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The current landscape of immunotherapy for pediatric brain tumors

Nature Cancer volume 3, pages 11–24 (2022)Cite this article

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Abstract

Pediatric central nervous system tumors are the most common solid malignancies in childhood, and aggressive therapy often leads to long-term sequelae in survivors, making these tumors challenging to treat. Immunotherapy has revolutionized prospects for many cancer types in adults, but the intrinsic complexity of treating pediatric patients and the scarcity of clinical studies of children to inform effective approaches have hampered the development of effective immunotherapies in pediatric settings. Here, we review recent advances and ongoing challenges in pediatric brain cancer immunotherapy, as well as considerations for efficient clinical translation of efficacious immunotherapies into pediatric settings.

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Fig. 1: The cycle of immunotherapy responses in pediatric CNS tumors.
Fig. 2: Immunotherapy approaches for pediatric CNS tumors.

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References

  1. Pollack, I. F. Brain tumors in children. N. Engl. J. Med. 331, 1500–1507 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Cohen, K. J. et al. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children’s Oncology Group. Neuro Oncol. 13, 410–416 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chan, T. A., Wolchok, J. D. & Snyder, A. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 373, 1984 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Okada, H. et al. Immunotherapeutic approaches for glioma. Crit. Rev. Immunol. 29, 1–42 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Walker, P. R., Calzascia, T., de Tribolet, N. & Dietrich, P. Y. T-cell immune responses in the brain and their relevance for cerebral malignancies. Brain Res. Brain Res. Rev. 42, 97–122 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Platten, M. & Reardon, D. A. Concepts for immunotherapies in gliomas. Semin. Neurol. 38, 62–72 (2018).

  8. Engelhardt, B. Molecular mechanisms involved in T cell migration across the blood–brain barrier. J. Neural Transm. 113, 477–485 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Krakowski, M. L. & Owens, T. The central nervous system environment controls effector CD4+ T cell cytokine profile in experimental allergic encephalomyelitis. Eur. J. Immunol. 27, 2840–2847 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Albert, M. L. et al. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat. Med. 4, 1321–1324 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Okada, H. & Pollack, I. F. Cytokine gene therapy for malignant glioma. Expert Opin. Biol. Ther. 4, 1609–1620 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Okada, H. et al. Gene therapy of malignant gliomas: a pilot study of vaccination with irradiated autologous glioma and dendritic cells admixed with IL-4 transduced fibroblasts to elicit an immune response. Hum. Gene Ther. 12, 575–595 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Okada, H. et al. Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas. J. Transl. Med. 5, 67 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Liau, L. M. 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).

    Article  CAS  PubMed  Google Scholar 

  15. Wheeler, C. J. et al. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res. 68, 5955–5964 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Yamanaka, R. et al. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin. Cancer Res. 11, 4160–4167 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Yu, J. S. et al. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 64, 4973–4979 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Liau, L. M. et al. First results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J. Transl. Med. 16, 142 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dutoit, V. et al. Antigenic expression and spontaneous immune responses support the use of a selected peptide set from the IMA950 glioblastoma vaccine for immunotherapy of grade II and III glioma. Oncoimmunology 7, e1391972 (2018).

    Article  PubMed  Google Scholar 

  20. Okada, H. 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).

    Article  CAS  PubMed  Google Scholar 

  21. Weller, M. et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 18, 1373–1385 (2017).

    Article  CAS  PubMed  Google Scholar 

  22. Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565, 240–245 (2019).

    Article  CAS  PubMed  Google Scholar 

  23. Tocagen. Tocagen Reports Results of Toca 5 Phase 3 Trial in Recurrent Brain Cancer http://ir.tocagen.com/news-releases/news-release-details/tocagen-reports-results-toca-5-phase-3-trial-recurrent-brain (2019).

