi S et al. A phase I study of temozolomide and lapatinib combination in patients with recurrent high‑grade gliomas. J Neurol 2013; 260(6): 1469– 1480.

55. Thiessen B, Stewart C, Tsao M, Kamel‑ Reid S, Schaiquevich P, Mason W 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(2): 353– 361.

56. Belda‑ Iniesta C, Carpeño Jde C, Saenz EC, Gutiérrez M, Perona R, Barón MG. Long term responses with cetuximab therapy in glioblastoma multiforme. Cancer Biol Ther 2006; 5(8): 912– 914.

57. Mellinghoff IK, Wang MY, Vivanco I, Haas‑ Kogan DA, Zhu S, Dia EQ et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005; 353(19): 2012– 2024.

58. Raymond E, Brandes AA, Dittrich C, Fumoleau P, Coudert B, Clement PM et al. Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group Study. J Clin Oncol 2008; 26(28): 4659– 4665.

59. Hainsworth JD, Ervin T, Friedman E, Priego V, Murphy PB, Clark BL et al. Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the firstline treatment of patients with glioblastoma multiforme. Cancer 2010; 116(15): 3663– 3669.

60. Drappatz J, Norden AD, Wong ET, Doherty LM, Lafrankie DC, Ciampa A et al. Phase I study of vandetanib with radiotherapy and temozolomide for newly dia­gnosed glioblastoma. Int J Radiat Oncol Biol Phys 2010; 78(1): 85– 90.

61. Kieran MW, Packer RJ, Onar A, Blaney SM, Phillips P, Pollack IF et al. Phase I and pharmacokinetic study of the oral farnesyltransferase inhibitor lonafarnib administered twice daily to pediatric patients with advanced central nervous system tumors using a modified continuous reassessment method: a pediatric brain tumor consortium study. J Clin Oncol 2007; 25(21): 3137– 3143.

62. Brandes AA, Ermani M, Turazzi S, Scelzi E, Berti F, Amistà P et al. Procarbazine and high‑dose tamoxifen as a second‑line regimen in recurrent high‑grade gliomas: a phase II study. J Clin Oncol 1999; 17(2): 645– 650.

63. Spence AM, Peterson RA, Scharnhorst JD, Silbergeld DL, Rostomily RC. Phase II study of concurrent continuous temozolomide (TMZ) and tamoxifen (TMX) for recurrent malignant astrocytic gliomas. J Neurooncol 2004; 70(1): 91– 95.

64. Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM et al. Phase IIIstudy of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 2010; 28(7): 1168– 1174.

65. Kreisl TN, Kotliarova S, Butman JA, Albert PS, Kim L,Musib L et al. A phase I/ II trial of enzastaurin in patients with recurrent high‑grade gliomas. Neuro Oncol 2010; 12(2): 181– 189.

66. Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J 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(23): 5294– 5304.

67. Chi A, Norden AD, Wen PY. Inhibition of angiogenesis and invasion in malignant gliomas. Expert Rev Anticancer Ther 2007; 7(11): 1537– 1560.

68. Norden AD, Drappatz J, Wen PY. Novel anti‑angiogenic therapies for malignant gliomas. Lancet Neurol 2008; 7(12): 1152– 1160.

69. Salmaggi A, Eoli M, Frigerio S, Silvani A, Gelati M, Corsini E et al. Intracavitary VEGF, bFGF, IL‑8, IL‑12 levels in primary and recurrent malignant glioma. J Neurooncol 2003; 62(3): 297– 303.

70. Nam DH, Park K, Suh YL, Kim JH. Expression of VEGF and brain specific angiogenesis inhibitor‑ 1 in glioblastoma: prognostic significance. Oncol Rep 2004; 11(4): 863– 869.

71. Beal K, Abrey LE, Gutin PH. Antiangiogenic agents in the treatment of recurrent or newly dia­gnosed glioblastoma: analysis of single‑agent and combined modality approaches. Radiat Oncol 2011; 6: 2.

