Teaching pack: Glioma & glioblastoma

Gliomas are classified by the WHO 2021 system on molecular grounds: IDH-wild-type glioblastoma (grade 4, ~50% of gliomas, median age 65, median survival ~15 months with maximal therapy), IDH-mutant astrocytoma (grades 2-4) and 1p/19q-codeleted oligodendroglioma (better prognosis, decades of survival possible), and paediatric-type tumours including H3 K27M-mutant diffuse midline glioma (median survival ~11 months) and BRAF-altered low-grade glioma (the commonest childhood brain tumour, rarely fatal but chronically disabling). The two shared barriers are the blood-brain barrier, which excludes most drugs, and diffuse infiltration, which makes complete resection impossible.

Glioblastoma treatment has been static since 2005: maximal safe resection (improved by 5-ALA fluorescence, intraoperative MRI, and awake mapping), radiotherapy with concurrent and adjuvant temozolomide (Stupp), and tumour treating fields (EF-14). MGMT promoter methylation predicts temozolomide benefit; unmethylated patients derive little. Every major systemic trial since has failed: bevacizumab (PFS only), rindopepimut (ACT IV), nivolumab (CheckMate 143, 498, 548), depatuxizumab mafodotin (INTELLANCE-1), and many more. At recurrence, lomustine, re-resection, re-irradiation, LITT, and bevacizumab for oedema are the options, with median survival under a year. DCVax-L's externally controlled phase 3 remains contested.

• Vorasidenib in low-grade glioma.
• Methylation-based diagnosis.
• TTFields.
• Three first-in-class targeted approvals for glioma subtypes in 2024-25: vorasidenib (IDH-mutant), tovorafenib (BRAF paediatric), dordaviprone (H3 K27M).
• Molecular classification (WHO 2021, methylation classifier, intraoperative nanopore) now defines diagnosis.
• Locoregional CAR-T produces objective responses in recurrent glioblastoma and DIPG, though transient.

1. 1926Bailey and Cushing classify gliomas
2. 1978Radiotherapy proven to extend survival (BTSG)
3. 1999Temozolomide approved (anaplastic astrocytoma)
4. 2005Stupp regimen: temozolomide + RT
5. 2008IDH1 mutations discovered in glioma
6. 2009Bevacizumab accelerated approval at recurrence
7. 2014AVAglio / RTOG 0825: bevacizumab no OS benefit; 5-ALA and methylation classifier emerge
8. 2015TTFields improves OS (EF-14)
9. 2016WHO 2016 integrates molecular markers; ACT IV vaccine fails
10. 2017CheckMate 143: immunotherapy fails at recurrence

• Armoured, logic-gated & next-gen CARs (technology)
• Boron neutron capture therapy (technology)
• Hyperthermia (technology)
• CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target) (technology)
• Focused-ultrasound blood-brain barrier opening (technology)
• Laser interstitial thermal therapy (LITT) (technology)
• DCVax-L (product)
• Dordaviprone (product)
• Tovorafenib (product)
• Neoadjuvant immunotherapy with surgical window for glioblastoma (idea)
• Focused-ultrasound BBB opening to deliver ADCs and radioligands to glioma (idea)
• Personalised neoantigen (mRNA) vaccines (technology)

• EORTC 26981 / NCIC CE.3 (Stupp trial) (phase 3, n=573): Overall survival: 14.6 months vs 12.1 months, HR 0.63
• EF-14 (phase 3, n=695): Progression-free survival: 6.7 months vs 4 months, HR 0.63
• INDIGO (phase 3, n=331): Progression-free survival (BIRC): 27.7 months vs 11.1 months, HR 0.39
• CheckMate 548 & CheckMate 143 & CheckMate 498 (phase 3, n=716): Overall survival, MGMT-methylated glioblastoma: 28.9 months vs 32.1 months, HR 1.1
• ACT IV (phase 3, n=745): Overall survival, minimal residual disease population: 20.1 months vs 20 months, HR 1.01
• ERGO2: ketogenic diet and fasting during re-irradiation of recurrent glioma (phase 2, n=50): Progression-free survival at 6 months: 20% vs 16%

• Blood-brain barrier.
• Immunologically cold, heterogeneous, infiltrative.
• No progress in glioblastoma survival in 20 years.
• Glioblastoma median survival has not moved in 20 years; every phase 3 systemic agent since temozolomide has failed.
• MGMT-unmethylated glioblastoma (~60%) gains almost nothing from chemotherapy and has no approved alternative.
• Blood-brain barrier and diffuse infiltration limit delivery and resection; imaging cannot distinguish progression from pseudoprogression reliably.

1. What was the first approval in nearly thirty years specific to locally advanced pancreatic cancer?
   Answer

   Optune Pax (tumour treating fields) with gemcitabine/nab-paclitaxel, approved Q1 2026 on PANOVA-3.
2. What was the first personalised cancer vaccine to win a phase 3 trial?
   Answer

   Intismeran autogene (V940/mRNA-4157, Moderna/Merck) with pembrolizumab in resected stage IIB-IV melanoma: INTerpath-001 met recurrence-free and distant-metastasis-free survival, announced 19 August 2026.
3. How is a personalised mRNA cancer vaccine made?
   Answer

   The tumour and normal DNA are sequenced, software predicts up to 34 neoantigens unique to the tumour, a patient-specific mRNA encoding them is manufactured in lipid nanoparticles over about six weeks, and it is given with a PD-1 blocker.
4. What is in vivo CAR-T and why is it exciting?
   Answer

   Targeted lipid nanoparticles or viral vectors deliver CAR-encoding mRNA or DNA to T cells inside the patient, avoiding manufacturing, lymphodepletion, and wait time and allowing redosing; first-in-human data in 2025-26 show B-cell depletion. AbbVie bought Capstan for up to $2.1B.
5. What is tumour treating fields and which cancers is it approved for?
   Answer

   Wearable electrode arrays delivering alternating electric fields that disrupt cell division; approved for glioblastoma, mesothelioma, NSCLC after platinum, and (2026) locally advanced pancreatic cancer.
6. Why might personalised vaccines work better after surgery than in metastatic disease?
   Answer

   Tumour burden is low so immune responses are not overwhelmed, there is time for the six-week manufacturing, immunosuppression from bulky disease is absent, and recurrence-free survival is a clean endpoint; INTerpath-001 tested exactly this adjuvant setting.

• Wikipedia: https://en.wikipedia.org/wiki/Glioblastoma
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425