Diffuse intrinsic pontine glioma treatment

• PNOC009: Convection-enhanced delivery of liposomal irinotecan in patients with newly diagnosed diffuse intrinsic pontine glioma
• Targeting the CD40 costimulatory receptor to improve virotherapy efficacy in diffuse midline gliomas
• From Seeing to Healing: The Clinical Potential of Radiotracers in Pediatric Neuro-Oncology
• Nimotuzumab Combined With Chemoradiation Therapy in Newly Diagnosed Pediatric Diffuse Intrinsic Pontine Glioma
• Exploring the tumor microenvironment in diffuse intrinsic pontine glioma: immunological insights and therapeutic challenges
• Integrative Multi-Omics Analysis Identifies Nuclear Factor I as a Key Driver of Dysregulated Purine Metabolism in DIPG
• Combination therapy of supercharged NK cells and ONC201 or ONC206 to target aggressive K27M brain tumor
• Beyond Base Camp: Promise and Pitfalls of PI3K/mTOR Inhibition in Pediatric High- Grade Gliomas

Surgical approaches to intrinsic pontine lesions are technically difficult and prone to complications.

Early treatment of hydrocephalus presents a very low complications rate with satisfying clinical outcome, as it allows the patients to continue the neurooncological therapies being a part of the treatment armamentarium instead of a palliative solution ¹⁾.

CAR-T cell therapy for diffuse intrinsic pontine glioma

Whole genome sequencing (WGS) data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multi-center setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe ²⁾.

Radiotherapy is the traditional therapy for newly diagnosed DIPGs. It uses high-energy rays (radiation) from a specialized machine to damage or kill cancer cells and shrink tumors. Conventional limited-field radiation produces responses in more than 90 percent of children with DIPGs. These responses are short-lived, however, lasting about six to nine months on average. Several trials to increase the dose of radiation therapy have been performed and none have improved survival.

Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis with no chemotherapy regimen so far resulting in any significant improvement over standard radiotherapy. In this trial, a prolonged regimen (21/28d) of temozolomide was studied with the aim of overcoming O(6)-methylguanine methyltransferase (MGMT) mediated resistance. Forty-three patients with a defined clinico-radiological diagnosis of DIPG received radiotherapy and concomitant temozolomide (75 mg/m(2)) after which up to 12 courses of 21d of adjuvant temozolomide (75-100mg/m(2)) were given 4 weekly. The trial used a 2-stage design and passed interim analysis. At diagnosis median age was 8 years (2-20 years), 81% had cranial nerve abnormalities, 76% ataxia and 57% long tract signs. Median Karnofsky/Lansky score was 80 (10-100). Patients received a median of three courses of adjuvant temozolomide, five received all 12 courses and seven did not start adjuvant treatment. Three patients were withdrawn from study treatment due to haematological toxicity and 10 had a dose reduction. No other significant toxicity related to temozolomide was noted. Overall survival (OS) (95% confidence interval (CI)) was 56% (40%, 69%) at 9 months, 35% (21%, 49%) at 1 year and 17% (7%, 30%) at 2 years. Median survival was 9.5 months (range 7.5-11.4 months). There were five 2-year survivors with a median age of 13.6 years at diagnosis. This trial demonstrated no survival benefit of the addition of dose dense temozolomide, to standard radiotherapy in children with classical DIPG. However, a subgroup of adolescent DIPG patients did have a prolonged survival, which needs further exploration ³⁾.

Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor with dismal prognosis despite initial radiation therapy (RT). The clinical consequences of attempting reirradiation (reRT) in these patients to alleviate both symptomatology and improve prognosis are currently unclear. Thus, the aim of this systematic review and meta-analysis was to clarify the efficacy and safety of reRT in DIPG.

Searches of seven electronic databases from inception to January 2019 were conducted following the appropriate guidelines. Articles were screened against prespecified criteria. The incidence and duration of clinical outcomes were then extracted and pooled by means of meta-analysis from the included studies.

A total of 7 studies satisfied all criteria, describing 90 cases of DIPG in which reRT was attempted 11.8-14 months after initial RT. Based on a random-effects model, the incidences of clinical improvement and radiologic response following reRT were 87% (95% CI, 78-95%) and 69% (95% CI, 52-84%), respectively. The incidence of acute serious toxicity was 0% (95% CI, 0-4%). Pooled overall survivals from initial diagnosis and time of reRT were 18.0 months (95% CI, 14.2-21.7) and 6.2 months (95% CI, 5.5-7.0), respectively.

Based on these results, the clinical consequences of reRT for DIPG when administered appropriately and safely at first progression appear acceptable, and potentially favorable, based on the limited evidence in the current literature. Concerns regarding acute serious toxicity were not realized. It is likely that a subcohort of all DIPG diagnoses will be most amenable to improve prognosis with reRT, and greater investigation is required to identify their characteristics ⁴⁾.

A proof-of-concept study provides a novel demonstration of marked DIPG cell susceptibility to low intensity electric fields delivered using intratumoral modulation therapy (IMT). The potent impact as a monotherapy and when integrated into multi-modality treatment platforms justifies further investigations into the potential of IMT as a critically needed biomedical innovation for DIPG ⁵⁾.

