Brain Tumor Res Treat.  2013 Apr;1(1):2-8. 10.14791/btrt.2013.1.1.2.

Current Trends in Glioblastoma Multiforme Treatment: Radiation Therapy and Immune Checkpoint Inhibitors

• Nicholas S
• Mathios D
• Ruzevick J
• Jackson C
• Yang I
• Lim M

• KMID: 2165215
• DOI: http://doi.org/10.14791/btrt.2013.1.1.2

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain cancer. Even with aggressive combination therapy, the median life expectancy for patients with GBM remains approximately 14 months. In order to improve the outcomes of patients with GBM, the development of newer treatments is critical. The concept of using the immune system as a therapeutic option has been suggested for several decades; by harnessing the body's adaptive immune mechanisms, immunotherapy could provide a durable and targeted treatment against cancer. However, many cancers, including GBM, have developed mechanisms that protect tumor cells from being recognized and eliminated by the immune system. For new immunotherapeutic regimens to be successful, overcoming immunosuppression via immune checkpoint signaling should be taken into consideration.

Keyword

Glioblastoma multiforme; Stereotactic radiosurgery; Immunotherapy; Anti-CTLA-4; Anti-PD-1; Temozolomide

MeSH Terms

Brain Neoplasms
Glioblastoma*
Humans
Immune System
Immunosuppression
Immunotherapy
Life Expectancy
Radiosurgery

Reference

1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352:987–996.

2. Curran WJ Jr, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst. 1993; 85:704–710.

3. Buckner JC. Factors influencing survival in high-grade gliomas. Semin Oncol. 2003; 30:6 Suppl 19. 10–14.

4. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005; 352:997–1003.

5. Stupp R, Hegi ME, Mason WP, 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; 10:459–466.

6. Pàez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009; 15:220–231.

7. Skog J. Glioma-specific antigens for immune tumor therapy. Expert Rev Vaccines. 2006; 5:793–802.

8. Facoetti A, Nano R, Zelini P, et al. Human leukocyte antigen and antigen processing machinery component defects in astrocytic tumors. Clin Cancer Res. 2005; 11:8304–8311.

9. Gomez GG, Kruse CA. Mechanisms of malignant glioma immune resistance and sources of immunosuppression. Gene Ther Mol Biol. 2006; 10:133–146.

10. Laws ER, Parney IF, Huang W, et al. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J Neurosurg. 2003; 99:467–473.

11. Yamaguchi S, Kobayashi H, Terasaka S, et al. The impact of extent of resection and histological subtype on the outcome of adult patients with high-grade gliomas. Jpn J Clin Oncol. 2012; 42:270–277.

12. Kristiansen K, Hagen S, Kollevold T, et al. Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer. 1981; 47:649–652.

13. Walker MD, Alexander E Jr, Hunt WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg. 1978; 49:333–343.

14. Chang CH, Horton J, Schoenfeld D, et al. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Cancer. 1983; 52:997–1007.

15. Brem H, Ewend MG, Piantadosi S, Greenhoot J, Burger PC, Sisti M. The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. J Neurooncol. 1995; 26:111–123.

16. Valtonen S, Timonen U, Toivanen P, et al. Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery. 1997; 41:44–48. discussion 48-9.

17. Westphal M, Hilt DC, Bortey E, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003; 5:79–88.

18. Sawaya R, Hammoud M, Schoppa D, et al. Neurosurgical outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors. Neurosurgery. 1998; 42:1044–1055. discussion 1055-6.

19. Dirks P, Bernstein M, Muller PJ, Tucker WS. The value of reoperation for recurrent glioblastoma. Can J Surg. 1993; 36:271–275.

20. Harsh GR 4th, Levin VA, Gutin PH, Seager M, Silver P, Wilson CB. Reoperation for recurrent glioblastoma and anaplastic astrocytoma. Neurosurgery. 1987; 21:615–621.

21. Barker FG 2nd, Chang SM, Gutin PH, et al. Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery. 1998; 42:709–720. discussion 720-3.

22. Park JK, Hodges T, Arko L, et al. Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol. 2010; 28:3838–3843.

23. Brem H, Piantadosi S, Burger PC, et al. The Polymer-brain Tumor Treatment Group. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet. 1995; 345:1008–1012.

24. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009; 27:4733–4740.

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; 27:740–745.

26. Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000; 47:291–298.

27. Souhami L, Scott C, Brachman D, et al. Randomized prospective comparison of stereotactic radiosurgery (SRS) followed by conventional radiotherapy (RT) with BCNU to RT with BCNU alone for selected patients with supratentorial glioblastoma multiforme (GBM): report of RTOG 93-05 protocol. Int J Radiat Oncol Biol Phys. 2002; 54:94–95.

28. Tsao MN, Mehta MP, Whelan TJ, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys. 2005; 63:47–55.

29. Einstein DB, Wessels B, Bangert B, et al. Phase II trial of radiosurgery to magnetic resonance spectroscopy-defined high-risk tumor volumes in patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2012; 84:668–674.

30. Pouratian N, Crowley RW, Sherman JH, Jagannathan J, Sheehan JP. Gamma Knife radiosurgery after radiation therapy as an adjunctive treatment for glioblastoma. J Neurooncol. 2009; 94:409–418.

31. Combs SE, Gutwein S, Thilmann Ch, Huber P, Debus J, Schulz-Ertner D. Stereotactically guided fractionated re-irradiation in recurrent glioblastoma multiforme. J Neurooncol. 2005; 74:167–171.

32. Shrieve DC, Alexander E 3rd, Wen PY, et al. Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery. 1995; 36:275–282. discussion 282-4.

33. Vordermark D, Kölbl O, Ruprecht K, Vince GH, Bratengeier K, Flentje M. Hypofractionated stereotactic re-irradiation: treatment option in recurrent malignant glioma. BMC Cancer. 2005; 5:55.

34. Laperriere NJ, Leung PM, McKenzie S, et al. Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma. Int J Radiat Oncol Biol Phys. 1998; 41:1005–1011.

35. Welsh J, Sanan A, Gabayan AJ, et al. GliaSite brachytherapy boost as part of initial treatment of glioblastoma multiforme: a retrospective multi-institutional pilot study. Int J Radiat Oncol Biol Phys. 2007; 68:159–165.

36. Archavlis E, Tselis N, Birn G, Ulrich P, Baltas D, Zamboglou N. Survival analysis of HDR brachytherapy versus reoperation versus temozolomide alone: a retrospective cohort analysis of recurrent glioblastoma multiforme. BMJ Open. 2013; 3:pii: e002262.

37. Larson DA, Suplica JM, Chang SM, et al. Permanent iodine 125 brachytherapy in patients with progressive or recurrent glioblastoma multiforme. Neuro Oncol. 2004; 6:119–126.

38. Halligan JB, Stelzer KJ, Rostomily RC, Spence AM, Griffin TW, Berger MS. Operation and permanent low activity 125I brachytheraphy for recurrent high-grade astrocytomas. Int J Radiat Oncol Biol Phys. 1996; 35:541–547.

39. Gabayan AJ, Green SB, Sanan A, et al. GliaSite brachytherapy for treatment of recurrent malignant gliomas: a retrospective multi-institutional analysis. Neurosurgery. 2006; 58:701–709. discussion 701-9.

40. Chan TA, Weingart JD, Parisi M, et al. Treatment of recurrent glioblastoma multiforme with GliaSite brachytherapy. Int J Radiat Oncol Biol Phys. 2005; 62:1133–1139.

41. Maier-Hauff K, Ulrich F, Nestler D, et al. Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme. J Neurooncol. 2011; 103:317–324.

42. Adkison JB, Tomé W, Seo S, et al. Reirradiation of large-volume recurrent glioma with pulsed reduced-dose-rate radiotherapy. Int J Radiat Oncol Biol Phys. 2011; 79:835–841.

43. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008; 8:467–477.

44. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005; 23:515–548.

45. Mellor AL, Keskin DB, Johnson T, Chandler P, Munn DH. Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. J Immunol. 2002; 168:3771–3776.

46. Friberg M, Jennings R, Alsarraj M, et al. Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int J Cancer. 2002; 101:151–155.

47. Hou DY, Muller AJ, Sharma MD, et al. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res. 2007; 67:792–801.

48. Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest. 2007; 117:1147–1154.

49. Bak SP, Alonso A, Turk MJ, Berwin B. Murine ovarian cancer vascular leukocytes require arginase-1 activity for T cell suppression. Mol Immunol. 2008; 46:258–268.

