1932

Abstract

Faced with unique immunobiology and marked heterogeneity, treatment strategies for glioblastoma require therapeutic approaches that diverge from conventional oncological strategies. The selection and prioritization of targeted and immunotherapeutic strategies will need to carefully consider these features and companion biomarkers developed alongside treatment strategies to identify the appropriate patient populations. Novel clinical trial strategies that interrogate the tumor microenvironment for drug penetration and target engagement will inform go/no-go later-stage clinical studies. Innovative trial designs and analyses are needed to move effective agents toward regulatory approvals more rapidly.

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2022-01-27
2024-04-26
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Literature Cited

  1. 1. 
    Louis DN, Perry A, Wesseling P et al. 2021. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro-Oncol 23:81231–51
    [Google Scholar]
  2. 2. 
    Ostrom QT, Patil N, Cioffi G et al. 2020. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013–2017. Neuro-Oncol 3022:12 Suppl. 2iv1–iv96
    [Google Scholar]
  3. 3. 
    Stupp R, Mason WP, van den Bent MJ et al. 2005. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 10352:10987–96
    [Google Scholar]
  4. 4. 
    Louis DN, Wesseling P, Aldape K et al. 2020. cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading. Brain Pathol 30:4844–56
    [Google Scholar]
  5. 5. 
    Weller M, van den Bent M, Preusser M et al. 2021. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat. Rev. Clin. Oncol. 18:17086
    [Google Scholar]
  6. 6. 
    Stupp R, Wong ET, Kanner AA et al. 2012. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur. J. Cancer 48:142192–202
    [Google Scholar]
  7. 7. 
    Stupp R, Taillibert S, Kanner A et al. 2017. Effect of tumor-treating fields plus maintenance temozolomide versus maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318:232306–16
    [Google Scholar]
  8. 8. 
    Qazi MA, Vora P, Venugopal C et al. 2017. Intratumoral heterogeneity: pathways to treatment resistance and relapse in human glioblastoma. Ann. Oncol. 28:71448–56
    [Google Scholar]
  9. 9. 
    Sanai N, Berger MS. 2018. Surgical oncology for gliomas: the state of the art. Nat. Rev. Clin. Oncol. 15:2112–25
    [Google Scholar]
  10. 10. 
    Terstappen GC, Meyer AH, Bell RD, Zhang W. 2021. Strategies for delivering therapeutics across the blood-brain barrier. Nat. Rev. Drug Discov. 20:5362–83
    [Google Scholar]
  11. 11. 
    Bao S, Wu Q, McLendon RE et al. 2006. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:7120756–60
    [Google Scholar]
  12. 12. 
    Chen J, Li Y, Yu TS et al. 2012. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:7412522–26
    [Google Scholar]
  13. 13. 
    Khaddour K, Johanns TM, Ansstas G. 2020. The landscape of novel therapeutics and challenges in glioblastoma multiforme: contemporary state and future directions. Pharmaceuticals 13:11389
    [Google Scholar]
  14. 14. 
    Lim M, Xia Y, Bettegowda C, Weller M. 2018. Current state of immunotherapy for glioblastoma. Nat. Rev. Clin. Oncol. 15:7422–42
    [Google Scholar]
  15. 15. 
    Wick W, Gorlia T, Bendszus M et al. 2017. Lomustine and bevacizumab in progressive glioblastoma. N. Engl. J. Med. 377:201954–63
    [Google Scholar]
  16. 16. 
    Lacroix M, Abi-Said D, Fourney DR et al. 2001. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J. Neurosurg. 95:2190–98
    [Google Scholar]
  17. 17. 
    Beiko J, Suki D, Hess KR et al. 2014. IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection. Neuro-Oncol 16:181–91
    [Google Scholar]
  18. 18. 
    Li YM, Suki D, Hess K, Sawaya R 2016. The influence of maximum safe resection of glioblastoma on survival in 1229 patients: Can we do better than gross-total resection?. J. Neurosurg. 124:4977–88
    [Google Scholar]
  19. 19. 