  24. Filley, A. C., Henriquez, M. & Dey, M. Recurrent glioma clinical trial, CheckMate-143: the game is not over yet. Oncotarget 8, 91779–91794 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bristol Myers Squibb. Bristol-Myers Squibb Announces Phase 3 CheckMate -498 Study Did Not Meet Primary Endpoint of Overall Survival with Opdivo (Nivolumab) Plus Radiation in Patients with Newly Diagnosed MGMT-Unmethylated Glioblastoma Multiforme https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-announces-phase-3-checkmate-498-study-did (2019).

  26. Bristol Myers Squibb. Bristol-Myers Squibb Provides Update on Phase 3 Opdivo (Nivolumab) CheckMate -548 Trial in Patients with Newly Diagnosed MGMT-Methylated Glioblastoma Multiforme https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-provides-update-phase-3-opdivo-nivolumab- (2019).

  27. Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Louis, D. N. et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 131, 803–820 (2016).

    Article  PubMed  Google Scholar 

  29. Sturm, D. et al. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat. Rev. Cancer 14, 92–107 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Watanabe, K. et al. Incidence and timing of p53 mutations during astrocytoma progression in patients with multiple biopsies. Clin. Cancer Res. 3, 523–530 (1997).

    CAS  PubMed  Google Scholar 

  31. Reilly, K. M., Loisel, D. A., Bronson, R. T., McLaughlin, M. E. & Jacks, T. Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat. Genet. 26, 109–113 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Mackay, A. et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32, 520–537 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Guerreiro Stucklin, A. S. et al. Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas. Nat. Commun. 10, 4343 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Chheda, Z. S. et al. Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy. J. Exp. Med. 215, 141–157 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sonabend, A. M. et al. Medulloblasoma: challenges for effective immunotherapy. J. Neurooncol. 108, 1–10 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Rutledge, W. C. et al. Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class. Clin. Cancer Res. 19, 4951–4960 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Krishnadas, D. K., Bai, F. & Lucas, K. G. Targeting cancer-testis antigens in recurrent pediatric brain tumors. J. Neurooncol. 123, 193–195 (2015).

    Article  PubMed  Google Scholar 

  40. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wainwright, D. A. et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin. Cancer Res. 18, 6110–6121 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ke, X. et al. Roles of CD4+CD25high FOXP3+ Tregs in lymphomas and tumors are complex. Front. Biosci. 13, 3986–4001 (2008).

    CAS  PubMed  Google Scholar 

  43. Lohr, J. et al. Effector T-cell infiltration positively impacts survival of glioblastoma patients and is impaired by tumor-derived TGF-β. Clin. Cancer Res. 17, 4296–4308 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Duraiswamy, J., Kaluza, K. M., Freeman, G. J. & Coukos, G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 73, 3591–3603 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kodumudi, K. N., Weber, A., Sarnaik, A. A. & Pilon-Thomas, S. Blockade of myeloid-derived suppressor cells after induction of lymphopenia improves adoptive T cell therapy in a murine model of melanoma. J. Immunol. 189, 5147–5154 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Margol, A. et al. Tumor associated macrophages in SHH subgroup of medulloblastomas. Clin. Cancer Res. 21, 1457–1465 (2014).

  47. Askew, K. et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep. 18, 391–405 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Heimberger, A. B. et al. Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin. Cancer Res. 14, 5166–5172 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  50. Schlager, C. et al. Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature 530, 349–353 (2016).

    Article  PubMed  Google Scholar 

  51. Beatty, G. L. & Moon, E. K. Chimeric antigen receptor T cells are vulnerable to immunosuppressive mechanisms present within the tumor microenvironment. Oncoimmunology 3, e970027 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  52. van der Burg, S. H., Arens, R., Ossendorp, F., van Hall, T. & Melief, C. J. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat. Rev. Cancer 16, 219–233 (2016).

    Article  PubMed  Google Scholar 

  53. Ochs, K. et al. K27M-mutant histone-3 as a novel target for glioma immunotherapy. Oncoimmunology. 6, e1328340 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Gattinoni, L. et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202, 907–912 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Suryadevara, C. M. et al. Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma. Oncoimmunology 7, e1434464 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Desjardins, A. et al. Recurrent glioblastoma treated with recombinant poliovirus. N. Engl. J. Med. 379, 150–161 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Fried, I. et al. Preliminary results of immune modulating antibody MDV9300 (pidilizumab) treatment in children with diffuse intrinsic pontine glioma. J. Neurooncol. 136, 189–195 (2018).