50. Ochoa AC, Zea AH, Hernandez C, Rodriguez PC. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res. 2007; 13(2 Pt 2):721s–726s.

51. Rodríguez PC, Ochoa AC. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev. 2008; 222:180–191.

52. Löb S, Königsrainer A, Zieker D, et al. IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother. 2009; 58:153–157.

53. Reisser D, Onier-Cherix N, Jeannin JF. Arginase activity is inhibited by L-NAME, both in vitro and in vivo. J Enzyme Inhib Med Chem. 2002; 17:267–270.

54. Fife BT, Pauken KE, Eagar TN, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol. 2009; 10:1185–1192.

55. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12:252–264.

56. Hathcock KS, Laszlo G, Dickler HB, Bradshaw J, Linsley P, Hodes RJ. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science. 1993; 262:905–907.

57. Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2009; 229:12–26.

58. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996; 14:233–258.

59. Freeman GJ, Gribben JG, Boussiotis VA, et al. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science. 1993; 262:909–911.

60. Azuma M, Ito D, Yagita H, et al. B70 antigen is a second ligand for CTLA-4 and CD28. Nature. 1993; 366:76–79.

61. Linsley PS, Clark EA, Ledbetter JA. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc Natl Acad Sci U S A. 1990; 87:5031–5035.

62. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991; 174:561–569.

63. Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity. 1994; 1:793–801.

64. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996; 271:1734–1736.

65. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999; 190:355–366.

66. Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003; 100:4712–4717.

67. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003; 100:8372–8377.

68. Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol. 2005; 23:8968–8977.

69. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363:711–723.

70. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002; 99:12293–12297.

71. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004; 10:5094–5100.

72. Kuang DM, Zhao Q, Peng C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med. 2009; 206:1327–1337.

73. Liu Y, Zeng B, Zhang Z, Zhang Y, Yang R. B7-H1 on myeloid-derived suppressor cells in immune suppression by a mouse model of ovarian cancer. Clin Immunol. 2008; 129:471–481.

74. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A. 2004; 101:17174–17179.

75. Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005; 11:2947–2953.

76. Ghebeh H, Mohammed S, Al-Omair A, et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia. 2006; 8:190–198.

77. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012; 13:459–465.

78. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010; 28:3167–3175.

79. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366:2443–2454.

80. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366:2455–2465.

81. Zeng J, See AP, Phallen J, et al. Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice With Intracranial Gliomas. Int J Radiat Oncol Biol Phys. 2013; [Epub ahead of print].

82. Knisely JP, Yu JB, Flanigan J, Sznol M, Kluger HM, Chiang VL. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg. 2012; 117:227–233.

83. Ipilimumab and Imatinib Mesylate in Advanced Cancer (NCT01738139). US NIH clinical trials registry;Accessed April 1, 2013. at http://www.clinicaltrials.gov.

84. Formenti SC, Demaria S. Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys. 2012; 84:879–880.

85. Stamell EF, Wolchok JD, Gnjatic S, Lee NY, Brownell I. The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys. 2013; 85:293–295.

86. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012; 366:925–931.

87. Ipilimumab and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Melanoma With Brain Metastases (NCT01703507). US NIH clinical trials registry;Accessed April 1, 2013. at http://clinicaltrials.gov/ct2/show/NCT01703507.

88. Pilot Ipilimumab in Stage IV Melanoma Receiving Palliative Radiation Therapy (NCT01449279). US NIH Clinical trials registry;2013. Accessed April 1, 2013. at http://clinicaltrials.gov/show/NCT01449279.

89. Study of Ipilimumab to Treat Melanoma in Patients With Brain Metastases (NCT00623766). US NIH Clinical trials registry;Accessed April 1, 2013. at http://clinicaltrials.gov/ct2/show/NCT00623766?term=Study+of+Ipilimumab+to+Treat+Melanoma+in+Patients+With+Brain+Metastases&rank=1.

90. Jackson C, Ruzevick J, Phallen J, Belcaid Z, Lim M. Challenges in immunotherapy presented by the glioblastoma multiforme microenvironment. Clin Dev Immunol. 2011; 2011:732413.

91. Pazdur R. FDA Approval for Ipilimumab. Accessed April 1, 2013. at http://www.cancer.gov/cancertopics/druginfo/fda-ipilimumab.