Advertisement

Diffuse Intrinsic Pontine Glioma: From Diagnosis to Next-Generation Clinical Trials

  • Nicholas A. Vitanza
  • Michelle MonjeEmail author
Neuro-oncology (R Soffietti, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Neuro-oncology

Abstract

Purpose of review

This review of diffuse intrinsic pontine glioma (DIPG) provides clinical background, a systematic approach to diagnosis and initial care, and synthesizes historical, modern, and future directions for treatment. We present evidence supporting neurosurgical biopsy, early palliative care involvement, limitation of glucocorticoid use, and the leveraging of preclinical DIPG models as a pipeline to next-generation clinical trials.

Recent findings

New molecular understanding of pediatric high-grade gliomas has led to the reclassification of DIPG as one member of a family of diffuse gliomas occurring in the midline of the central nervous system that exhibit pathognomonic mutations in genes encoding histone 3 (H3 K27M). DIPG remains a clinically relevant term, though diagnostically the 80% of DIPG cases that exhibit the H3 K27M mutation have been reclassified as diffuse midline glioma, H3 K27M-mutant. Re-irradiation has been shown to be well-tolerated and of potential benefit. Epigenetic targeting of transcriptional dependencies in preclinical models is fueling molecularly targeted clinical trials. Chimeric antigen receptor T cell immunotherapy has also demonstrated efficacy in preclinical models and provides a promising new clinical strategy.

Summary

DIPG is a universally fatal, epigenetically driven tumor of the pons that is considered part of a broader class of diffuse midline gliomas sharing H3 K27M mutations. Radiation remains the standard of care, single-agent temozolomide is not recommended, and glucocorticoids should be used only sparingly. A rapid evolution of understanding in the chromatin, signaling, and immunological biology of DIPG may soon result in clinical breakthroughs.

Keywords

Diffuse intrinsic pontine glioma DIPG H3 K27M mutation Diffuse midline glioma DMG 

Notes

Acknowledgements

The authors gratefully acknowledge support from the National Institute of Neurological Disorders and Stroke (R01NS092597), NIH Director’s Pioneer Award (DP1NS111132), Unravel Pediatric Cancer, McKenna Claire Foundation, Virginia and D.K. Ludwig Fund for Cancer Research, ChadTough Foundation, Defeat DIPG, and Abbie’s Army Foundation.

Compliance with Ethical Standards

Conflict of Interest

Nicholas A. Vitanza declares no potential conflicts of interest. Michelle Monje has a pending patent entitled “CAR T cell therapy to treat H3K27M midline gliomas.”