    Pessina F, Navarria P, Cozzi L et al. 2017. Maximize surgical resection beyond contrast-enhancing boundaries in newly diagnosed glioblastoma multiforme: Is it useful and safe? A single institution retrospective experience. J. Neurooncol. 135:1129–39
    [Google Scholar]
  20. 20. 
    Eyüpoglu IY, Hore N, Merkel A et al. 2016. Supra-complete surgery via dual intraoperative visualization approach (DiVA) prolongs patient survival in glioblastoma. Oncotarget 7:1825755–68
    [Google Scholar]
  21. 21. 
    Sanai N, Polley M-Y, McDermott MW et al. 2011. An extent of resection threshold for newly diagnosed glioblastomas. J. Neurosurg. 115:13–8
    [Google Scholar]
  22. 22. 
    Brown TJ, Brennan MC, Li M et al. 2016. Association of the extent of resection with survival in glioblastoma: a systematic review and meta-analysis. JAMA Oncol 2:111460–69
    [Google Scholar]
  23. 23. 
    Grabowski MM, Recinos PF, Nowacki AS et al. 2014. Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma. J. Neurosurg. 121:51115–23
    [Google Scholar]
  24. 24. 
    De Leeuw BI, Van Baarsen KM, Snijders TJ, Robe P. 2019. Interrelationships between molecular subtype, anatomical location, and extent of resection in diffuse glioma: a systematic review and meta-analysis. Neuro-oncol. Adv. 1:1vdz032
    [Google Scholar]
  25. 25. 
    Hegi ME, Diserens A-C, Gorlia T et al. 2005. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352:10997–1003
    [Google Scholar]
  26. 26. 
    Stupp R, Hegi ME, Mason WP et al. 2009. 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 10:5459–66
    [Google Scholar]
  27. 27. 
    Alexander BM, Ba S, Berger MS et al. 2018. Adaptive global innovative learning environment for glioblastoma: GBM AGILE. Clin. Cancer Res. 24:4737–43
    [Google Scholar]
  28. 28. 
    Touat M, Li YY, Boynton AN et al. 2020. Mechanisms and therapeutic implications of hypermutation in gliomas. Nature 580:7804517–23
    [Google Scholar]
  29. 29. 
    Herrlinger U, Tzaridis T, Mack F et al. 2019. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial. Lancet 393:10172678–88
    [Google Scholar]
  30. 30. 
    Donawho CK, Luo Y, Luo Y et al. 2007. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin. Cancer Res. 13:92728–37
    [Google Scholar]
  31. 31. 
    Gupta SK, Kizilbash SH, Carlson BL et al. 2016. Delineation of MGMT hypermethylation as a biomarker for veliparib-mediated temozolomide-sensitizing therapy of glioblastoma. J. Natl. Cancer Inst. 108:5djv369
    [Google Scholar]
  32. 32. 
    Barazzuol L, Jena R, Burnet NG et al. 2013. Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma. Radiat. Oncol. 8:65
    [Google Scholar]
  33. 33. 
    Clarke MJ, Mulligan EA, Grogan PT et al. 2009. Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines. Mol. Cancer Ther. 8:2407–14
    [Google Scholar]
  34. 34. 
    McDonald K, Nozue-Okada K, Khasraw M. 2014. Combining VELIPARIB (ABT-888) with temozolomide shows strong synergy when treating temozolomide-resistant and recurrent GBM cell lines. Cancer Res 74:19 Suppl3777 Abstr.)
    [Google Scholar]
  35. 35. 
    Jue TR, Nozue K, Lester AJ et al. 2017. Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma. J. Transl. Med. 15:61
    [Google Scholar]
  36. 36. 
    McEllin B, Camacho CV, Mukherjee B et al. 2010. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res 70:135457–64
    [Google Scholar]
  37. 37. 
    Lin F, de Gooijer MC, Roig EM et al. 2014. ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. Clin. Cancer Res. 20:102703–13
    [Google Scholar]
  38. 38. 