    Article  CAS  PubMed  Google Scholar 

  58. Geoerger, B. Anti-PD-1 shows promise against advanced paediatric Hodgkin lymphoma—author’s reply. Lancet Oncol. 21, e127 (2020).

    Article  PubMed  Google Scholar 

  59. Kostine, M. et al. Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events. Eur. J. Cancer 157, 474–484 (2021).

    Article  PubMed  Google Scholar 

  60. Grabovska, Y. et al. Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity. Nat. Commun. 11, 4324 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cloughesy, T. F. et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat. Med. 25, 477–486 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gholamin, S. et al. Disrupting the CD47–SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci. Transl. Med. 9, eaaf2968 (2017).

  63. Choi, B. D. et al. Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma. Proc. Natl Acad. Sci. USA 110, 270–275 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Choi, B. D. et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat. Biotechnol. 37, 1049–1058 (2019).

    Article  CAS  PubMed  Google Scholar 

  65. Heiss, J. D. et al. Phase I trial of convection-enhanced delivery of IL13–Pseudomonas toxin in children with diffuse intrinsic pontine glioma. J. Neurosurg. Pediatr. 23, 333–342 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Souweidane, M. M. et al. Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial. Lancet Oncol. 19, 1040–1050 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Yerrabelli, R. S. et al. IntraOmmaya compartmental radioimmunotherapy using 131I-omburtamab-pharmacokinetic modeling to optimize therapeutic index. Eur. J. Nucl. Med. Mol. Imaging 48, 1166–1177 (2021).

    Article  CAS  PubMed  Google Scholar 

  68. He, P. et al. Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid. Eur. J. Nucl. Med. Mol. Imaging 38, 334–342 (2011).

    Article  PubMed  Google Scholar 

  69. Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. Hong, J. J. et al. Successful treatment of melanoma brain metastases with adoptive cell therapy. Clin. Cancer Res. 16, 4892–4898 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Goff, S. L. et al. Pilot trial of adoptive transfer of chimeric antigen receptor-transduced T cells targeting EGFRvIII in patients with glioblastoma. J. Immunother. 42, 126–135 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ahmed, N. et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol. 3, 1094–1101 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Akhavan, D. et al. CAR T cells for brain tumors: lessons learned and road ahead. Immunol. Rev. 290, 60–84 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. O’Rourke, D. M. et al. 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, eaaa0984 (2017).

  75. Mount, C. W. et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M. Nat. Med. 24, 572–579 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Majzner, R. G. et al. CAR T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and brain tumors. Clin. Cancer Res. 25, 2560–2574 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Long, A. H. et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 21, 581–590 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Patterson, J. D., Henson, J. C., Breese, R. O., Bielamowicz, K. J. & Rodriguez, A. CAR T cell therapy for pediatric brain tumors. Front. Oncol. 10, 1582 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Khuong-Quang, D. A. et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 124, 439–447 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mueller, S. et al. Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma. J. Clin. Invest. 130, 6325–6337 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Pollack, I. F. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Pollack, I. F. et al. Antigen-specific immunoreactivity and clinical outcome following vaccination with glioma-associated antigen peptides in children with recurrent high-grade gliomas: results of a pilot study. J. Neurooncol. 130, 517–527 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ahluwalia, M. et al. SurVaxM with standard therapy in newly diagnosed glioblastoma: phase II trial update. J. Clin. Oncol. 37, 15_suppl (2016).

