Glioblastoma in the post-2021 era: Diagnostic recalibration, therapeutic innovations, and future horizons

Table 1 Selected post-2021 clinical and translational landmarks

Year	Milestone/trial	Context/population	Key result/insight	Ref.
2021	Official WHO CNS5 adoption	All gliomas	Molecular reclassification; IDH-wt glioblastoma defined	[3,4]
2021-2025	TTFields reanalysis and adoption debates	Newly diagnosed GBM	Reaffirmed modest benefit, raised compliance/cost issues	[25-28]
2021	Proton vs photon radiotherapy (randomized phase II)	Newly diagnosed glioblastoma	Proton RT reduced grade ≥ 3 radiation-induced lymphopenia (14% vs 39%) with comparable tumor control; no OS/PFS superiority (NCT01854554)	[94]
2024	Multicenter CAR-T trial launches	Recurrent GBM	Locoregional dosing in selected patients	[68]
2024	First public bivalent CAR-T interim reports	Refractory GBM	Intrathecal dual-antigen responses	[70]
2022-2024	G47Δ (teserpaturev) oncolytic virus approval (Japan)	Residual/recurrent GBM	Safety and select durable responses	[61,62]
2021-2025	Liquid biopsy advances	Glioma/GBM	Better ctDNA/EV detection in CSF	[77-79]

CNS5: Central nervous system 5; IDH: Isocitrate dehydrogenase; IDH-wt: Isocitrate dehydrogenase wild type; GBM: Glioblastoma; TTFields: Tumor treating fileds; CAR-T cell: Chimeric antigen receptor T cell; ctDNA: Circulating tumor DNA; EV: Extracellular vesicles; CSF: Cerebrospinal fluid; OS: Overall survival; PFS: Progression free survival.

Table 2 Summary of “randomized disappointments” with immunotherapy in unselected glioblastoma

Ref.	n	Trial number	Phase	Patient population	Design	Results
Reardon et al[35]	369	NCT02017717 Checkmate 143	Phase 3 RCT	Recurrent GBM	Nivolumab vs bevacizumab	mPFS 1.5 months vs 3.5 months, mOS 9.8 months vs 10 months, ORR 7.8% vs 23.1%
Nayak et al[32]	80	NCT02337491	Phase 2 RCT	Recurrent GBM	Pembrolizumab + bevacizumab vs pembrolizumab	PFS6 rate 26% vs 6.7%; mOS 8.8 months vs 10.3 months; ORR 20% vs 0%
Iwamoto et al[33]	60	NCT03661723	Phase 2 RCT	Recurrent GBM	Pembrolizumab + ReRT (bevacizumab naïve) vs bevacizumab continuation	mPFS 4 months each; mOS 11 months vs 7 months
Lim et al[36]	716	NCT02667587 CheckMate 548	Phase 3 RCT	Newly diagnosed GBM, MGMT methylated	Nivolumab + RT + TMZ vs placebo + RT + TMZ	mPFS 10.6 months vs 10.3 months; mOS 28.9 months vs 32.1 months
Omuro et al[37]	560	NCT02617589 CheckMate 498	Phase 3 RCT	Newly diagnosed GBM, MGMT unmethylated	Nivolumab + RT vs TMZ + RT	mPFS 6.0 months vs 6.2 months; mOS 13.4 months vs 14.9 months
Lassman et al[38]	159	NCT04396860 NRG Oncology BN007	Phase 2 RCT	Newly diagnosed GBM, MGMT unmethylated	Nivolumab + ipilimumab + RT vs TMZ + RT	mPFS 7.7 months vs 8.5 months; OS immature (approximately 13 months each)
Brown et al[39]	119	ISRCTN84434175 Ipi-Glio trial	Phase 2 RCT	Newly diagnosed GBM	Ipilimumab + TMZ vs TMZ	mPFS 10.8 months vs 12.5 months; mOS months 18.0 vs 23.0 months

RCT: Randomized controlled trial; mOS: Median overall survival; mPFS: Median progression free survival; GBM: Glioblastoma; PFS6: 6 months progression free survival; ORR: Objective response rate; RT: Radiotherapy; TMZ: Temozolomide; Ipi: Ipilimumab.

Table 3 Strategies, opportunities, and reframing challenges

Strategy/modality	Therapeutic rationale	Key challenges and barriers	Research directions
CAR-T/cell immunotherapy	Engineered T cells targeting tumor antigens	Antigen heterogeneity, neurotoxicity, manufacturing, infiltration	Multivalent/armored constructs, locoregional dosing, repeat infusions
Checkpoint inhibitors/immunotherapy	Release immune suppression	Cold tumor microenvironment, low TMB	Combination therapies, microenvironment modulation, biomarker selection
Vaccines and oncolytic viruses	Prime systemic/Locoregional immune responses	Delivery, immune suppression, limited by scale	Combinatorial adjuvants, intratumoral delivery, optimized scheduling
TTFields	Disrupt mitosis and sensitize cells	Compliance, cost, modest benefit	Synergy with immunotherapy, biomarker-guided use
Liquid biopsy	Dynamic molecular monitoring	Low sensitivity, compartmentalization	Improved assay sensitivity, integration into adaptive trials
Spatial profiling/single-cell	Map heterogeneity and niche interactions	Data complexity, translation to therapy	Use to guide trial designs and antigen selection
Adaptive and platform trials	Efficient evaluation across arms	Statistical complexity, regulatory harmonization	Master protocols, biomarker stratification, real-time adaptive arms

TMB: Tumor mutational burden; TTFields: Tumor treating fileds; CAR-T cell: Chimeric antigen receptor T cell.