    Gupta SK, Smith EJ, Mladek AC et al. 2018. PARP inhibitors for sensitization of alkylation chemotherapy in glioblastoma: impact of blood-brain barrier and molecular heterogeneity. Front. Oncol. 8:670
    [Google Scholar]
  39. 39. 
    Kleinberg L, Supko JG, Mikkelsen T et al. 2013. Phase I adult brain tumor consortium (ABTC) trial of ABT-888 (veliparib), temozolomide (TMZ), and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM) including pharmacokinetic (PK) data. J. Clin. Oncol. 31:15 Suppl2065
    [Google Scholar]
  40. 40. 
    Sim HW, McDonald KL, Lwin Z et al. 2021. A randomized phase II trial of veliparib, radiotherapy and temozolomide in patients with unmethylated MGMT glioblastoma: the VERTU study. Neuro-Oncol 23:10173649
    [Google Scholar]
  41. 41. 
    Brennan CW, Verhaak RG, McKenna A et al. 2013. The somatic genomic landscape of glioblastoma. Cell 155:2462–77
    [Google Scholar]
  42. 42. 
    Wang Q, Hu B, Hu X et al. 2017. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell 32:142–56.e6
    [Google Scholar]
  43. 43. 
    Barthel FP, Johnson KC, Varn FS et al. 2019. Longitudinal molecular trajectories of diffuse glioma in adults. Nature 576:7785112–20
    [Google Scholar]
  44. 44. 
    Yung WK, Vredenburgh JJ, Cloughesy TF et al. 2010. Safety and efficacy of erlotinib in first-relapse glioblastoma: a phase II open-label study. Neuro-Oncol 12:101061–70
    [Google Scholar]
  45. 45. 
    Prados MD, Chang SM, Butowski N et al. 2009. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J. Clin. Oncol. 27:4579–84
    [Google Scholar]
  46. 46. 
    Lassman A, Pugh S, Wang T et al. 2019. ACTR-21. A randomized, double-blind, placebo-controlled phase 3 trial of depatuxizumab mafodotin (ABT-414) in epidermal growth factor receptor (EGFR) amplified (AMP) newly diagnosed glioblastoma (nGBM). Neuro-Oncol 21:Suppl. 6vi17
    [Google Scholar]
  47. 47. 
    Van Den Bent M, Eoli M, Sepulveda JM et al. 2020. INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide versus temozolomide or lomustine in recurrent EGFR amplified glioblastoma. Neuro-Oncol 22:5684–93
    [Google Scholar]
  48. 48. 
    Sampson JH, Heimberger AB, Archer GE et al. 2010. 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. 28:314722–29
    [Google Scholar]
  49. 49. 
    Ameratunga M, Pavlakis N, Wheeler H et al. 2018. Anti-angiogenic therapy for high-grade glioma. Cochrane Database Syst. Rev. 11:11Cd008218
    [Google Scholar]
  50. 50. 
    Khasraw M, Ameratunga M, Grommes C 2014. Bevacizumab for the treatment of high-grade glioma: an update after phase III trials. Expert Opin. Biol. Ther. 14:5729–40
    [Google Scholar]
  51. 51. 
    Gustafson MP, Lin Y, New KC et al. 2010. Systemic immune suppression in glioblastoma: the interplay between CD14+HLA-DRlo/neg monocytes, tumor factors, and dexamethasone. Neuro-Oncol 12:7631–44
    [Google Scholar]
  52. 52. 
    Filley AC, Henriquez M, Dey M. 2017. Recurrent glioma clinical trial, CheckMate-143: the game is not over yet. Oncotarget 8:5391779–94
    [Google Scholar]
  53. 53. 
    Chinot OL, Wick W, Mason W et al. 2014. Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370:8709–22
    [Google Scholar]
  54. 54. 
    Batchelor TT, Mulholland P, Neyns B et al. 2013. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J. Clin. Oncol. 31:263212
    [Google Scholar]
  55. 55. 