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Harris W. A case of pontine glioma, with special reference to the paths of gustatory sensation. Proc R Soc Med. 1926;19(Neurol Sect):1–5.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20.PubMedGoogle Scholar
  3. 3.
    •• Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 2012;124(3):439–47.PubMedPubMedCentralGoogle Scholar
  4. 4.
    •• Wu G, Broniscer A, McEachron TA, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012;44(3):251–3.PubMedPubMedCentralGoogle Scholar
  5. 5.
    •• Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and chromatin remodeling genes in pediatric glioblastoma. Nature. 2012;482(7384):226–31.Wu et al., Khuong-Quang et al. and Schwartzentruber et al. discovered the highly recurrent H3 K27M mutation in DIPG and other pediatric midline gliomas. This discovery of an “oncohistone” has revolutionized our understanding of the pathophysiology of this disease and underscores the central role for epigenetic dysregulation in DIPG and other pediatric malignancies.PubMedGoogle Scholar
  6. 6.
    Albright AL, Packer RJ, Zimmerman R, et al. Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children’s Cancer Group. Neurosurgery. 1993;33(6):1026–9 discussion 1029–30.PubMedGoogle Scholar
  7. 7.
    Hankinson TC, Campagna EJ, Foreman NK, et al. Interpretation of magnetic resonance images in diffuse intrinsic pontine glioma: a survey of pediatric neurosurgeons. J Neurosurg Pediatr. 2011;8(1):97–102.PubMedGoogle Scholar
  8. 8.
    Barkovich AJ, Krischer J, Kun LE, et al. Brain stem gliomas: a classification system based on magnetic resonance imaging. Pediatr Neurosurg. 1990;16(2):73–83.PubMedGoogle Scholar
  9. 9.
    Pajtler, K.W., S.C. Mack, V. Ramaswamy, et al. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol. 2016.Google Scholar
  10. 10.
    Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123(4):465–72.PubMedGoogle Scholar
  11. 11.
    Reis GF, Tihan T. Therapeutic targets in pilocytic astrocytoma based on genetic analysis. Semin Pediatr Neurol. 2015;22(1):23–7.PubMedGoogle Scholar
  12. 12.
    Lapin DH, Tsoli M, Ziegler DS. Genomic insights into diffuse intrinsic pontine glioma. Front Oncol. 2017;7:57.PubMedPubMedCentralGoogle Scholar
  13. 13.
    • Lieberman NAP, Vitanza NA, Crane CA. Immunotherapy for brain tumors: understanding early successes and limitations. Expert Rev Neurother. 2018;18(3):251–9.PubMedGoogle Scholar
  14. 14.
    Lieberman NAP, DeGolier K, Kovar HM, et al. Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: implications for development of immunotherapy. Neuro Oncol. 2019;21(1):83–94.PubMedGoogle Scholar
  15. 15.
    •• Nagaraja S, Vitanza NA, Woo PJ, et al. Transcriptional dependencies in diffuse intrinsic pontine glioma. Cancer Cell. 2017, 31(5):635–652 e6.This preclinical work discovered DIPG’s vulnerabilities to BRD4 and CDK7 blockade, as well as their synergistic benefit when combined with HDAC inhibition.PubMedPubMedCentralGoogle Scholar
  16. 16.
    • Lin GL, Nagaraja S, Filbin MG, et al. Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma. Acta Neuropathol Commun. 2018;6(1):51 Lin et al. and Lieberman et al. independently discovered the microenvironment in DIPG is neither immunosuppresive nor inflammatory, making it distinct from that of adult GBM.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Becher OJ, Hambardzumyan D, Walker TR, et al. Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma. Cancer Res. 2010;70(6):2548–57.PubMedGoogle Scholar
  18. 18.
    Biery, M., C. Myers, E. Girard, et al. A novel HDAC inhibitor in new patient-derived diffuse intrinsic pontine glioma (DIPG) models, in ISPNO2018 - International Symposium on Pediatric Neuro-Oncology. DIPG-35, Presentation. 2018: Denver, CO, USA. p. i56.Google Scholar
  19. 19.
    Cage TA, Samagh SP, Mueller S, et al. Feasibility, safety, and indications for surgical biopsy of intrinsic brainstem tumors in children. Childs Nerv Syst. 2013;29(8):1313–9.PubMedGoogle Scholar
  20. 20.
    Grasso CS, Tang Y, Truffaux N, et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med. 2015;21(6):555–9.PubMedPubMedCentralGoogle Scholar
  21. 21.
    • Gupta, N., L.C. Goumnerova, P. Manley, et al. Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma. Neuro Oncol. 2018;20(11):1547–1555.An important prospective study evaluating the safety of biopsy for patients with DIPG.Google Scholar
  22. 22.
    Larson JD, Kasper LH, Paugh BS, et al. Histone H3.3 K27M accelerates spontaneous brainstem glioma and drives restricted changes in bivalent gene expression. Cancer Cell. 2019;35(1):140–155 e7.PubMedGoogle Scholar
  23. 23.
    Lin GL, Monje M. A protocol for rapid post-mortem cell culture of diffuse intrinsic pontine glioma (DIPG). J Vis Exp. 2017;(121).Google Scholar
  24. 24.
    Puget S, Beccaria K, Blauwblomme T, et al. Biopsy in a series of 130 pediatric diffuse intrinsic pontine gliomas. Childs Nerv Syst. 2015;31(10):1773–80.PubMedGoogle Scholar
