Advertisement

The Role of Checkpoint Inhibitors in Glioblastoma

  • Kunal DesaiEmail author
  • Anne Hubben
  • Manmeet Ahluwalia
Review Article

Abstract

Given its poor prognosis, glioblastoma represents an area of high unmet clinical need. Standard of care for the treatment of glioblastoma in the frontline setting is limited to surgical resection, radiation, and temozolomide, with the more recent addition of Tumor Treating Fields. Several agents, including bevacizumab, lomustine, and carmustine have been approved in the recurrent setting. To date, no therapies have demonstrated substantial survival benefit beyond standard of care. An expanding understanding of the role of the immune system in fighting cancer has led to the development and approval of various immunotherapeutic approaches across solid tumors. In glioblastoma, the notion of a highly immune-restricted central nervous system has also evolved, further providing the rationale for testing therapies that promote immune trafficking to the CNS and infiltration into the tumor to counteract the immunosuppressive mechanisms that support tumor progression. There are five broad categories of immunotherapies currently being tested in GBM: vaccines, cytokine therapy, oncolytic viral therapy, chimeric antigen receptor T cell therapy, and checkpoint inhibitors. This review focuses on checkpoint inhibitors in GBM, the rationale for its use, preclinical data, and early clinical experience. Efficacy data are limited, and while a number of late-stage trials are ongoing, early trials showed no benefit in survival. There is a dizzying array of combinations being tested in clinical studies with an urgent need for a rational approach to determine the role of checkpoint inhibitors in glioblastoma, including the optimal combinations, and identification of biomarkers or predictive models to determine which patients may benefit from immunotherapy.

Notes

Compliance with Ethical Standards

Conflict of Interest

Dr. Kunal Desai and Dr. Anne Hubben declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. Dr. Ahluwalia has received consulting fees or honorarium from Prime Education, Prime Oncology, Elsevier, Monteris AstraZeneca, Bristol-Myers Squibb, Abbvie, CBT Pharmaceuticals, Kadmon, VBI Vaccines, Flatiron Health, Varian Medical Systems, Karyopharm Therapeutics. Dr. Ahluwalia has stock/stock options in Mimivax and Doctible. Dr. Ahluwalia has grants received or pending from Novartis, Novocure, Astrazeneca, Abbvie, BMS, Pharamacyclics, Incyte, Merck, Bayer, Mimivax, and Boston Biomedical.

Funding

No external funding was used in the preparation of this article.