Results support continued development of PPM1D inhibitors for Phase I/II trials in children with DIPG ⁶⁾.

1: Honda M, Fukuoka K, Tanami Y, Kurihara J, Koh K. Bevacizumab for the early clinical progression of diffuse intrinsic pontine glioma. Pediatr Int. 2023 Jan- Dec;65(1):e15575. doi: 10.1111/ped.15575. PMID: 37551654.

2: Evans M, Gill R, Bull KS. Does a Bevacizumab-based regime have a role in the treatment of children with diffuse intrinsic pontine glioma? A systematic review. Neurooncol Adv. 2022 Jun 24;4(1):vdac100. doi: 10.1093/noajnl/vdac100. PMID: 35821674; PMCID: PMC9270727.

3: Kim HJ, Lee JH, Kim Y, Lim DH, Park SH, Ahn SD, Kim IA, Im JH, Chung JW, Kim JY, Kim IH, Yoon HI, Suh CO. Suggestions for Escaping the Dark Ages for Pediatric Diffuse Intrinsic Pontine Glioma Treated with Radiotherapy: Analysis of Prognostic Factors from the National Multicenter Study. Cancer Res Treat. 2023 Jan;55(1):41-49. doi: 10.4143/crt.2021.1514. Epub 2022 Mar 4. PMID: 35255651; PMCID: PMC9873330.

4: McCrea HJ, Ivanidze J, O'Connor A, Hersh EH, Boockvar JA, Gobin YP, Knopman J, Greenfield JP. Intraarterial delivery of bevacizumab and cetuximab utilizing blood-brain barrier disruption in children with high-grade glioma and diffuse intrinsic pontine glioma: results of a phase I trial. J Neurosurg Pediatr. 2021 Aug 6;28(4):371-379. doi: 10.3171/2021.3.PEDS20738. PMID: 34359048.

5: El-Khouly FE, Veldhuijzen van Zanten SEM, Jansen MHA, Bakker DP, Sanchez Aliaga E, Hendrikse NH, Vandertop WP, van Vuurden DG, Kaspers GJL. A phase I/II study of bevacizumab, irinotecan and erlotinib in children with progressive diffuse intrinsic pontine glioma. J Neurooncol. 2021 Jun;153(2):263-271. doi: 10.1007/s11060-021-03763-1. Epub 2021 May 7. PMID: 33963476; PMCID: PMC8211596.

6: Crotty EE, Leary SES, Geyer JR, Olson JM, Millard NE, Sato AA, Ermoian RP, Cole BL, Lockwood CM, Paulson VA, Browd SR, Ellenbogen RG, Hauptman JS, Lee A, Ojemann JG, Vitanza NA. Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children's Hospital experience. J Neurooncol. 2020 Jul;148(3):607-617. doi: 10.1007/s11060-020-03558-w. Epub 2020 Jun 16. PMID: 32556862.

7: Su JM, Murray JC, McNall-Knapp RY, Bowers DC, Shah S, Adesina AM, Paulino AC, Jo E, Mo Q, Baxter PA, Blaney SM. A phase 2 study of valproic acid and radiation, followed by maintenance valproic acid and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma or high-grade glioma. Pediatr Blood Cancer. 2020 Jun;67(6):e28283. doi: 10.1002/pbc.28283. Epub 2020 Apr 14. PMID: 32285998.

8: Hall MD, Odia Y, Allen JE, Tarapore R, Khatib Z, Niazi TN, Daghistani D, Schalop L, Chi AS, Oster W, Mehta MP. First clinical experience with DRD2/3 antagonist ONC201 in H3 K27M-mutant pediatric diffuse intrinsic pontine glioma: a case report. J Neurosurg Pediatr. 2019 Apr 5;23(6):719-725. doi: 10.3171/2019.2.PEDS18480. PMID: 30952114.

9: Chua J, Nafziger E, Leung D. Evidence-Based Practice: Temozolomide Beyond Glioblastoma. Curr Oncol Rep. 2019 Mar 5;21(4):30. doi: 10.1007/s11912-019-0783-5. PMID: 30835007.

10: Gupta N, Goumnerova LC, Manley P, Chi SN, Neuberg D, Puligandla M, Fangusaro J, Goldman S, Tomita T, Alden T, DiPatri A, Rubin JB, Gauvain K, Limbrick D, Leonard J, Geyer JR, Leary S, Browd S, Wang Z, Sood S, Bendel A, Nagib M, Gardner S, Karajannis MA, Harter D, Ayyanar K, Gump W, Bowers DC, Weprin B, MacDonald TJ, Aguilera D, Brahma B, Robison NJ, Kiehna E, Krieger M, Sandler E, Aldana P, Khatib Z, Ragheb J, Bhatia S, Mueller S, Banerjee A, Bredlau AL, Gururangan S, Fuchs H, Cohen KJ, Jallo G, Dorris K, Handler M, Comito M, Dias M, Nazemi K, Baird L, Murray J, Lindeman N, Hornick JL, Malkin H, Sinai C, Greenspan L, Wright KD, Prados M, Bandopadhayay P, Ligon KL, Kieran MW. Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma. Neuro Oncol. 2018 Oct 9;20(11):1547-1555. doi: 10.1093/neuonc/noy070. PMID: 29741745; PMCID: PMC6176802.