    Kalpathy-Cramer J, Chandra V, Da X et al. 2017. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. J. Neuro-oncol. 131:3603–10
    [Google Scholar]
  56. 56. 
    Iwamoto FM, Lamborn KR, Robins HI et al. 2010. Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro-Oncol 12:8855–61
    [Google Scholar]
  57. 57. 
    Hutterer M, Nowosielski M, Haybaeck J et al. 2014. A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07). Neuro-Oncol 16:192–102
    [Google Scholar]
  58. 58. 
    Lombardi G, De Salvo GL, Brandes AA et al. 2019. Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol 20:1110–19
    [Google Scholar]
  59. 59. 
    Jiménez-Alcázar M, Curiel-García Á, Nogales P et al. 2021. Dianhydrogalactitol overcomes multiple temozolomide resistance mechanisms in glioblastoma. Mol. Cancer Ther. 20:61029–38
    [Google Scholar]
  60. 60. 
    Wen PY, Cloughesy TF, Olivero AG et al. 2020. First-in-human phase I study to evaluate the brain-penetrant PI3K/mTOR inhibitor GDC-0084 in patients with progressive or recurrent high-grade glioma. Clin. Cancer Res. 26:81820–28
    [Google Scholar]
  61. 61. 
    Cancer Genome Atlas Res. Netw 2008. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:72161061–68
    [Google Scholar]
  62. 62. 
    Wen PY, Touat M, Alexander BM et al. 2019. Buparlisib in patients with recurrent glioblastoma harboring phosphatidylinositol 3-kinase pathway activation: an open-label, multicenter, multi-arm, phase II trial. J. Clin. Oncol. 37:9741–50
    [Google Scholar]
  63. 63. 
    Wick W, Gorlia T, Bady P et al. 2016. Phase II study of radiotherapy and temsirolimus versus radiochemotherapy with temozolomide in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (EORTC 26082). Clin. Cancer Res. 22:194797–806
    [Google Scholar]
  64. 64. 
    Dahiya S, Emnett RJ, Haydon DH et al. 2014. BRAF-V600E mutation in pediatric and adult glioblastoma. Neuro-Oncol 16:2318–19
    [Google Scholar]
  65. 65. 
    Kaley T, Touat M, Subbiah V et al. 2018. BRAF inhibition in BRAFV600-mutant gliomas: results from the VE-BASKET study. J. Clin. Oncol. 36:353477–84
    [Google Scholar]
  66. 66. 
    Wen P, Stein A, van den Bent M et al. 2019. ACTR-30. Updated efficacy and safety of dabrafenib plus trametinib in patients with recurrent/refractory BRAF V600E–mutated high-grade glioma (HGG) and low-grade glioma (LGG). Neuro-Oncol 21:Suppl. 6vi19–vi20
    [Google Scholar]
  67. 67. 
    Drilon A, Laetsch TW, Kummar S et al. 2018. Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. N. Engl. J. Med. 378:8731–39
    [Google Scholar]
  68. 68. 
    Demetri GD, Paz-Ares L, Farago AF et al. 2018. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumours: pooled analysis of STARTRK-2, STARTRK-1, and ALKA-372-001. Ann. Oncol. 29:Suppl. 9ix175
    [Google Scholar]
  69. 69. 
    Whittaker S, Madani D, Joshi S et al. 2017. Combination of palbociclib and radiotherapy for glioblastoma. Cell Death Discov 3:117033
    [Google Scholar]
  70. 70. 
    Verhaak RG, Hoadley KA, Purdom E et al. 2010. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:198–110
    [Google Scholar]
  71. 71. 
    Wen P, Trippa L, Lee E et al. 2020. CTNI-12. Preliminary results of the abemaciclib arm in the individualized screening trial of innovative glioblastoma therapy (INSIGHT): a phase II platform trial using Bayesian adaptive randomization. Neuro-Oncol 22:Suppl. 2ii44
    [Google Scholar]
  72. 72. 