References

  1. 1.
    Weller M, Wick W, Aldape K, Brada M, Berger M, Pfister SM, et al. Glioma. Nat Rev Dis Primers. 2015;1:15017.CrossRefPubMedGoogle Scholar
  2. 2.
    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol. 2017;19(suppl_5):1–88.CrossRefGoogle Scholar
  4. 4.
    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):987–96.CrossRefPubMedGoogle Scholar
  5. 5.
    Sulman EP, Ismaila N, Armstrong TS, Tsien C, Batchelor TT, Cloughesy T, et al. Radiation therapy for glioblastoma: American Society of clinical oncology clinical practice guideline endorsement of the American Society for radiation oncology guideline. J Clin Oncol. 2017;35(3):361–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999;17(8):2572–8.CrossRefPubMedGoogle Scholar
  7. 7.
    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):740–5.CrossRefPubMedGoogle Scholar
  8. 8.
    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):4733–40.CrossRefPubMedGoogle Scholar
  9. 9.
    Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–22.CrossRefPubMedGoogle Scholar
  11. 11.
    Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017;377(20):1954–63.CrossRefPubMedGoogle Scholar
  12. 12.
    Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996;2(10):1096–103.CrossRefPubMedGoogle Scholar
  13. 13.
    Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 2013;73(2):539–49.CrossRefPubMedGoogle Scholar
  14. 14.
    Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70(15):6171–80.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Murphy JB, Sturm E. Conditions determining the transplantability of tissues in the brain. J Exp Med. 1923;38(2):183–97.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Willis RA. Experiments on the intracerebral implantation of embryo tissues in rats. Proc R Soc B. 1935;117(805):400–12.CrossRefGoogle Scholar
  17. 17.
    Medawar PB. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol. 1948;29(1):58–69.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Widner H, Brundin P. Immunological aspects of grafting in the mammalian central nervous system. A review and speculative synthesis. Brain Res. 1988;472(3):287–324.CrossRefPubMedGoogle Scholar
  19. 19.
    Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA. Evidence for a ‘paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res. 1985;326(1):47–63.CrossRefPubMedGoogle Scholar
  20. 20.
    Rennels ML, Blaumanis OR, Grady PA. Rapid solute transport throughout the brain via paravascular fluid pathways. Adv Neurol. 1990;52:431–9.PubMedGoogle Scholar
  21. 21.
    Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4(147):147ra11.CrossRefGoogle Scholar
  22. 22.
    Yang L, Kress BT, Weber HJ, Thiyagarajan M, Wang B, Deane R, et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J Transl Med. 2013;11:107.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Andres KH, von During M, Muszynski K, Schmidt RF. Nerve fibres and their terminals of the dura mater encephali of the rat. Anat Embryol. 1987;175(3):289–301.CrossRefPubMedGoogle Scholar
  24. 24.
    Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015;212(7):991–9.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–41.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Nagra G, Koh L, Zakharov A, Armstrong D, Johnston M. Quantification of cerebrospinal fluid transport across the cribriform plate into lymphatics in rats. Am J Physiol Regul Integr Comp Physiol. 2006;291(5):R1383–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Rouhani SJ, Eccles JD, Riccardi P, Peske JD, Tewalt EF, Cohen JN, et al. Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction. Nat Commun. 2015;6:6771.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Cohen JN, Tewalt EF, Rouhani SJ, Buonomo EL, Bruce AN, Xu X, et al. Tolerogenic properties of lymphatic endothelial cells are controlled by the lymph node microenvironment. PLoS One. 2014;9(2):e87740.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Engelhardt B, Carare RO, Bechmann I, Flugel A, Laman JD, Weller RO. Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 2016;132(3):317–38.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wilson EH, Weninger W, Hunter CA. Trafficking of immune cells in the central nervous system. J Clin Investig. 2010;120(5):1368–79.CrossRefPubMedGoogle Scholar
  31. 31.