  25. 25.
    Roujeau T, Machado G, Garnett MR, et al. Stereotactic biopsy of diffuse pontine lesions in children. J Neurosurg. 2007;107(1 Suppl):1–4.PubMedGoogle Scholar
  26. 26.
    Tsoli M, Shen H, Mayoh C, et al. International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma. J Neurooncol. 2018.Google Scholar
  27. 27.
    Wang ZJ, Rao L, Bhambhani K, et al. Diffuse intrinsic pontine glioma biopsy: a single institution experience. Pediatr Blood Cancer. 2015;62(1):163–5.PubMedGoogle Scholar
  28. 28.
    Freeman CR, Farmer JP. Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys. 1998;40(2):265–71.PubMedGoogle Scholar
  29. 29.
    • Cooney T, Lane A, Bartels U, et al. Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study. Neuro Oncol. 2017;19(9):1279–80 An important update on international survival endpoints for children with DIPG.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Veldhuijzen van Zanten SE, Jansen MH, Sanchez Aliaga E, et al. A twenty-year review of diagnosing and treating children with diffuse intrinsic pontine glioma in The Netherlands. Expert Rev Anticancer Ther. 2014;15(2):157–64Google Scholar
  31. 31.
    Lassman LP, Arjona VE. Pontine gliomas of childhood. Lancet. 1967;1(7496):913–5.PubMedGoogle Scholar
  32. 32.
    Fisher PG, Breiter SN, Carson BS, et al. A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities. Cancer. 2000;89(7):1569–76.PubMedGoogle Scholar
  33. 33.
    Fried I, Hawkins C, Scheinemann K, et al. Favorable outcome with conservative treatment for children with low grade brainstem tumors. Pediatr Blood Cancer. 2012;58(4):556–60.PubMedGoogle Scholar
  34. 34.
    Giussani C, Poliakov A, Ferri RT, et al. DTI fiber tracking to differentiate demyelinating diseases from diffuse brain stem glioma. Neuroimage. 2010;52(1):217–23.PubMedGoogle Scholar
  35. 35.
    Lober RM, Cho YJ, Tang Y, et al. Diffusion-weighted MRI derived apparent diffusion coefficient identifies prognostically distinct subgroups of pediatric diffuse intrinsic pontine glioma. J Neurooncol. 2014;117(1):175–82.PubMedGoogle Scholar
  36. 36.
    Caretti V, Bugiani M, Freret M, et al. Subventricular spread of diffuse intrinsic pontine glioma. Acta Neuropathol. 2014;128(4):605–7.PubMedPubMedCentralGoogle Scholar
  37. 37.
    • Huang TY, Piunti A, Lulla RR, et al. Detection of Histone H3 mutations in cerebrospinal fluid-derived tumor DNA from children with diffuse midline glioma. Acta Neuropathol Commun. 2017;5(1):28.Considering DIPG biopsy’s requirement of neurosurgical precision, limited availability, low but significant risk of complications, and the decision’s emotional toll on families, this is an important study showing histone H3 mutations can be detected in CSF.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Saratsis AM, Yadavilli S, Magge S, et al. Insights into pediatric diffuse intrinsic pontine glioma through proteomic analysis of cerebrospinal fluid. Neuro Oncol. 2012;14(5):547–60.PubMedGoogle Scholar
  39. 39.
    Pan C, Diplas BH, Chen X, et al. Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA. Acta Neuropathol. 2018;137(2):297–306.PubMedGoogle Scholar
  40. 40.
    Buczkowicz P, Bartels U, Bouffet E, et al. Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta Neuropathol. 2014;128(4):573–81.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Bozkurt SU, Dagcinar A, Tanrikulu B, et al. Significance of H3K27M mutation with specific histomorphological features and associated molecular alterations in pediatric high-grade glial tumors. Childs Nerv Syst. 2018;34(1):107–16.PubMedGoogle Scholar
  42. 42.
    Pritchard CC, Salipante SJ, Koehler K, et al. Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens. J Mol Diagn. 2014;16(1):56–67.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Lewis PW, Muller MM, Koletsky MS, et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science. 2013;340(6134):857–61.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Shankar GM, Lelic N, Gill CM, et al. BRAF alteration status and the histone H3F3A gene K27M mutation segregate spinal cord astrocytoma histology. Acta Neuropathol. 2016;131(1):147–50.PubMedGoogle Scholar
  45. 45.
    •• Mackay A, Burford A, Carvalho D, et al. Integrated molecular meta-analysis of 1000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell. 2017;32(4):520–537. A comprehensive analysis of DIPG’s molecular aberrations and their clinical significance.Google Scholar
  46. 46.
    Guida L, Roux FE, Massimino M, et al. Safety and efficacy of endoscopic third ventriculostomy in diffuse intrinsic pontine glioma related hydrocephalus: a systematic review. World Neurosurg. 2019;124:29–35.Google Scholar
  47. 47.
    Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. 2011;335(1):2–13.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Drozdowicz LB, Bostwick JM. Psychiatric adverse effects of pediatric corticosteroid use. Mayo Clin Proc. 2014;89(6):817–34.PubMedGoogle Scholar