    Alexander BM, Trippa L, Gaffey S et al. 2019. Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): a Bayesian adaptive platform trial to develop precision medicines for patients with glioblastoma. JCO Precis Oncol 3:1–13
    [Google Scholar]
  73. 73. 
    Wick W, Dettmer S, Berberich A et al. 2018. N2M2 (NOA-20) phase I/II trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed non-MGMT hypermethylated glioblastoma. Neuro-Oncol 21:195–105
    [Google Scholar]
  74. 74. 
    Pfaff E, Kessler T, Balasubramanian GP et al. 2018. Feasibility of real-time molecular profiling for patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation—the NCT Neuro Master Match (N2M2) pilot study. Neuro-Oncol 20:6826–37
    [Google Scholar]
  75. 75. 
    Prowell TM, Theoret MR, Pazdur R. 2016. Seamless oncology-drug development. N. Engl. J. Med. 374:212001–3
    [Google Scholar]
  76. 76. 
    Louveau A, Smirnov I, Keyes TJ et al. 2015. Structural and functional features of central nervous system lymphatic vessels. Nature 523:7560337–41
    [Google Scholar]
  77. 77. 
    Aspelund A, Antila S, Proulx ST et al. 2015. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212:7991–99
    [Google Scholar]
  78. 78. 
    Goldberg SB, Schalper KA, Gettinger SN et al. 2020. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol 21:5655–63
    [Google Scholar]
  79. 79. 
    Tawbi HA, Forsyth PA, Algazi A et al. 2018. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N. Engl. J. Med. 379:8722–30
    [Google Scholar]
  80. 80. 
    Reardon DA, Omuro A, Brandes AA et al. 2017. OS10.3 Randomized phase 3 study evaluating the efficacy and safety of nivolumab versus bevacizumab in patients with recurrent glioblastoma: CheckMate 143. Neuro-Oncol 19:Suppl. 3iii21
    [Google Scholar]
  81. 81. 
    Garber ST, Hashimoto Y, Weathers SP et al. 2016. Immune checkpoint blockade as a potential therapeutic target: surveying CNS malignancies. Neuro-Oncol 18:101357–66
    [Google Scholar]
  82. 82. 
    Nduom EK, Wei J, Yaghi NK et al. 2016. PD-L1 expression and prognostic impact in glioblastoma. Neuro-Oncol 18:2195–205
    [Google Scholar]
  83. 83. 
    Hodges TR, Ott M, Xiu J et al. 2017. Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro-Oncol 19:81047–57
    [Google Scholar]
  84. 84. 
    Kipnis J. 2016. Multifaceted interactions between adaptive immunity and the central nervous system. Science 353:6301766–71
    [Google Scholar]
  85. 85. 
    Fecci PE, Heimberger AB, Sampson JH. 2014. Immunotherapy for primary brain tumors: no longer a matter of privilege. Clin Cancer Res 20:225620–29
    [Google Scholar]
  86. 86. 
    Nduom EK, Weller M, Heimberger AB. 2015. Immunosuppressive mechanisms in glioblastoma. Neuro-Oncol 17:Suppl. 7vii9–14
    [Google Scholar]
  87. 87. 
    Wei J, Chen P, Gupta P et al. 2020. Immune biology of glioma-associated macrophages and microglia: functional and therapeutic implications. Neuro Oncol 22:2180–94
    [Google Scholar]
  88. 88. 
    Goswami S, Walle T, Cornish AE et al. 2020. Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma. Nat. Med. 26:139–46
    [Google Scholar]
  89. 89. 
    Woroniecka KI, Rhodin KE, Chongsathidkiet P et al. 2018. T-cell dysfunction in glioblastoma: applying a new framework. Clin. Cancer Res. 24:163792–802
    [Google Scholar]
  90. 90. 
    Schartner JM, Hagar AR, Van Handel M et al. 2005. Impaired capacity for upregulation of MHC class II in tumor-associated microglia. Glia 51:4279–85
    [Google Scholar]
  91. 91. 
