Review Article | Published:

Vaccine-based immunotherapeutic approaches to gliomas and beyond

Nature Reviews Neurology volume 13, pages 363374 (2017) | Download Citation

Abstract

Astrocytic and oligodendroglial gliomas are intrinsic brain tumours characterized by infiltrative growth and resistance to classic cancer therapies, which renders them inevitably lethal. Glioblastoma, the most common type of glioma, also exhibits neoangiogenesis and profound immunosuppressive properties. Accordingly, strategies to revert glioma-associated immunosuppression and promote tumour-directed immune responses have been extensively explored in rodent models and in large clinical trials of tumour immunotherapy. This Review describes vaccination approaches investigated for the treatment of glioma. Several strategies have reached phase III clinical trials, including vaccines targeting epidermal growth factor receptor variant III, and the use of either immunogenic peptides or tumour lysates to stimulate autologous dendritic cells. Other approaches in early phases of clinical development employ multipeptide vaccines such as IMA-950, cytomegalovirus-derived peptides, or tumour-derived peptides such as heat shock protein-96 peptide complexes and the Arg132His mutant form of isocitrate dehydrogenase. However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression.

Key points

  • Glioblastoma is the paradigm of tumour-associated immunosuppression

  • Several glioma-specific peptide vaccines, with or without dendritic cell support, are in late clinical development

  • Vaccines can be combined with agents that nonspecifically boost immune responses, such as immune checkpoint inhibitors or TGFβ pathway inhibitors

  • Standardization of clinical trial conduct might facilitate progress in this challenging field of oncology

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References

  1. 1.

    , & Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 17 (Suppl. 7), vii9–vii14 (2015).

  2. 2.

    , & The network of immunosuppressive pathways in glioblastoma. Biochem. Pharmacol. 130, 1–9 (2017).

  3. 3.

    , & Modulation of T-cell function by gliomas. Immunol. Today 12, 370–374 (1991).

  4. 4.

    , , , & Extraneural metastases of primary brain tumors. J. Neurooncol. 53, 107–114 (2001).

  5. 5.

    et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 17 (Suppl. 4), iv1–iv62 (2015).

  6. 6.

    et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425–437 (2012).

  7. 7.

    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. 120, 707–718 (2010).

  8. 8.

    et al. Age-specific signatures of glioblastoma at the genomic, genetic, and epigenetic levels. PLoS ONE 8, e62982 (2013).

  9. 9.

    et al. Immunocompetent murine models for the study of glioblastoma immunotherapy. J. Transl. Med. 12, 107 (2014).

  10. 10.

    , , & Current review of in vivo GBM rodent models: emphasis on the CNS-1 tumour model. ASN Neuro 3, e00063 (2011).

  11. 11.

    , & Tumorigenic cell culture lines from a spontaneous VM/Dk murine astrocytoma (SMA). Acta Neuropathol. 51, 53–64 (1980).

  12. 12.

    et al. Characterization of a spontaneous murine astrocytoma and abrogation of its tumorigenicity by cytokine secretion. Neurosurgery 41, 1365–1372 (1997).

  13. 13.

    et al. How stemlike are sphere cultures from long-term cancer cell lines? Lessons from mouse glioma models. J. Neuropathol. Exp. Neurol. 73, 1062–1077 (2014).

  14. 14.

    et al. Development of a flexible and specific gene delivery system for production of murine tumor models. Oncogene 18, 5253–5260 (1999).

  15. 15.

    et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8, 119–130 (2005).

  16. 16.

    et al. MICA/NKG2D-mediated immunogene therapy of experimental gliomas. Cancer Res. 63, 8996–9006 (2003).

  17. 17.

    , , & New prospects on the NKG2D/NKG2DL system for oncology. Oncoimmunology 2, e26097 (2013).

  18. 18.

    et al. MIP-1α antagonizes the effect of a GM-CSF-enhanced subcutaneous vaccine in a mouse glioma model. J. Neurooncol. 66, 147–154 (2004).

  19. 19.

    et al. Vaccination for experimental gliomas using GM-CSF-transduced glioma cells. Cancer Gene Ther. 4, 345–352 (1997).

  20. 20.

    et al. Superior efficacy of tumor cell vaccines grown in physiologic oxygen. Clin. Cancer Res. 16, 4800–4808 (2010).

  21. 21.

    et al. Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma. J. Neuroimmunol. 103, 16–25 (2000).