    Baruch K, Schwartz M. CNS-specific T cells shape brain function via the choroid plexus. Brain Behav Immun. 2013;34:11–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Strominger I, Elyahu Y, Berner O, Reckhow J, Mittal K, Nemirovsky A, et al. The choroid plexus functions as a niche for T-cell stimulation within the central nervous system. Front Immunol. 2018;9:1066.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Meeker RB, Williams K, Killebrew DA, Hudson LC. Cell trafficking through the choroid plexus. Cell Adhes Migr. 2012;6(5):390–6.CrossRefGoogle Scholar
  34. 34.
    Ratnam NM, Gilbert MR, Giles AJ. Immunotherapy in CNS cancers: the role of immune cell trafficking. Neuro Oncol. 2019;21(1):37–46.CrossRefPubMedGoogle Scholar
  35. 35.
    Zhang ET, Inman CB, Weller RO. Interrelationships of the pia mater and the perivascular (Virchow–Robin) spaces in the human cerebrum. J Anat. 1990;170:111–23.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Davies DC. Blood–brain barrier breakdown in septic encephalopathy and brain tumours. J Anat. 2002;200(6):639–46.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Sagar D, Foss C, El Baz R, Pomper MG, Khan ZK, Jain P. Mechanisms of dendritic cell trafficking across the blood–brain barrier. J Neuroimmune Pharmacol. 2012;7(1):74–94.CrossRefPubMedGoogle Scholar
  38. 38.
    Campbell IL, Abraham CR, Masliah E, Kemper P, Inglis JD, Oldstone MB, et al. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci USA. 1993;90(21):10061–5.CrossRefPubMedGoogle Scholar
  39. 39.
    Akwa Y, Hassett DE, Eloranta ML, Sandberg K, Masliah E, Powell H, et al. Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration. J Immunol. 1998;161(9):5016–26.PubMedGoogle Scholar
  40. 40.
    Wyss-Coray T, Borrow P, Brooker MJ, Mucke L. Astroglial overproduction of TGF-beta 1 enhances inflammatory central nervous system disease in transgenic mice. J Neuroimmunol. 1997;77(1):45–50.CrossRefPubMedGoogle Scholar
  41. 41.
    Amankulor NM, Kim Y, Arora S, Kargl J, Szulzewsky F, Hanke M, et al. Mutant IDH1 regulates the tumor-associated immune system in gliomas. Genes Dev. 2017;31(8):774–86.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature. 2014;512(7514):324–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Oelkrug C, Ramage JM. Enhancement of T cell recruitment and infiltration into tumours. Clin Exp Immunol. 2014;178(1):1–8.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Mangani D, Weller M, Roth P. The network of immunosuppressive pathways in glioblastoma. Biochem Pharmacol. 2017;130:1–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Nduom EK, Weller M, Heimberger AB. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 2015;17(Suppl 7):9–14.CrossRefGoogle Scholar
  46. 46.
    Doucette T, Rao G, Rao A, Shen L, Aldape K, Wei J, et al. Immune heterogeneity of glioblastoma subtypes: extrapolation from the cancer genome atlas. Cancer Immunol Res. 2013;1(2):112–22.CrossRefPubMedGoogle Scholar
  47. 47.
    Chen W, Wang D, Du X, He Y, Chen S, Shao Q, et al. Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes. Med Oncol. 2015;32(3):43.CrossRefPubMedGoogle Scholar
  48. 48.
    Oliveira R, Christov C, Guillamo JS, de Bouard S, Palfi S, Venance L, et al. Contribution of gap junctional communication between tumor cells and astroglia to the invasion of the brain parenchyma by human glioblastomas. BMC Cell Biol. 2005;6(1):7.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Venkatesh HS, Johung TB, Caretti V, Noll A, Tang Y, Nagaraja S, et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell. 2015;161(4):803–16.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hide T, Komohara Y, Miyasato Y, Nakamura H, Makino K, Takeya M, et al. Oligodendrocyte progenitor cells and macrophages/microglia produce glioma stem cell niches at the tumor border. EBio Med. 2018;30:94–104.Google Scholar
  51. 51.
    Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL, Rich JN. Cancer stem cells in glioblastoma. Genes Dev. 2015;29(12):1203–17.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Di Tomaso T, Mazzoleni S, Wang E, Sovena G, Clavenna D, Franzin A, et al. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin Cancer Res. 2010;16(3):800–13.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Wei J, Barr J, Kong LY, Wang Y, Wu A, Sharma AK, et al. Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. Mol Cancer Ther. 2010;9(1):67–78.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Wei J, Wu A, Kong LY, Wang Y, Fuller G, Fokt I, et al. Hypoxia potentiates glioma-mediated immunosuppression. PLoS One. 2011;6(1):e16195.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Wu A, Wei J, Kong LY, Wang Y, Priebe W, Qiao W, et al. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol. 2010;12(11):1113–25.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Gieryng A, Pszczolkowska D, Walentynowicz KA, Rajan WD, Kaminska B. Immune microenvironment of gliomas. Lab Investig. 2017;97(5):498–518.CrossRefPubMedGoogle Scholar