    Ou A, Ott M, Fang D, Heimberger AB. 2021. The role and therapeutic targeting of JAK/STAT signaling in glioblastoma. Cancers 13:3437
    [Google Scholar]
  92. 92. 
    Wainwright DA, Chang AL, Dey M et al. 2014. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin. Cancer Res. 20:205290–301
    [Google Scholar]
  93. 93. 
    Chongsathidkiet P, Jackson C, Koyama S et al. 2018. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat. Med. 24:91459–68
    [Google Scholar]
  94. 94. 
    Woroniecka K, Chongsathidkiet P, Rhodin K et al. 2018. T-cell exhaustion signatures vary with tumor type and are severe in glioblastoma. Clin. Cancer Res. 24:174175–86
    [Google Scholar]
  95. 95. 
    Ott M, Tomaszowski KH, Marisetty A et al. 2020. Profiling of patients with glioma reveals the dominant immunosuppressive axis is refractory to immune function restoration. JCI Insight 5:17e134386
    [Google Scholar]
  96. 96. 
    Chiocca EA, Rabkin SD. 2014. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol. Res. 2:4295–300
    [Google Scholar]
  97. 97. 
    Bommareddy PK, Shettigar M, Kaufman HL. 2018. Integrating oncolytic viruses in combination cancer immunotherapy. Nat. Rev. Immunol. 18:8498–513
    [Google Scholar]
  98. 98. 
    Andtbacka RH, Kaufman HL, Collichio F et al. 2015. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33:252780–88
    [Google Scholar]
  99. 99. 
    Lang FF, Conrad C, Gomez-Manzano C et al. 2018. Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J. Clin. Oncol. 36:141419–27
    [Google Scholar]
  100. 100. 
    Cloughesy TF, Landolfi J, Vogelbaum MA et al. 2018. Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. Neuro-Oncol 20:101383–92
    [Google Scholar]
  101. 101. 
    Gujar S, Pol JG, Kroemer G. 2018. Heating it up: oncolytic viruses make tumors ‘hot’ and suitable for checkpoint blockade immunotherapies. Oncoimmunology 7:8e1442169
    [Google Scholar]
  102. 102. 
    Samson A, Scott KJ, Taggart D et al. 2018. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci. Transl. Med. 10:422aam7577
    [Google Scholar]
  103. 103. 
    Desjardins A, Gromeier M, Herndon JE et al. 2018. Recurrent glioblastoma treated with recombinant poliovirus. N. Engl. J. Med. 379:2150–61
    [Google Scholar]
  104. 104. 
    Harrington K, Freeman DJ, Kelly B, Harper J, Soria JC. 2019. Optimizing oncolytic virotherapy in cancer treatment. Nat. Rev. Drug Discov. 18:9689–706
    [Google Scholar]
  105. 105. 
    Corrales L, Glickman LH, McWhirter SM et al. 2015. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep 11:71018–30
    [Google Scholar]
  106. 106. 
    Ohkuri T, Ghosh A, Kosaka A et al. 2014. STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol. Res. 2:121199–208
    [Google Scholar]
  107. 107. 
    Le Naour J, Zitvogel L, Galluzzi L et al. 2020. Trial watch: STING agonists in cancer therapy. Oncoimmunology 9:11777624
    [Google Scholar]
  108. 108. 
    Boudreau CE, Najem H, Ott M et al. 2021. Intratumoral delivery of STING agonist results in clinical responses in canine glioblastoma. Clin. Cancer Res 27:552835
    [Google Scholar]
  109. 109. 
    Gedeon PC, Schaller TH, Chitneni SK et al. 2018. A rationally designed fully human EGFRvIII:CD3-targeted bispecific antibody redirects human T cells to treat patient-derived intracerebral malignant glioma. Clin. Cancer Res. 24:153611–31
    [Google Scholar]
  110. 110. 
    Pituch KC, Zannikou M, Ilut Let al 2021. Neural stem cells secreting bispecific T cell engager to induce selective antiglioma activity. PNAS 118:9e2015800118
    [Google Scholar]
  111. 111. 