  22. 22.

    et al. Elimination of regulatory T cells is essential for an effective vaccination with tumor lysate-pulsed dendritic cells in a murine glioma model. Int. J. Cancer 122, 1794–1802 (2008).

  23. 23.

    et al. Dendritic cells are essential for priming but inefficient for boosting antitumour immune response in an orthotopic murine glioma model. Cancer Immunol. Immunother. 55, 254–267 (2006).

  24. 24.

    et al. Marked enhancement of antitumor immune responses in mouse brain tumor models by genetically modified dendritic cells producing Semliki Forest virus-mediated interleukin-12. J. Neurosurg. 97, 611–618 (2002).

  25. 25.

    , & Immunotherapeutic targeting of shared melanoma-associated antigens in a murine glioma model. Cancer Res. 63, 8487–8491 (2003).

  26. 26.

    et al. Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Res. 66, 10247–10252 (2006).

  27. 27.

    et al. Systemic inhibition of transforming growth factor-β in glioma-bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Clin. Cancer Res. 15, 6551–6559 (2009).

  28. 28.

    et al. PD-1 blockade enhances the vaccination-induced immune response in glioma. JCI Insight 1, e87059 (2016).

  29. 29.

    , , , & Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors. J. Immunother. 35, 385–389 (2012).

  30. 30.

    Huszthy P. C. et al. In vivo models of primary brain tumors: pitfalls and perspectives. Neuro Oncol. 14, 979–993 (2012).

  31. 31.

    et al. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin. Cancer Res. 9, 4247–4254 (2003).

  32. 32.

    et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324–327 (2014).

  33. 33.

    et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol. Immunother. 62, 125–135 (2013).

  34. 34.

    US National Library of Medicine. ClinicalTrials.gov (2016).

  35. 35.

    et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol. 16, 274–279 (2014).

  36. 36.

    , & Whole tumor antigen vaccines: where are we? Vaccines (Basel) 3, 344–372 (2015).

  37. 37.

    , , , & Immunological challenges for peptide-based immunotherapy in glioblastoma. Cancer Treat. Rev. 40, 248–258 (2014).

  38. 38.

    et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).

  39. 39.

    et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J. Clin. Oncol. 27, 5743–5750 (2009).

  40. 40.

    et al. Assessment and prognostic significance of the epidermal growth factor receptor vIII mutation in glioblastoma patients treated with concurrent and adjuvant temozolomide radiochemotherapy. Int. J. Cancer 134, 2437–2447 (2014).

  41. 41.

    et al. Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ. 6, 1251–1259 (1995).

  42. 42.

    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. 28, 4722–4729 (2010).

  43. 43.

    et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 13, 324–333 (2011).

  44. 44.

    et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. 17, 854–861 (2015).

  45. 45.

    et al. ACT IV: an international, double-blind, phase 3 trial of rindopepimut in newly diagnosed, EGFRvIII-expressing glioblastoma. Neuro Oncol. 18, (Suppl. 6), vi17–vi18 (2016).

  46. 46.

    et al. ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma [abstract]. J. Clin. Oncol. 33 (Suppl.), 2009 (2015).

  47. 47.

    et al. MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma. Proc. Natl Acad. Sci. USA 111, 12550–12555 (2014).

  48. 48.

    , , , & Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy. Exp. Opin. Biol. Ther. 7, 449–460 (2007).

  49. 49.

    et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015).

  50. 50.

    et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–722 (2014).

  51. 51.

    et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014).

  52. 52.

    et al. EORTC 26101 phase III trial exploring the combination of bevacizumab and lomustine in patients with first progression of a glioblastoma [abstract]. J. Clin. Oncol. 34 (Suppl.), 2001 (2016).

  53. 53.

    et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci. Transl. Med. 7, 275ra22 (2015).

  54. 54.

    et al. Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas. J. Clin. Oncol. 32, 2050–2058 (2014).

  55. 55.

    et al. Induction of robust type-I CD8+ T-cell responses in WHO grade 2 low-grade glioma patients receiving peptide-based vaccines in combination with poly-ICLC. Clin. Cancer Res. 21, 286–294 (2015).

  56. 56.

    et al. Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain 135, 1042–1054 (2012).

  57. 57.

    et al. A Cancer Research UK first time in human phase I trial of IMA950 (novel multipeptide therapeutic vaccine) in patients with newly diagnosed glioblastoma. Clin. Cancer Res. 22, 4776–4785 (2016).