  57. 57.
    Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–74.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Investig. 2015;125(9):3356–64.CrossRefPubMedGoogle Scholar
  59. 59.
    Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB. The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol. 2006;8(3):261–79.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011;11(11):762–74.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci. 2011;14(9):1142–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Morantz RA, Wood GW, Foster M, Clark M, Gollahon K. Macrophages in experimental and human brain tumors Part 2: studies of the macrophage content of human brain tumors. J Neurosurg. 1979;50(3):305–11.CrossRefPubMedGoogle Scholar
  63. 63.
    Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Gabrusiewicz K, Rodriguez B, Wei J, Hashimoto Y, Healy LM, Maiti SN, et al. Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight. 2016;1(2):85841.CrossRefPubMedGoogle Scholar
  65. 65.
    Zhang J, Sarkar S, Cua R, Zhou Y, Hader W, Yong VW. A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR65/interleukin-6 axis. Carcinogenesis. 2012;33(2):312–9.CrossRefPubMedGoogle Scholar
  66. 66.
    Paulus W, Baur I, Huettner C, Schmausser B, Roggendorf W, Schlingensiepen KH, et al. Effects of transforming growth factor-beta 1 on collagen synthesis, integrin expression, adhesion and invasion of glioma cells. J Neuropathol Exp Neurol. 1995;54(2):236–44.CrossRefPubMedGoogle Scholar
  67. 67.
    Roesch S, Rapp C, Dettling S, Herold-Mende C. When immune cells turn bad-tumor-associated microglia/macrophages in glioma. Int J Mol Sci. 2018;19(2):E436.CrossRefPubMedGoogle Scholar
  68. 68.
    Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016;19(1):20–7.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Suzumura A, Sawada M, Yamamoto H, Marunouchi T. Transforming growth factor-beta suppresses activation and proliferation of microglia in vitro. J Immunol. 1993;151(4):2150–8.PubMedGoogle Scholar
  70. 70.
    Frei K, Lins H, Schwerdel C, Fontana A. Antigen presentation in the central nervous system. The inhibitory effect of IL-10 on MHC class II expression and production of cytokines depends on the inducing signals and the type of cell analyzed. J Immunol. 1994;152(6):2720–8.PubMedGoogle Scholar
  71. 71.
    Piao Y, Liang J, Holmes L, Zurita AJ, Henry V, Heymach JV, et al. Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype. Neuro Oncol. 2012;14(11):1379–92.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Chen X, Zhang L, Zhang IY, Liang J, Wang H, Ouyang M, et al. RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma. Cancer Res. 2014;74(24):7285–97.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    De Vleeschouwer S, Bergers G. Glioblastoma: to target the tumor cell or the microenvironment? In: De Vleeschouwer S, editor. Glioblastoma. 6th ed. Brisbane: Codon Publications; 2017.CrossRefGoogle Scholar
  74. 74.
    Wiendl H, Mitsdoerffer M, Hofmeister V, Wischhusen J, Bornemann A, Meyermann R, et al. A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J Immunol. 2002;168(9):4772–80.CrossRefPubMedGoogle Scholar
  75. 75.
    Fadul CE, Fisher JL, Gui J, Hampton TH, Cote AL, Ernstoff MS. Immune modulation effects of concomitant temozolomide and radiation therapy on peripheral blood mononuclear cells in patients with glioblastoma multiforme. Neuro Oncol. 2011;13(4):393–400.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Heimberger AB, Abou-Ghazal M, Reina-Ortiz C, Yang DS, Sun W, Qiao W, et al. Incidence and prognostic impact of FoxP3 + regulatory T cells in human gliomas. Clin Cancer Res. 2008;14(16):5166–72.CrossRefPubMedGoogle Scholar
  77. 77.
    Poli A, Wang J, Domingues O, Planaguma J, Yan T, Rygh CB, et al. Targeting glioblastoma with NK cells and mAb against NG2/CSPG4 prolongs animal survival. Oncotarget. 2013;4(9):1527–46.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Kmiecik J, Zimmer J, Chekenya M. Natural killer cells in intracranial neoplasms: presence and therapeutic efficacy against brain tumours. J Neurooncol. 2014;116(1):1–9.CrossRefPubMedGoogle Scholar
  79. 79.
    Morford LA, Elliott LH, Carlson SL, Brooks WH, Roszman TL. T cell receptor-mediated signaling is defective in T cells obtained from patients with primary intracranial tumors. J Immunol. 1997;159(9):4415–25.PubMedGoogle Scholar