72. Vredenburgh JJ, Desjardins A, Herndon JE jr, Marcello J, Reardon DA, Quinn JA et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007; 25(30): 4722– 4729.

73. Friedman HS, Prados MD, Wen PY, Mikkelsen T,Schiff D, Abrey LE et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27(28): 4733– 4740.

74. Narayana A, Kelly P, Golfinos J, Parker E, Johnson G,Knopp E et al. Antiangiogenic therapy using bevacizumab in recurrent high‑grade glioma: impact on local control and patient survival. J Neurosurg 2009; 110(1): 173– 180.

75. Poulsen HS, Grunnet K, Sorensen M, Olsen P, Hasselbalch B, Nelausen K et al. Bevacizumab plus irinotecan in the treatment patients with progressive recurrent malignant brain tumours. Acta Oncol 2009; 48(1): 52– 58.

76. Zuniga RM, Torcuator R, Jain R, Anderson J, Doyle T, Ellika S et al. Efficacy, safety and patterns of response and recurrence inpatients with recurrent high‑grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol 2009; 91(3): 329– 336.

77. Verhoeff JJ, Lavini C, van Linde ME, Stalpers LJ, Majoie CB, Reijneveld JC et al. Bevacizumab and dose‑intense temozolomide in recurrent high‑grade glioma. Ann Oncol 2010; 21(8): 1723– 1727.

78. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I 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– 745.

79. Avastin® [package insert]. South San Francisco, CA: Genentech, Inc; 2009.

80. Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O’Neill A, Plotkin S et al. Randomized phase II study of cilengitide, an integrin‑targeting arginineglycine‑  aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 2008; 26(34): 5610– 5617.

81. de Groot JF, Lamborn KR, Chang SM, Gilbert MR, Cloughesy TF, Aldape K et al. Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study. J Clin Oncol 2011; 29(19): 2689– 2695.

82. Gomez‑ Manzano C, Holash J, Fueyo J, Xu J, Conrad CA, Aldape KD et al. VEGF Trap induces antiglioma effect at different stages of disease. Neuro Oncol 2008; 10(6): 940– 945.

83. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS et al. AZD2171, a pan‑ VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007; 11(1): 83– 95.

84. Gerstner ER, Chen PJ, Wen PY, Jain RK, Batchelor TT, Sorensen G. Infiltrative patterns of glioblastoma spread detected via diffusion MRI after treatment with cediranib. Neuro Oncol 2010; 12(5): 466– 472.

85. de Groot JF, Fuller G, Kumar AJ, Piao Y, Eterovic K,Ji Y et al. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol 2010; 12(3): 233– 242.

86. Kunnakkat S, Narayana A. Bevacizumab in the treatment of high‑grade gliomas: an overview. Angiogenesis 2011; 14(4): 423– 430.

87. Wick A, Dörner N, Schäfer N, Hofer S, Heiland S, Schemmer D et al. Bevacizumab does not increase the risk of remote relapse in malignant glioma. Ann Neurol 2011; 69(3): 586– 592.

88. Pope WB, Xia Q, Paton VE, Das A, Hambleton J, Kim HJ et al. Patterns of progression in patients with recurrent glioblastoma treated with bevacizumab. Neurology 2011; 76(5): 432– 437.

89. Chamberlain MC. Radiographic patterns of relapse in glioblastoma. J Neurooncol 2011; 101(2): 319– 323.

90. Hodi FS, O‘Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711– 723.

91. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF et al. Sipuleucel‑ T immunotherapy for castration‑resistant prostate cancer. N Engl J Med 2010; 363(5): 411– 422.

92. Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH et al. Greater chemotherapy‑induced lymphopenia enhances tumor‑ specific immune responses that eliminate EGFRvIII‑ expres-sing tumor cells in patients with glioblastoma. Neuro Oncol 2011; 13(3): 324– 333.

93. 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.

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