  86. Fenstermaker, R. A. et al. Clinical study of a survivin long peptide vaccine (SurVaxM) in patients with recurrent malignant glioma. Cancer Immunol. Immunother. 65, 1339–1352 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Flores, C. et al. Massive clonal expansion of medulloblastoma-specific T cells during adoptive cellular therapy. Sci. Adv. 5, eaav9879 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Aurelian, L. Oncolytic viruses as immunotherapy: progress and remaining challenges. Onco Targets Ther. 9, 2627–2637 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Regina, A. et al. ANG4043, a novel brain-penetrant peptide–mAb conjugate, is efficacious against HER2-positive intracranial tumors in mice. Mol. Cancer Ther. 14, 129–140 (2015).

    Article  CAS  PubMed  Google Scholar 

  90. Haanen, J. B. A. G. et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29, iv264–iv266 (2018).

    Article  CAS  PubMed  Google Scholar 

  91. Brahmer, J. R., Lacchetti, C. & Thompson, J. A. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline summary. J. Oncol. Pract. 14, 247–249 (2018).

    Article  PubMed  Google Scholar 

  92. Thompson, J. A. New NCCN Guidelines: Recognition and Management of Immunotherapy-Related Toxicity. J. Natl Compr. Canc. Netw. 16, 594–596 (2018).

    Article  PubMed  Google Scholar 

  93. Puzanov, I. et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J. Immunother. Cancer 5, 95 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Johnson, D. B. et al. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375, 1749–1755 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Johnson, D. B. & Balko, J. M. Biomarkers for immunotherapy toxicity: are cytokines the answer? Clin. Cancer Res. 25, 1452–1454 (2019).

    Article  CAS  PubMed  Google Scholar 

  96. Johnson, D. B. et al. Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study. J. Immunother. Cancer 7, 134 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Johnson, D. B. et al. Immune checkpoint inhibitor toxicities: systems-based approaches to improve patient care and research. Lancet Oncol. 21, e398–e404 (2020).

    Article  CAS  PubMed  Google Scholar 

  98. Kennedy, L. B. & Salama, A. K. S. A review of immune-mediated adverse events in melanoma. Oncol. Ther. 7, 101–120 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Weber, J. S. et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J. Clin. Oncol. 35, 785–792 (2017).

    Article  CAS  PubMed  Google Scholar 

  100. Roth, P. et al. Neurological complications of cancer immunotherapy. Cancer Treat. Rev. 97, 102189 (2021).

    Article  CAS  PubMed  Google Scholar 

  101. Morgan, R. A. et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 36, 133–151 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Acharya, U. H. et al. Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy. Expert Rev. Hematol. 12, 195–205 (2019).

    Article  CAS  PubMed  Google Scholar 

  103. Gust, J. et al. Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 7, 1404–1419 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Locke, F. L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 20, 31–42 (2019).

    Article  CAS  PubMed  Google Scholar 

  105. Schuster, S. J. et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 45–56 (2019).

    Article  CAS  PubMed  Google Scholar 

  106. Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).

    Article  CAS  PubMed  Google Scholar 

  107. Yu, L. et al. GD2-specific chimeric antigen receptor-modified T cells for the treatment of refractory and/or recurrent neuroblastoma in pediatric patients. J. Cancer Res. Clin. Oncol. https://doi.org/10.1007/s00432-021-03839-5 (2021).

  108. Castel, D. et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol. 130, 815–827 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Solomon, D. A. et al. Diffuse midline gliomas with histone H3-K27M mutation: a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol. 26, 569–580 (2016).

    Article  CAS  PubMed  Google Scholar 

  110. Misuraca, K. L., Cordero, F. J. & Becher, O. J. Pre-clinical models of diffuse intrinsic pontine glioma. Front. Oncol. 5, 172 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Dey, J. et al. A distinct Smoothened mutation causes severe cerebellar developmental defects and medulloblastoma in a novel transgenic mouse model. Mol. Cell. Biol. 32, 4104–4115 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Pei, Y. et al. An animal model of MYC-driven medulloblastoma. Cancer Cell 21, 155–167 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Huang, M. et al. Engineering genetic predisposition in human neuroepithelial stem cells recapitulates medulloblastoma tumorigenesis. Cell Stem Cell 25, 433–446 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Cordero, F. J. et al. Histone H3.3K27M represses p16 to accelerate gliomagenesis in a murine model of DIPG. Mol. Cancer Res. 15, 1243–1254 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ng, J. M. et al. Generation of a mouse model of atypical teratoid/rhabdoid tumor of the central nervous system through combined deletion of Snf5 and p53. Cancer Res. 75, 4629–4639 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Piccioni, D. E. et al. Analysis of cell-free circulating tumor DNA in 419 patients with glioblastoma and other primary brain tumors. CNS Oncol. 8, CNS34 (2019).