  80. 80.
    Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 2006;66(6):3294–302.CrossRefPubMedGoogle Scholar
  81. 81.
    Kmiecik J, Poli A, Brons NH, Waha A, Eide GE, Enger PO, et al. Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. J Neuroimmunol. 2013;264(1–2):71–83.CrossRefPubMedGoogle Scholar
  82. 82.
    Chongsathidkiet P, Jackson C, Koyama S, Loebel F, Cui X, Farber SH, et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med. 2018;24(9):1459–68.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Perng P, Lim M. Immunosuppressive mechanisms of malignant gliomas: parallels at Non-CNS sites. Front Oncol. 2015;5:153.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Wintterle S, Schreiner B, Mitsdoerffer M, Schneider D, Chen L, Meyermann R, et al. Expression of the B7-related molecule B7–H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res. 2003;63(21):7462–7.PubMedGoogle Scholar
  85. 85.
    Razavi SM, Lee KE, Jin BE, Aujla PS, Gholamin S, Li G. Immune evasion strategies of glioblastoma. Front Surg. 2016;3:11.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492–9.CrossRefPubMedGoogle Scholar
  87. 87.
    Grossman SA, Ye X, Lesser G, Sloan A, Carraway H, Desideri S, et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res. 2011;17(16):5473–80.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Gander M, Leyvraz S, Decosterd L, Bonfanti M, Marzolini C, Shen F, et al. Sequential administration of temozolomide and fotemustine: depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours. Ann Oncol. 1999;10(7):831–8.CrossRefPubMedGoogle Scholar
  89. 89.
    Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980;284(5756):555–6.CrossRefPubMedGoogle Scholar
  90. 90.
    Wong ET, Lok E, Gautam S, Swanson KD. Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma. Br J Cancer. 2015;113(2):232–41.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Pitter KL, Tamagno I, Alikhanyan K, Hosni-Ahmed A, Pattwell SS, Donnola S, et al. Corticosteroids compromise survival in glioblastoma. Brain. 2016;139(Pt 5):1458–71.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Xia M, Gasser J, Feige U. Dexamethasone enhances CTLA-4 expression during T cell activation. Cell Mol Life Sci CMLS. 1999;55(12):1649–56.CrossRefPubMedGoogle Scholar
  93. 93.
    Xing K, Gu B, Zhang P, Wu X. Dexamethasone enhances programmed cell death 1 (PD-1) expression during T cell activation: an insight into the optimum application of glucocorticoids in anti-cancer therapy. BMC Immunol. 2015;16:39.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Fecci PE, Ochiai H, Mitchell DA, Grossi PM, Sweeney AE, Archer GE, et al. Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clin Cancer Res. 2007;13(7):2158–67.CrossRefPubMedGoogle Scholar
  95. 95.
    Fong B, Jin R, Wang X, Safaee M, Lisiero DN, Yang I, et al. Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients. PLoS One. 2012;7(4):e32614.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Wainwright DA, Chang AL, Dey M, Balyasnikova IV, Kim C, Tobias AL, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4 and PD-L1 in mice with brain tumors. Clin Cancer Res. 2014;20(20):5290–301.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, et al. Glioblastoma eradication following immune checkpoint blockade in an orthotopic immunocompetent model. Cancer Immunol Res. 2016;4(2):124–35.CrossRefPubMedGoogle Scholar
  98. 98.
    Dai B, Qi N, Li J, Zhang G. Temozolomide combined with PD-1 antibody therapy for mouse orthotopic glioma model. Biochem Biophys Res Commun. 2018;501(4):871–6.CrossRefPubMedGoogle Scholar
  99. 99.
    Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick 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;86(2):343–9.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Kim JE, Patel MA, Mangraviti A, Kim ES, Theodros D, Velarde E, et al. Combination therapy with anti-PD-1, Anti-TIM-3, and focal radiation results in regression of murine gliomas. Clin Cancer Res. 2017;23(1):124–36.CrossRefPubMedGoogle Scholar
  101. 101.
    Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543–53.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Xue S, Hu M, Iyer V, Yu J. Blocking the PD-1/PD-L1 pathway in glioma: a potential new treatment strategy. J Hematol Oncol. 2017;10(1):81.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Chamberlain MC, Kim BT. Nivolumab for patients with recurrent glioblastoma progressing on bevacizumab: a retrospective case series. J Neurooncol. 2017;133(3):561–9.CrossRefPubMedGoogle Scholar
  105. 105.
