Active immunization strategies in glioblastoma - clinical outcomes and effect modifiers for dendritic vaccines and adoptive cell therapies: a systematic review.

[BACKGROUND] High-grade gliomas are especially known for their high rate of recurrence. Despite the current standard of care treatment protocol-including resection, chemotherapy, and radiation-morbidity and mortality are still commonplace amongst patients diagnosed with glioblastoma (GBM).

[METHODS] Phase II/III evidence on active immunotherapies for GBM was synthesized, focusing on dendritic cell (DC) vaccines and adoptive cellular approaches, versus contemporary standard therapy, and to identify effect modifiers (MGMT status, extent of resection, and corticosteroids) that should guide surgical and adjuvant decision-making. Following PRISMA methods, a systematic review of MEDLINE (PubMed), Embase, and Cochrane (2020-2025) for adult GBM trials with a comparator arm was conducted. Outcomes included overall survival (OS), progression-free survival (PFS), safety, and prespecified modifiers.

[RESULTS] Of 797 records, 13 trials met criteria (9 newly diagnosed, 3 recurrent, 1 mixed).Among active immunotherapies, DC vaccines and adoptive cell therapies showed the most consistent clinical signals. DCVax-L improved median OS versus external controls in newly diagnosed GBM (19.3 vs 16.5 months; 5-year OS 13.0% vs 5.7%). Cytokine-induced killer (CIK) cells prolonged PFS and were an independent predictor of longer OS in pathologically pure GBM (median OS 23.1 vs 14.9 months; PFS 8.1 vs 5.5 months). In contrast, adding PD-1/CTLA-4 inhibition to chemoradiation failed to improve first-line OS/PFS, and at recurrence, bevacizumab outperformed nivolumab for PFS with similar OS; pembrolizumab plus bevacizumab improved 6-month PFS versus pembrolizumab alone. Grade 3 or higher adverse events ranged from approximately 15% to 52% across interventions and were generally manageable. Baseline corticosteroid exposure consistently attenuated the benefit of immunotherapy; maximal safe resection correlated with better outcomes and larger apparent effects of vaccines/adoptive cells. MGMT status displayed modality-specific interactions (i.e., DCVax-L benefit in MGMT-methylated disease; interferon-α signal in unmethylated disease).

[CONCLUSIONS] Immunotherapy in high-grade glioma remains investigational, with randomized evidence to date demonstrating limited benefit for routine checkpoint inhibition in both newly diagnosed and recurrent disease. Selected vaccine and adoptive cellular strategies have shown encouraging survival signals in defined contexts, particularly when integrated following maximal safe resection. Persistent biological barriers, including tumor heterogeneity, antigen escape, low tumor mutational burden, and an immunosuppressive environment, continue to constrain durable responses. Future progress will depend on biologically informed trial design, optimized delivery strategies, and careful patient selection to ascertain the potential efficacy of immunotherapy in treating GBM.