  58. 58.

    et al. The regulatory landscape for actively personalized cancer immunotherapies. Nat. Biotechnol. 31, 880–882 (2013).

  59. 59.

    US National Library of Medicine. ClinicalTrials.gov (2016).

  60. 60.

    et al. Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours. Pediatr. Blood Cancer 54, 519–525 (2010).

  61. 61.

    et al. Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial. Cancer Immunol. Immunother. 61, 2033–2044 (2012).

  62. 62.

    et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin. Cancer Res. 11, 5515–5525 (2005).

  63. 63.

    et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin. Cancer Res. 17, 1603–1615 (2011).

  64. 64.

    US National Library of Medicine. ClinicalTrials.gov (2016).

  65. 65.

    et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with α-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J. Clin. Oncol. 29, 330–336 (2011).

  66. 66.

    et al. A randomized double blind placebo-controlled phase 2 trial of dendritic cell (DC) vaccine ICT-107 following standard treatment in newly diagnosed patients with GBM. Neuro Oncol. 16 (Suppl. 5), v22 (2014).

  67. 67.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  68. 68.

    et al. Effective immuno-targeting of the IDH1 mutation R132H in a murine model of intracranial glioma. Acta Neuropathol. Commun. 3, 4 (2015).

  69. 69.

    et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

  70. 70.

    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. 118, 469–474 (2009).

  71. 71.

    , & Isocitrate dehydrogenase mutations in gliomas. Neuro Oncol. 18, 16–26 (2016).

  72. 72.

    & Cancer immunotherapy: exploiting neoepitopes. Cell Res. 25, 887–888 (2015).

  73. 73.

    et al. Proximity ligation assay evaluates IDH1 R132H presentation in gliomas. J. Clin. Invest. 125, 593–606 (2015).

  74. 74.

    Mutation-specific T cells for immunotherapy of gliomas. N. Engl. J. Med. 372, 1956–1958 (2015).

  75. 75.

    , , & Mutant IDH1: an immunotherapeutic target in tumors. Oncoimmunology 3, e974392 (2014).

  76. 76.

    US National Library of Medicine. ClinicalTrials.gov (2016).

  77. 77.

    et al. Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro Oncol. 15, 57–68 (2013).

  78. 78.

    & A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 269, 1585–1588 (1995).

  79. 79.

    , , , & Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science 278, 117–120 (1997).

  80. 80.

    et al. Heat shock protein vaccines against glioblastoma: from bench to bedside. J. Neurooncol. 123, 441–448 (2015).

  81. 81.

    et al. Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 kD chaperone protein. Clin. Cancer Res. 19, 205–214 (2013).

  82. 82.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  83. 83.

    et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol. 10, 10–18 (2008).

  84. 84.

    et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 62, 3347–3350 (2002).

  85. 85.

    , & Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N. Engl. J. Med. 359, 539–541 (2008).

  86. 86.

    et al. Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics. Neuro Oncol. 16, 1469–1477 (2014).

  87. 87.

    , & Absence of cytomegalovirus in high-coverage DNA sequencing of human glioblastoma multiforme. Int. J. Cancer 136, 977–981 (2015).

  88. 88.

    et al. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 14, 246–255 (2012).

  89. 89.

    , , , & Significant association of multiple human cytomegalovirus genomic loci with glioblastoma multiforme samples. J. Virol. 86, 854–864 (2012).

  90. 90.

    et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 300, 413–422 (2008).

  91. 91.

    et al. Ex vivo generation of human cytomegalovirus-specific cytotoxic T cells by peptide-pulsed dendritic cells. Br. J. Haematol. 113, 231–239 (2001).

  92. 92.

    , , & Generation of cytotoxic T lymphocytes specific for human cytomegalovirus using dendritic cells in vitro. J. Immunother. 24, 242–249 (2001).

  93. 93.

    , , , & Dendritic cells cross-presenting viral antigens derived from autologous cells as a sensitive tool for visualization of human cytomegalovirus-reactive CD8+ T cells. Transplantation 73, 998–1002 (2002).

  94. 94.

    & Clinical trials with CMV-specific T cells. Cytotherapy 4, 21–28 (2002).

  95. 95.

    et al. Isolation and expansion of cytomegalovirus-specific cytotoxic T lymphocytes to clinical scale from a single blood draw using dendritic cells and HLA-tetramers. Blood 98, 505–512 (2001).

  96. 96.

    et al. Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells. Clin. Cancer Res. 20, 2684–2694 (2014).