  118. Zhang, L., Li, Y., Meng, W., Ni, Y. & Gao, Y. Dynamic urinary proteomic analysis in a Walker 256 intracerebral tumor model. Cancer Med. 8, 3553–3565 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Elshafeey, N. et al. Multicenter study demonstrates radiomic features derived from magnetic resonance perfusion images identify pseudoprogression in glioblastoma. Nat. Commun. 10, 3170 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Schwalbe, E. C. et al. Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study. Lancet Oncol. 18, 958–971 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Pajtler, K. W. et al. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol. 133, 5–12 (2017).

    Article  CAS  PubMed  Google Scholar 

  123. Buczkowicz, P. et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat. Genet. 46, 451–456 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Donson, A. M. et al. Immune gene and cell enrichment is associated with a good prognosis in ependymoma. J. Immunol. 183, 7428–7440 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Doucette, T. et al. Immune heterogeneity of glioblastoma subtypes: extrapolation from the Cancer Genome Atlas. Cancer Immunol. Res. 1, 112–122 (2013).

    Article  CAS  PubMed  Google Scholar 

  126. Davis, A. A. & Patel, V. G. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J. Immunother. Cancer 7, 278 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Rozeman, E. A. & Blank, C. U. Combining checkpoint inhibition and targeted therapy in melanoma. Nat. Med. 25, 879–882 (2019).

    Article  CAS  PubMed  Google Scholar 

  128. Deng, J. et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 8, 216–233 (2018).

    Article  CAS  PubMed  Google Scholar 

  129. Franchimont, D. Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies. Ann. NY Acad. Sci. 1024, 124–137 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Maxwell, R. et al. Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system. Oncoimmunology 7, e1500108 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Pan, E. Y., Merl, M. Y. & Lin, K. The impact of corticosteroid use during anti-PD1 treatment. J. Oncol. Pharm. Pract. 26, 814–822 (2020).

  132. Zhu, X. et al. Severe cerebral edema following nivolumab treatment for pediatric glioblastoma: case report. J. Neurosurg. Pediatr. 19, 249–253 (2017).

    Article  PubMed  Google Scholar 

  133. Hwang, E. et al. Outcome of patients with recurrent diffuse intrinsic pontine glioma (DIPG) treated with pembrolizumab (anti-PD-1): a pediatric brain tumor consortium study (PBTC045). Neuro Oncol. 20, i100 (2018).

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

    Article  PubMed  PubMed Central  Google Scholar 

  135. Ceschin, R. et al. Parametric response mapping of apparent diffusion coefficient as an imaging biomarker to distinguish pseudoprogression from true tumor progression in peptide-based vaccine therapy for pediatric diffuse intrinsic pontine glioma. AJNR Am. J. Neuroradiol. 36, 2170–2176 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Bloch, O. et al. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin. Cancer Res. 19, 3165–3175 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Pham, C. D. et al. Differential immune microenvironments and response to immune checkpoint blockade among molecular subtypes of murine medulloblastoma. Clin. Cancer Res. 22, 582–595 (2016).