    Nair SK, De Leon G, Boczkowski D et al. 2014. Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells. Clin. Cancer Res. 20:102684–94
    [Google Scholar]
  112. 112. 
    Reap EA, Suryadevara CM, Batich KA et al. 2018. Dendritic cells enhance polyfunctionality of adoptively transferred T cells that target cytomegalovirus in glioblastoma. Cancer Res 78:1256–64
    [Google Scholar]
  113. 113. 
    Batich KA, Reap EA, Archer GE et al. 2017. Long-term survival in glioblastoma with cytomegalovirus pp65-targeted vaccination. Clin. Cancer Res. 23:81898–909
    [Google Scholar]
  114. 114. 
    Mitchell DA, Batich KA, Gunn MD et al. 2015. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519:7543366–69
    [Google Scholar]
  115. 115. 
    Weathers SP, Penas-Prado M, Pei BL et al. 2020. Glioblastoma-mediated immune dysfunction limits CMV-specific T cells and therapeutic responses: results from a phase I/II trial. Clin. Cancer Res. 26:143565–77
    [Google Scholar]
  116. 116. 
    Sabbagh A, Beccaria K, Ling X et al. 2021. Opening of the blood-brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models. Clin. Cancer Res. 27:154325–37
    [Google Scholar]
  117. 117. 
    Hilf N, Kuttruff-Coqui S, Frenzel K et al. 2019. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565:7738240–45
    [Google Scholar]
  118. 118. 
    Wick W, Dietrich P-Y, Kuttruff S et al. 2018. GAPVAC-101: first-in-human trial of a highly personalized peptide vaccination approach for patients with newly diagnosed glioblastoma. J. Clin.Oncol. 36:15 Suppl2000
    [Google Scholar]
  119. 119. 
    Keskin DB, Anandappa AJ, Sun J et al. 2019. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565:7738234–39
    [Google Scholar]
  120. 120. 
    Liu CJ, Schaettler M, Blaha DT et al. 2020. Treatment of an aggressive orthotopic murine glioblastoma model with combination checkpoint blockade and a multivalent neoantigen vaccine. Neuro-Oncol 22:91276–88
    [Google Scholar]
  121. 121. 
    Antonios JP, Soto H, Everson RG et al. 2016. PD-1 blockade enhances the vaccination-induced immune response in glioma. JCI Insight 1:10e87059
    [Google Scholar]
  122. 122. 
    Lee-Chang C, Miska J, Hou D et al. 2020. Activation of 4-1BBL+ B cells with CD40 agonism and IFNγ elicits potent immunity against glioblastoma. J. Exp. Med. 218:1e20200913
    [Google Scholar]
  123. 123. 
    Lee-Chang C, Rashidi A, Miska J et al. 2019. Myeloid-derived suppressive cells promote B cell-mediated immunosuppression via transfer of PD-L1 in glioblastoma. Cancer Immunol. Res. 7:121928–43
    [Google Scholar]
  124. 124. 
    O'Rourke DM, Nasrallah MP, Desai A et al. 2017. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl. Med. 9:399eaaa0984
    [Google Scholar]
  125. 125. 
    Brown CE, Alizadeh D, Starr R et al. 2016. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375:262561–69
    [Google Scholar]
  126. 126. 
    Hyrenius-Wittsten A, Su Y, Park M et al. 2021. SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models. Sci. Transl. Med. 13:591eabd8836
    [Google Scholar]
  127. 127. 
    Hegde M, Mukherjee M, Grada Z et al. 2016. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J. Clin. Investig. 126:83036–52
    [Google Scholar]
  128. 128. 
    Wang D, Starr R, Chang WC et al. 2020. Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Sci. Transl. Med. 12:533eaaw2672
    [Google Scholar]
  129. 129. 
    Shaim H, Sanabria MH, Basar R et al. 2021. Targeting the αv integrin-TGF-β axis improves natural killer cell function against glioblastoma stem cells. J. Clin. Investig 131:14e142116
    [Google Scholar]
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