  97. 97.

    et al. CMV-independent lysis of glioblastoma by ex vivo expanded/activated Vδ1+ γδ T cells. PLoS ONE 8, e68729 (2013).

  98. 98.

    et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519, 366–369 (2015).

  99. 99.

    et al. GDF-15 contributes to proliferation and immune escape of malignant gliomas. Clin. Cancer Res. 16, 3851–3859 (2010).

  100. 100.

    et al. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol. 12, 1113–1125 (2010).

  101. 101.

    et al. Human glioma-derived interleukin-10 inhibits antitumor immune responses in vitro. Neurosurgery 37, 1160–1166 (1995).

  102. 102.

    et al. HLA-E contributes to an immune-inhibitory phenotype of glioblastoma stem-like cells. J. Neuroimmunol. 250, 27–34 (2012).

  103. 103.

    et al. Costimulatory protein 4IgB7H3 drives the malignant phenotype of glioblastoma by mediating immune escape and invasiveness. Clin. Cancer Res. 18, 105–117 (2012).

  104. 104.

    et al. MicroRNA-mediated down-regulation of NKG2D ligands contributes to glioma immune escape. Oncotarget 5, 7651–7662 (2014).

  105. 105.

    , , , & Prostaglandin E2 as an immunomodulating factor released in vitro by human glioma cells. Acta Neuropathol. 69, 278–282 (1986).

  106. 106.

    , , , & Fas ligand expression and depletion of T-cell infiltration in astrocytic tumors. Brain Tumor Pathol. 18, 37–42 (2001).

  107. 107.

    et al. Malignant glioma cells counteract antitumor immune responses through expression of lectin-like transcript-1. Cancer Res. 67, 3540–3544 (2007).

  108. 108.

    , , , & Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat. Rev. Neurol. 11, 504–514 (2015).

  109. 109.

    et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

  110. 110.

    et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

  111. 111.

    et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 16, 257–265 (2015).

  112. 112.

    et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol. 17, 1064–1075 (2015).

  113. 113.

    et al. PD-L1 expression and prognostic impact in glioblastoma. Neuro Oncol. 18, 195–205 (2016).

  114. 114.

    et al. Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res. 63, 7462–7467 (2003).

  115. 115.

    et al. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol. Res. 4, 124–135 (2016).

  116. 116.

    et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J. Clin. Oncol. 34, 2206–2211 (2016).

  117. 117.

    , & Immunotherapy for glioblastoma: concepts and challenges. Curr. Opin. Neurol. 28, 639–646 (2015).

  118. 118.

    et al. OX40 ligand expressed in glioblastoma modulates adaptive immunity depending on the microenvironment: a clue for successful immunotherapy. Mol. Cancer 14, 41 (2015).

  119. 119.

    , , , & Immune stimulatory effects of CD70 override CD70-mediated immune cell apoptosis in rodent glioma models and confer long-lasting antiglioma immunity in vivo. Int. J. Cancer 118, 1728–1735 (2006).

  120. 120.

    et al. A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro Oncol. 18, 1146–1156 (2016).

  121. 121.

    , & Shaping the glioma immune microenvironment through tryptophan metabolism. CNS Oncol. 1, 99–106 (2012).

  122. 122.

    et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).

  123. 123.

    et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin. Cancer Res. 20, 5290–5301 (2014).

  124. 124.

    , & The role of STAT3 in tumor-mediated immune suppression. J. Neurooncol. 123, 385–394 (2015).

  125. 125.

    US National Library of Medicine. ClinicalTrials.gov (2016).

  126. 126.

    et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 66, 3294–3302 (2006).

  127. 127.

    & An increase in CD4+CD25+FOXP3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme. J. Neurooncol. 8, 234–243 (2006).

  128. 128.

    et al. CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo. Int. J. Cancer. 121, 95–105 (2007).

  129. 129.

    et al. Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol. 13, 591–599 (2011).

  130. 130.

    , & Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors. J. Neurosurg. 105, 430–437 (2006).

  131. 131.

    et al. Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood 112, 610–618 (2008).

  132. 132.

    et al. Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clin. Cancer Res. 16, 5067–5078 (2010).

  133. 133.

    et al. Selective elimination of human regulatory T lymphocytes in vitro with the recombinant immunotoxin LMB-2. J. Immunother. 29, 208–214 (2006).

  134. 134.

    et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 16, e534–e542 (2015).

  135. 135.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  136. 136.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  137. 137.