    Article  CAS  PubMed  Google Scholar 

  138. Nguyen, A. T. et al. Evidence for BRAF V600E and H3F3A K27M double mutations in paediatric glial and glioneuronal tumours. Neuropathol. Appl. Neurobiol. 41, 403–408 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. Duan, S. et al. PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype. Nat. Commun. 6, 10068 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. Bian, S. et al. Genetically engineered cerebral organoids model brain tumor formation. Nat. Methods 15, 631–639 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ogawa, J., Pao, G. M., Shokhirev, M. N. & Verma, I. M. Glioblastoma model using human cerebral organoids. Cell Rep. 23, 1220–1229 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Koga, T. et al. Longitudinal assessment of tumor development using cancer avatars derived from genetically engineered pluripotent stem cells. Nat. Commun. 11, 550 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Monje, M. et al. Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc. Natl Acad. Sci. USA 108, 4453–4458 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Hashizume, R. et al. Characterization of a diffuse intrinsic pontine glioma cell line: implications for future investigations and treatment. J. Neurooncol. 110, 305–313 (2012).

    Article  PubMed  Google Scholar 

  145. Harutyunyan, A. S. et al. H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis. Nat. Commun. 10, 1262 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Chen, Z. et al. Advanced pediatric diffuse pontine glioma murine models pave the way towards precision medicine. Cancers 13, 1114 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Lan, X. et al. Modeling human pediatric and adult gliomas in immunocompetent mice through costimulatory blockade. Oncoimmunology 9, 1776577 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Čančer, M. et al. Humanized stem cell models of pediatric medulloblastoma reveal an Oct4/mTOR axis that promotes malignancy. Cell Stem Cell 25, 855–870.e11 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Badodi, S. et al. Convergence of BMI1 and CHD7 on ERK signaling in medulloblastoma. Cell Rep. 21, 2772–2784 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Shiraishi, R. & Kawauchi, D. Epigenetic regulation in medulloblastoma pathogenesis revealed by genetically engineered mouse models. Cancer Sci. 112, 2948–2957 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Theruvath, J. et al. Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. Nat. Med. 26, 712–719 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Terada, Y. et al. Human pluripotent stem cell-derived tumor model uncovers the embryonic stem cell signature as a key driver in atypical teratoid/rhabdoid tumor. Cell Rep. 26, 2608–2621.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  153. Smith, K. S. et al. Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource. Acta Neuropathol. 140, 209–225 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Huq, S. et al. Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma. J. Neurosurg. Pediatr. 5, 1–7 (2021).

    Google Scholar 

  155. Andradas, C. et al. Assessment of cannabidiol and Δ9-tetrahydrocannabiol in mouse models of medulloblastoma and ependymoma. Cancers 13, 330 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Yu, L. et al. A clinically relevant orthotopic xenograft model of ependymoma that maintains the genomic signature of the primary tumor and preserves cancer stem cells in vivo. Neuro Oncol. 12, 580–594 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Haydar, D. et al. Cell-surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery. Neuro Oncol. 23, 999–1011 (2021).

    Article  PubMed  Google Scholar 

  158. Lenting, K., Verhaak, R., Ter Laan, M., Wesseling, P. & Leenders, W. Glioma: experimental models and reality. Acta Neuropathol. 133, 263–282 (2017).

  159. Russell, W. L. et al. Specific-locus test shows ethylnitrosourea to be the most potent mutagen in the mouse. Proc. Natl Acad. Sci. USA 76, 5818–5819 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Mukherjee, J., Ghosh, A., Ghosh, A. & Chaudhuri, S. ENU administration causes genomic instability along with single nucleotide polymorphisms in p53 during gliomagenesis: T11TS administration demonstrated in vivo apoptosis of these genetically altered tumor cells. Cancer Biol. Ther. 5, 156–164 (2006).

    Article  CAS  PubMed  Google Scholar 

  161. Zook, B. C., Simmens, S. J. & Jones, R. V. Evaluation of ENU-induced gliomas in rats: nomenclature, immunochemistry, and malignancy. Toxicol. Pathol. 28, 193–201 (2000).

    Article  CAS  PubMed  Google Scholar 

  162. Koschmann, C. et al. Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma. Oncotarget 7, 65696–65706 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Paugh, B. S. et al. Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res. 73, 6219–6229 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Puputti, M. et al. Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol. Cancer Res. 4, 927–934 (2006).