  49. 49.
    Goforth P, Gudas CJ. Effects of steroids on wound healing: a review of the literature. J Foot Surg. 1980;19(1):22–8.PubMedGoogle Scholar
  50. 50.
    Pappachan JM, Hariman C, Edavalath M, et al. Cushing’s syndrome: a practical approach to diagnosis and differential diagnoses. J Clin Pathol. 2017;70(4):350–9.PubMedGoogle Scholar
  51. 51.
    Fauquette W, Amourette C, Dehouck MP, et al. Radiation-induced blood-brain barrier damages: an in vitro study. Brain Res. 2012;1433:114–26.PubMedGoogle Scholar
  52. 52.
    Hue CD, Cho FS, Cao S, et al. Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein. J Cereb Blood Flow Metab. 2015;35(7):1191–8.PubMedPubMedCentralGoogle Scholar
  53. 53.
    • Luedi MM, Singh SK, Mosley JC, et al. A dexamethasone-regulated gene signature is prognostic for poor survival in glioblastoma patients. J Neurosurg Anesthesiol. 2017;29(1):46–58.This work highlights the importance of limiting steroid use in our patients.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Pitter KL, Tamagno I, Alikhanyan K, et al. Corticosteroids compromise survival in glioblastoma. Brain. 2016;139(Pt 5):1458–71.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Mandrell BN, Baker J, Levine D, et al. Children with minimal chance for cure: parent proxy of the child’s health-related quality of life and the effect on parental physical and mental health during treatment. J Neurooncol. 2016;129(2):373–81.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Langmoen IA, Lundar T, Storm-Mathisen I, et al. Management of pediatric pontine gliomas. Childs Nerv Syst. 1991;7(1):13–5.PubMedGoogle Scholar
  57. 57.
    Janssens GO, Jansen MH, Lauwers SJ, et al. Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis. Int J Radiat Oncol Biol Phys. 2013;85(2):315–20.PubMedGoogle Scholar
  58. 58.
    Zaghloul MS, Eldebawy E, Ahmed S, et al. Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): a randomized controlled trial. Radiother Oncol. 2014;111(1):35–40.PubMedGoogle Scholar
  59. 59.
    Hankinson TC, Patibandla MR, Green A, et al. Hypofractionated radiotherapy for children with diffuse intrinsic pontine gliomas. Pediatr Blood Cancer. 2015.Google Scholar
  60. 60.
    Packer RJ, Boyett JM, Zimmerman RA, et al. Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A Childrens Cancer Group Phase I/II Trial. Cancer. 1994;74(6):1827–34.PubMedGoogle Scholar
  61. 61.
    Freese C, Takiar V, Fouladi M, et al. Radiation and subsequent reirradiation outcomes in the treatment of diffuse intrinsic pontine glioma and a systematic review of the reirradiation literature. Pract Radiat Oncol. 2017;7(2):86–92.PubMedGoogle Scholar
  62. 62.
    Janssens GO, Gandola L, Bolle S, et al. Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: a matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group. Eur J Cancer. 2017;73:38–47.PubMedGoogle Scholar
  63. 63.
    Lassaletta A, Strother D, Laperriere N, et al. Reirradiation in patients with diffuse intrinsic pontine gliomas: the Canadian experience. Pediatr Blood Cancer. 2018;65(6):e26988.PubMedGoogle Scholar
  64. 64.
    Morales La Madrid A, Santa-Maria V, Cruz Martinez O, et al. Second re-irradiation for DIPG progression, re-considering “old strategies” with new approaches. Childs Nerv Syst. 2017;33(5):849–52.PubMedGoogle Scholar
  65. 65.
    Robison NJ, Kieran MW. Diffuse intrinsic pontine glioma: a reassessment. J Neurooncol. 2014;119(1):7–15.PubMedGoogle Scholar
  66. 66.
    Aquino-Parsons C, Hukin J, Green A. Concurrent carbogen and radiation therapy in children with high-risk brainstem gliomas. Pediatr Blood Cancer. 2008;50(2):397–9.PubMedGoogle Scholar
  67. 67.
    Bradley KA, Zhou T, McNall-Knapp RY, et al. Motexafin-gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a children’s oncology group phase 2 study. Int J Radiat Oncol Biol Phys. 2013;85(1):e55–60.PubMedGoogle Scholar
  68. 68.
    Freeman CR, Kepner J, Kun LE, et al. A detrimental effect of a combined chemotherapy-radiotherapy approach in children with diffuse intrinsic brain stem gliomas? Int J Radiat Oncol Biol Phys. 2000;47(3):561–4.PubMedGoogle Scholar
  69. 69.
    Massimino M, Spreafico F, Biassoni V, et al. Diffuse pontine gliomas in children: changing strategies, changing results? A mono-institutional 20-year experience. J Neurooncol. 2008;87(3):355–61.PubMedGoogle Scholar
  70. 70.
    Wagner S, Warmuth-Metz M, Emser A, et al. Treatment options in childhood pontine gliomas. J Neurooncol. 2006;79(3):281–7.PubMedGoogle Scholar
  71. 71.
    Cohen KJ, Heideman RL, Zhou T, 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. 2011;13(4):410–6.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Jalali R, Raut N, Arora B, et al. Prospective evaluation of radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma. Int J Radiat Oncol Biol Phys. 2010;77(1):113–8.PubMedGoogle Scholar
  73. 73.