    Blumenthal DT, Yalon M, Vainer GW, Lossos A, Yust S, Tzach L, et al. Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors. J Neurooncol. 2016;129(3):453–60.CrossRefPubMedGoogle Scholar
  106. 106.
    Sampson JH, Vlahovic G, Sahebjam S, Omuro AMP, Baehring JM, Hafler DA, et al. Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143. J Clin Oncol. 2015;33(15_Suppl):3010.CrossRefGoogle Scholar
  107. 107.
    Reardon DA, Sampson JH, Sahebjam S, Lim M, Baehring JM, Vlahovic G, et al. Safety and activity of nivolumab (nivo) monotherapy and nivo in combination with ipilimumab (ipi) in recurrent glioblastoma (GBM): updated results from checkmate-143. J Clin Oncol. 2016;34(15_Suppl):2014.CrossRefGoogle Scholar
  108. 108.
    Reardon DA, Omuro A, Brandes AA, Rieger J, Wick A, Sepulveda J, et al. OS10.3 randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143. Neuro Oncol. 2017;19(Suppl_3):21.CrossRefGoogle Scholar
  109. 109.
    Reardon DA, Kim T-M, Frenel J-S, Santoro A, Lopez J, Subramaniam DS, et al. ATIM-35 results of the phase Ib keynote-028 multi-cohort trial of pembrolizumab monotherapy in patients with recurrent PD-l1-positive glioblastoma MULTIFORME (GBM). Neuro Oncol. 2016;18(Suppl_6):25–6.CrossRefGoogle Scholar
  110. 110.
    Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 2019;25(3):477–86.CrossRefPubMedGoogle Scholar
  111. 111.
    Reardon DA, Kaley TJ, Dietrich J, Clarke JL, Dunn GP, Lim M, et al. Phase 2 study to evaluate safety and efficacy of MEDI4736 (durvalumab [DUR]) in glioblastoma (GBM) patients: an update. J Clin Oncol. 2017;35(15_Suppl):2042.CrossRefGoogle Scholar
  112. 112.
    Lim M, Omuro A, Vlahovic G, Reardon DA, Sahebjam S, Cloughesy T, et al. 325ONivolumab (nivo) in combination with radiotherapy (RT) ± temozolomide (TMZ): updated safety results from CheckMate 143 in pts with methylated or unmethylated newly diagnosed glioblastoma (GBM). Ann Oncol. 2017;28(Suppl_5):366.Google Scholar
  113. 113.
    Sahebjam S, Johnstone PA, Forsyth P, Arrington J, Jaglal M, Tran ND, et al. ATIM-15. A phase I trial of hypofractionated stereotactic irradiation (HFSRT) with pembrolizumab and bevacizumab in patients with recurrent high grade gliomas. Neuro Oncol. 2016;18(Suppl_6):21.CrossRefGoogle Scholar
  114. 114.
    Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev. 2017;276(1):97–111.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, et al. Th1-specific cell surface protein TIM-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415(6871):536–41.CrossRefPubMedGoogle Scholar
  116. 116.
    Kanzaki M, Wada J, Sugiyama K, Nakatsuka A, Teshigawara S, Murakami K, et al. Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes. Endocrinology. 2012;153(2):612–20.CrossRefPubMedGoogle Scholar
  117. 117.
    Prendergast GC, Malachowski WP, DuHadaway JB, Muller AJ. Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res. 2017;77(24):6795–811.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Zhai L, Ladomersky E, Lauing KL, Wu M, Genet M, Gritsina G, et al. Infiltrating T cells increase IDO1 expression in glioblastoma and contribute to decreased patient survival. Clin Cancer Res. 2017;23(21):6650–60.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Long GV, Dummer R, Hamid O, Gajewski T, Caglevic C, Dalle S, et al. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study. J Clin Oncol. 2018;36(15_Suppl):108.CrossRefGoogle Scholar
  120. 120.
    Soliman HH, Minton SE, Ismail-Khan R, Han HS, Vahanian NN, Ramsey WJ, et al. A phase 2 study of docetaxel in combination with indoximod in metastatic breast cancer. J Clin Oncol. 2014;32(15_Suppl):TPS3124.CrossRefGoogle Scholar
  121. 121.
    Zakharia Y, Johnson TS, Colman H, Vahanian NN, Link CJ, Kennedy E, et al. A phase I/II study of the combination of indoximod and temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors. J Clin Oncol. 2014;32(15_Suppl):TPS2107.CrossRefGoogle Scholar
  122. 122.
    Marshall HT, Djamgoz MBA. Immuno-oncology: emerging targets and combination therapies. Front Oncol. 2018;8:315.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202–6.CrossRefPubMedGoogle Scholar
  124. 124.
    Reardon DA, Nayak L, Peters KB, Clarke JL, Jordan JT, Groot JFD, et al. Phase II study of pembrolizumab or pembrolizumab plus bevacizumab for recurrent glioblastoma (rGBM) patients. J Clin Oncol. 2018;36(15_Suppl):2006.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Internal MedicineCleveland ClinicClevelandUSA
  2. 2.Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological InstituteCleveland ClinicClevelandUSA

Personalised recommendations