    Article  CAS  PubMed  Google Scholar 

  165. de Vries, N. A. et al. Rapid and robust transgenic high-grade glioma mouse models for therapy intervention studies. Clin. Cancer Res. 16, 3431–3441 (2010).

    Article  PubMed  Google Scholar 

  166. Holland, E. C. A mouse model for glioma: biology, pathology, and therapeutic opportunities. Toxicol. Pathol. 28, 171–177 (2000).

    Article  CAS  PubMed  Google Scholar 

  167. Bardella, C. et al. Expression of Idh1R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis. Cancer Cell 30, 578–594 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Uhrbom, L., Hesselager, G., Nistér, M. & Westermark, B. Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus. Cancer Res. 58, 5275–5279 (1998).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  170. Hede, S. M. et al. GFAP promoter driven transgenic expression of PDGFB in the mouse brain leads to glioblastoma in a Trp53 null background. Glia 57, 1143–1153 (2009).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Kwon, C. H. et al. Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res. 68, 3286–3294 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Yu, K. et al. PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis. Nature 578, 166–171 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Funato, K., Major, T., Lewis, P. W., Allis, C. D. & Tabar, V. Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science 346, 1529–1533 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Pathania, M. et al. H3.3K27M cooperates with Trp53 loss and PDGFRA gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas. Cancer Cell 32, 684–700.e9 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Larson, J. D. et al. Histone H3.3 K27M accelerates spontaneous brainstem glioma and drives restricted changes in bivalent gene expression. Cancer Cell 35, 140–155.e7 (2019).

    Article  CAS  PubMed  Google Scholar 

  177. Becher, O. et al. Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma. Cancer Res. 70, 2548–2557 (2010).

    Article  CAS  PubMed  Google Scholar 

  178. Halvorson, K. G. et al. A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent. PLoS One 10, e0118926 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Zuckermann, M. et al. Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling. Nat. Commun. 6, 7391 (2015).

    Article  CAS  PubMed  Google Scholar 

  180. Gibson, P. et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095–1099 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Robinson, G. et al. Novel mutations target distinct subgroups of medulloblastoma. Nature 488, 43–48 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Goodrich, L. V., Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997).

    Article  CAS  PubMed  Google Scholar 

  183. Lee, Y. et al. Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene 26, 6442–6447 (2007).

    Article  CAS  PubMed  Google Scholar 

  184. Uziel, T. et al. The tumor suppressors Ink4c and p53 collaborate independently with patched to suppress medulloblastoma formation. Genes Dev. 19, 2656–2667 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Wetmore, C., Eberhart, D. E. & Curran, T. Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res. 61, 513–516 (2001).

    CAS  PubMed  Google Scholar 

  186. Yang, Z. J. et al. Medulloblastoma can be initiated by deletion of patched in lineage-restricted progenitors or stem cells. Cancer Cell 14, 135–145 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Grammel, D. et al. Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem. Acta Neuropathol. 123, 601–614 (2012).

    Article  CAS  PubMed  Google Scholar 

  188. Forget, A. et al. Aberrant ERBB4-SRC signaling as a hallmark of group 4 medulloblastoma revealed by integrative phosphoproteomic profiling. Cancer Cell 34, 379–395.e7 (2018).

    Article  CAS  PubMed  Google Scholar 

  189. Hallahan, A. R. et al. The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res. 64, 7794–7800 (2004).

    Article  CAS  PubMed  Google Scholar 

  190. Schüller, U. et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14, 123–134 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Merk, D. J. et al. Opposing effects of CREBBP mutations govern the phenotype of Rubinstein-Taybi syndrome and adult SHH medulloblastoma. Dev. Cell 44, 709–724.e706 (2018).

    Article  CAS  PubMed  Google Scholar 

  192. Shi, X., Wang, Q., Gu, J., Xuan, Z. & Wu, J. I. SMARCA4/Brg1 coordinates genetic and epigenetic networks underlying Shh-type medulloblastoma development. Oncogene 35, 5746–5758 (2016).

