Prognostic utility of tumor grade and IDH-mutation status for immunotherapy response in high grade glioma: a systematic review and meta-analysis

Abstract

Introduction: Survival outcomes among patients with World Health Organization grade III gliomas and IDH-mutant (IDHmt) gliomas treated with immunotherapy (IT) remain understudied, with most research focusing on grade IV (G4) glioblastomas or IDH wild-type (IDHwt) tumors.

Methods: A systematic literature search was conducted in PubMed/MEDLINE, SCOPUS, Embase, Google Scholar, and Science Direct databases following PRISMA guidelines. A random-effects meta-analysis was conducted to assess overall survival and 5-year mortality. Outcomes were compared across IT treatments and between historically designated grade III versus grade IV/GBM cohorts and explicitly reported IDHmt versus IDHwt glioma cohorts within each included study.

Results: A total of 21 studies involving 207 patients with grade III gliomas and 11 studies involving 115 patients with IDHmt gliomas were included. IT agents studied included dendritic cell and peptide vaccines (32 grade III, 45 IDHmt), immune checkpoint inhibitors (1 grade III, 39 IDHmt), oncolytic viruses (10 grade III, 20 IDHmt), modified lymphocyte therapies (1 grade III, 11 IDHmt), cytokine immunotherapy (47 IDHmt) and radioimmunotherapy (110 grade III). Most treated grade III (65.6%) and IDHmt (72.7%) gliomas were recurrent tumors. Across all immunotherapy agents, recurrent and newly diagnosed grade III glioma did not exhibit significant differences in overall survival (21.90 versus 29.71 months, p = 0.237), 5-year mortality (77.10% versus 60.89%, p = 0.481), or overall mortality at last follow-up (78.91% versus 70.37%, p = 0.553). Newly diagnosed IDHmt glioma had significantly greater overall survival than recurrent IDHmt glioma (43.13 versus 19.57 months, p = 0.005) and significantly lower 5-year mortality (10.26% versus 59.78%, p < 0.001). Between immunotherapy modalities, grade III glioma did not exhibit differences in overall survival compared to GBM in equivalent treated cohorts (p = 0.123). However, dendritic cell and peptide vaccines had a higher overall survival compared to all other immunotherapy agents in IDHmt glioma (p = 0.002), including when compared to IDHwt glioma in equivalent treatment arms (p = 0.044).

Conclusion: Our study summarizes reported survival outcomes among patients with historically designated grade III and IDHmt gliomas treated with immunotherapy. Observed differences by histological grade, IDH status, and recurrence status are consistent with the established prognostic importance of these tumor features, and should not be interpreted as evidence that immunotherapy caused improved survival. Survival outcomes appeared more favorable in newly diagnosed IDHmt glioma and in IDHmt cohorts treated with dendritic cell or peptide vaccines; however, these findings are descriptive and hypothesis-generating given the predominance of single-arm studies, limited sample size, and potential confounding by baseline prognosis. Future prospective controlled trials are needed to determine whether specific immunotherapy approaches provide benefit in these glioma subgroups.

Keywords: Grade III glioma; High-grade glioma; IDH mutation; Immunotherapy; Meta-analysis; Neuro-oncology; Overall survival.