    Sharp JR, Bouffet E, Stempak D, et al. A multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma. Eur J Cancer. 2010;46(18):3271–9.PubMedGoogle Scholar
  74. 74.
    Bailey S, Howman A, Wheatley K, et al. Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy--results of a United Kingdom phase II trial (CNS 2007 04). Eur J Cancer. 2013;49(18):3856–62.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Broniscer A, Baker JN, Tagen M, et al. Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. J Clin Oncol. 2010;28(31):4762–8.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Broniscer A, Baker SD, Wetmore C, et al. Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma. Clin Cancer Res. 2013;19(11):3050–8.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Geoerger B, Hargrave D, Thomas F, et al. Innovative therapies for children with cancer pediatric phase I study of erlotinib in brainstem glioma and relapsing/refractory brain tumors. Neuro Oncol. 2011;13(1):109–18.PubMedGoogle Scholar
  78. 78.
    Haas-Kogan DA, Banerjee A, Poussaint TY, et al. Phase II trial of tipifarnib and radiation in children with newly diagnosed diffuse intrinsic pontine gliomas. Neuro Oncol. 2011;13(3):298–306.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Pollack IF, Jakacki RI, Blaney SM, et al. Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report. Neuro Oncol. 2007;9(2):145–60.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Bartels U, Wolff J, Gore L, et al. Phase 2 study of safety and efficacy of nimotuzumab in pediatric patients with progressive diffuse intrinsic pontine glioma. Neuro Oncol. 2014;16(11):1554–9.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Veldhuijzen van Zanten SEM, El-Khouly FE, Jansen MHA, et al. A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma. J Neurooncol. 2017;135(2):307–15.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Kilburn LB, Kocak M, Baxter P, et al. A pediatric brain tumor consortium phase II trial of capecitabine rapidly disintegrating tablets with concomitant radiation therapy in children with newly diagnosed diffuse intrinsic pontine gliomas. Pediatr Blood Cancer. 2018;65(2):e26832.Google Scholar
  83. 83.
    Pollack IF, Stewart CF, Kocak M, et al. A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: a report from the Pediatric Brain Tumor Consortium. Neuro Oncol. 2011;13(3):290–7.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Hashizume R, Andor N, Ihara Y, et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med. 2014;20(12):1394–6.PubMedPubMedCentralGoogle Scholar
  85. 85.
    • Vitanza NA, Johnson A, Beebe A, et al. Locoregional HER2CAR T cells for pediatric central nervous system tumors: preclinical efficacy to tolerability in first patient. IMMU-02, Oral Presentation, in Society of Neuro-Oncology Pediatric Basic and Translational Research Conference. 2019: San Francisco, CA. This work highlights the initial patient experience in locoregionally delivering HER2 CAR T cells to children with recurrent/refractory CNS tumors, providing a framework for future locoregional DIPG CAR T cell trials.Google Scholar
  86. 86.
    Ahmed N, Brawley V, Hegde M, et al. HER2-Specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol. 2017;3(8):1094–101.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Gardner RA, Finney O, Annesley C, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129(25):3322–31.PubMedPubMedCentralGoogle Scholar
  88. 88.
    • Mount CW, Majzner RG, Sundaresh S, et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas. Nat Med. 2018;24(5):572–9.The first published DIPG-specific preclinical CAR T cell work, highlighting the vulnerability of targeting GD2.PubMedPubMedCentralGoogle Scholar
  89. 89.
    • Majzner RG, Theruvath JL, Nellan A, 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. 2019;25(8):2560–2574.B7-H3 has been identified as a surface antigen present in many pediatric CNS tumors and this preclinical work served as the foundation for upcoming B7-H3 CAR T cell trials for pediatric CNS tumors including DIPG.PubMedGoogle Scholar
  90. 90.
    Halle B, Mongelard K, Poulsen FR. Convection-enhanced drug delivery for glioblastoma: a systematic review focused on methodological differences in the use of the convection-enhanced delivery method. Asian J Neurosurg. 2019;14(1):5–14.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Souweidane MM, Kramer K, Pandit-Taskar N, et al. Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial. Lancet Oncol. 2018;19(8):1040–50.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Department of Pediatrics, Seattle Children’s HospitalUniversity of WashingtonSeattleUSA
  2. 2.Center for Clinical and Translational ResearchSeattle Children’s Research InstituteSeattleUSA
  3. 3.Fred Hutchinson Cancer Research CenterSeattleUSA
  4. 4.Departments of Neurology and Neurological Sciences, PediatricsStanford University Medical SchoolStanfordUSA

Personalised recommendations