    Article  CAS  PubMed  Google Scholar 

  193. Hatton, B. A. et al. The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Res. 68, 1768–1776 (2008).

    Article  CAS  PubMed  Google Scholar 

  194. Fults, D., Pedone, C., Dai, C. & Holland, E. C. MYC expression promotes the proliferation of neural progenitor cells in culture and in vivo. Neoplasia 4, 32–39 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Jenkins, N. C. et al. Somatic cell transfer of c-Myc and Bcl-2 induces large-cell anaplastic medulloblastomas in mice. J. Neurooncol. 126, 415–424 (2016).

    Article  CAS  PubMed  Google Scholar 

  196. Dhar, S. S. et al. MLL4 is required to maintain broad H3K4me3 peaks and super-enhancers at tumor suppressor genes. Mol. Cell. 70, 825–841.e826 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Lee, C. et al. Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma. Nat. Commun. 10, 332 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Han, Z. Y. et al. The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation. Nat. Commun. 7, 10421 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Ozawa, T. et al. A de novo mouse model of C11orf95-RELA fusion-driven ependymoma identifies driver functions in addition to NF-κB. Cell Rep. 23, 3787–3797 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Pajtler, K. W. et al. YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis. Nat. Commun. 10, 3914 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Eder, N. et al. YAP1/TAZ drives ependymoma-like tumour formation in mice. Nat. Commun. 11, 2380 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This publication was supported in part by the ReMission Alliance against Brain Tumors.

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Authors and Affiliations

  1. Division of Oncology, Brain Tumor Institute, Children’s National Hospital, Washington, DC, USA

    Eugene I. Hwang

  2. Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA

    Elias J. Sayour, Catherine T. Flores, Lan B. Hoang-Minh, John W. Figg, Kate M. Candelario, Jason E. Blatt, Lance S. Governale & Duane A. Mitchell

  3. Division of Pediatric Neurosurgery, Lucile Packard Children’s Hospital, Stanford University, Palo Alto, CA, USA

    Gerald Grant

  4. Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

    Robert Wechsler-Reya

  5. Day One Biopharmaceuticals, San Francisco, CA, USA

    Mark W. Kieran

  6. Brain Tumor Foundation, Ashville, NC, USA

    Joanne Salcido

  7. Departments of Neurosurgery and Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Robert M. Prins

  8. Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University and CCU Brain Tumor Immunology, DKFZ, Heidelberg, Germany

    Michael Platten

  9. Children’s Brain Trust, Coral Springs, FL, USA

    Paul G. Hale

  10. Department of Neurosurgery, University of California, San Francisco, CA, USA

    Hideho Okada

  11. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ian F. Pollack

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  1. Eugene I. Hwang
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Contributions

Conceived of and collected data: E.I.H., E.J.S., C.T.F., G.G., R.W.-R., L.B.H.-M., M.W.K., J.S., R.M.P., J.W.F., M.P., K.M.C., P.G.H., J.E.B., L.S.G., H.O., D.A.M. and I.F.P. Drafted, reviewed and edited the manuscript: E.I.H., E.J.S., C.T.F., G.G., R.W.-R., L.B.H.-M., M.W.K., J.S., R.M.P., J.W.F., M.P., K.M.C., P.G.H., J.E.B., L.S.G., H.O., D.A.M. and I.F.P.

Corresponding author

Correspondence to Eugene I. Hwang.

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Competing interests

All authors declare no conflict of interest, with the following exceptions: M.W.K. is an employee and stock holder of Day One Biopharmaceuticals and M.P. holds patents on histone anti-cancer vaccines (US20180155403A1) and on tryptophan metabolism in cancer immunotherapy (EP2753315B1 and EP3464248A1).

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Hwang, E.I., Sayour, E.J., Flores, C.T. et al. The current landscape of immunotherapy for pediatric brain tumors. Nat Cancer 3, 11–24 (2022). https://doi.org/10.1038/s43018-021-00319-0

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