    US National Library of Medicine. ClinicalTrials.gov (2014).

  138. 138.

    US National Library of Medicine. ClinicalTrials.gov (2014).

  139. 139.

    US National Library of Medicine. ClinicalTrials.gov (2016).

  140. 140.

    US National Library of Medicine. ClinicalTrials.gov (2015).

  141. 141.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  142. 142.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  143. 143.

    US National Library of Medicine. ClinicalTrials.gov (2017).

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Acknowledgements

The authors' research work is supported by grants from the Canton of Zurich HSM-2 (Hochspezialisierte Medizin 2) programme, the German Research Fund (Deutsche Forschungsgemeinschaft), the Swiss National Science Foundation and the Swiss Cancer League (all to M.W. and P.R.).

Author information

Affiliations

  1. Department of Neurology and Brain Tumour Centre, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland.

    • Michael Weller
    •  & Patrick Roth
  2. Department of Medicine I and Comprehensive Cancer Centre CNS Unit, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria.

    • Matthias Preusser
  3. Neurology Clinic, Heidelberg University Medical Centre and Neuro-oncology Programme, National Centre for Tumour Diseases Heidelberg, Im Neuenheimer Feld (INF) 400, 69120 Heidelberg, Germany.

    • Wolfgang Wick
    •  & Michael Platten
  4. Dana-Farber Cancer Institute, 450 Brookline Avenue, D-2134, Boston 02215–5450, Massachusetts, USA.

    • David A. Reardon
  5. Neurology Clinic, Mannheim Medical Centre, Heidelberg University and Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumour Immunology, German Cancer Research Centre, Im Neuenheimer Feld (INF) 280, 69120 Heidelberg, Germany.

    • Michael Platten
  6. Department of Neurosurgery, Duke University Medical Center, 200 Trent Drive, Duke South, Blue Zone, 1st Floor, Room 1554, Durham 27710, North Carolina, USA.

    • John H. Sampson

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Contributions

All authors wrote the manuscript, researched data for the article, undertook review or editing of the manuscript before submission and contributed substantially to discussions of the article content.

Competing interests

The authors declare that M.W. has received research grants from Acceleron, Actelion, Bayer, Isarna, Merck Sharp & Dohme, Merck EMD (Emanuel Merck, Darmstadt), Novocure, Piqur and Roche and honoraria for lectures, advisory board participation or consulting from Bristol-Myers Squibb, Celldex, Immunocellular Therapeutics, Isarna, Magforce, Merck Sharp & Dohme, Merck EMD, Northwest Biotherapeutics, Novocure, Pfizer, Roche, Teva and Tocagen. M. Preusser has received research support from Böhringer-Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme and Roche, as well as honoraria for lectures, advisory board participation or consulting from Bristol-Myers Squibb, CMC Contrast, Gerson Lehrman Group, GlaxoSmithKline, Mundipharma, Novartis and Roche. D.A.R. has received research grants from Celldex Therapeutics, Incyte and Midatech, as well as honoraria for lectures, advisory board participation or consulting from Abbvie, Amgen, Bristol-Myers Squibb, Cavion, Celldex Therapeutics, EMD Serono, Genentech (Roche), Inovio, Juno Pharmaceuticals, Merck & Co, Midatech, Momenta Pharmaceuticals, Novartis, Novocure, Oxigene, Regeneron, and Stemline Therapeutics. M. Platten has received research support from Merck and Novartis, as well as honoraria for lectures, consultation or advisory board participation from Alexion, Bayer, Genentech (Roche), Merck & Co, Medac, Miltenyi Biotec, Novartis and Teva. M. Platten also holds patents on isocitrate dehydrogenase vaccines and aryl hydrocarbon receptor inhibition. P.R. has received research support from Merck Sharp & Dohme and honoraria for lectures or advisory board participation from Merck Sharp & Dohme, Molecular Partners, Novartis and Roche. W.W. has received research funding from Apogenix, Böhringer-Ingelheim, Genentech (Roche), Merck Sharp & Dohme and Pfizer, as well as honoraria for participating in a speaker's bureau for Merck Sharp & Dohme and consulting for Genentech (Roche). J.H.S. declares that he is an employee of Annias, a shareholder in Annias and Istari, and has received honoraria for consulting from Celldex, BrainLAB and Medicenna, as well as licensing fees from Celldex.

Corresponding author

Correspondence to Michael Weller.

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https://doi.org/10.1038/nrneurol.2017.64

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