Diffuse Intrinsic Pontine Glioma: From Diagnosis to Next-Generation Clinical Trials
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.
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.
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.
KeywordsDiffuse intrinsic pontine glioma DIPG H3 K27M mutation Diffuse midline glioma DMG
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
- 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
- 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
- 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.• 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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.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
- 59.Hankinson TC, Patibandla MR, Green A, et al. Hypofractionated radiotherapy for children with diffuse intrinsic pontine gliomas. Pediatr Blood Cancer. 2015.Google Scholar
- 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
- 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
- 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.• 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