11: Veldhuijzen van Zanten SEM, Sewing ACP, van Lingen A, Hoekstra OS, Wesseling P, Meel MH, van Vuurden DG, Kaspers GJL, Hulleman E, Bugiani M. Multiregional Tumor Drug-Uptake Imaging by PET and Microvascular Morphology in End-Stage Diffuse Intrinsic Pontine Glioma. J Nucl Med. 2018 Apr;59(4):612-615. doi: 10.2967/jnumed.117.197897. Epub 2017 Aug 17. PMID: 28818988.

12: Jansen MH, Veldhuijzen van Zanten SEM, van Vuurden DG, Huisman MC, Vugts DJ, Hoekstra OS, van Dongen GA, Kaspers GL. Molecular Drug Imaging: ⁸⁹Zr- Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma. J Nucl Med. 2017 May;58(5):711-716. doi: 10.2967/jnumed.116.180216. Epub 2016 Oct 20. PMID: 27765855.

13: Jansen MH, Lagerweij T, Sewing AC, Vugts DJ, van Vuurden DG, Molthoff CF, Caretti V, Veringa SJ, Petersen N, Carcaboso AM, Noske DP, Vandertop WP, Wesseling P, van Dongen GA, Kaspers GJ, Hulleman E. Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models. Mol Cancer Ther. 2016 Sep;15(9):2166-74. doi: 10.1158/1535-7163.MCT-15-0558. Epub 2016 Jun 20. PMID: 27325687.

14: Hummel TR, Salloum R, Drissi R, Kumar S, Sobo M, Goldman S, Pai A, Leach J, Lane A, Pruitt D, Sutton M, Chow LM, Grimme L, Doughman R, Backus L, Miles L, Stevenson C, Fouladi M, DeWire M. A pilot study of bevacizumab-based therapy in patients with newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas. J Neurooncol. 2016 Mar;127(1):53-61. doi: 10.1007/s11060-015-2008-6. Epub 2015 Dec 1. PMID: 26626490.

15: Kamiya-Matsuoka C, Cachia D, Olar A, Armstrong TS, Gilbert MR. Primary brain tumors and posterior reversible encephalopathy syndrome. Neurooncol Pract. 2014 Dec;1(4):184-190. doi: 10.1093/nop/npu024. Epub 2014 Sep 14. PMID: 26034631; PMCID: PMC4369712.

16: Salloum R, DeWire M, Lane A, Goldman S, Hummel T, Chow L, Miles L, Sutton M, Stevenson C, Fouladi M, Leach J. Patterns of progression in pediatric patients with high-grade glioma or diffuse intrinsic pontine glioma treated with Bevacizumab-based therapy at diagnosis. J Neurooncol. 2015 Feb;121(3):591-8. doi: 10.1007/s11060-014-1671-3. Epub 2014 Nov 30. PMID: 25433556.

17: Zaky W, Wellner M, Brown RJ, Blüml S, Finlay JL, Dhall G. Treatment of children with diffuse intrinsic pontine gliomas with chemoradiotherapy followed by a combination of temozolomide, irinotecan, and bevacizumab. Pediatr Hematol Oncol. 2013 Oct;30(7):623-32. doi: 10.3109/08880018.2013.829895. PMID: 24050762.

18: Okada K, Yamasaki K, Tanaka C, Fujisaki H, Osugi Y, Hara J. Phase I study of bevacizumab plus irinotecan in pediatric patients with recurrent/refractory solid tumors. Jpn J Clin Oncol. 2013 Nov;43(11):1073-9. doi: 10.1093/jjco/hyt124. Epub 2013 Sep 3. PMID: 24002900.

19: Aguilera DG, Mazewski C, Hayes L, Jordan C, Esiashivilli N, Janns A, Macdonald TJ. Prolonged survival after treatment of diffuse intrinsic pontine glioma with radiation, temozolamide, and bevacizumab: report of 2 cases. J Pediatr Hematol Oncol. 2013 Jan;35(1):e42-6. doi: 10.1097/MPH.0b013e318279aed8. PMID: 23249962.

20: Wolff JE, Rytting ME, Vats TS, Zage PE, Ater JL, Woo S, Kuttesch J, Ketonen L, Mahajan A. Treatment of recurrent diffuse intrinsic pontine glioma: the MD Anderson Cancer Center experience. J Neurooncol. 2012 Jan;106(2):391-7. doi: 10.1007/s11060-011-0677-3. Epub 2011 Aug 20. PMID: 21858608; PMCID: PMC3990187.

21: MacDonald TJ, Aguilera D, Kramm CM. Treatment of high-grade glioma in children and adolescents. Neuro Oncol. 2011 Oct;13(10):1049-58. doi: 10.1093/neuonc/nor092. Epub 2011 Jul 22. PMID: 21784756; PMCID: PMC3177659.