What question did this study set out to answer?

The research aims to explore the biology and vulnerabilities of IDH mutant gliomas characterized by DNA replication-repair deficiency.

June 26, 2026

ID #324 Trans-species analysis of DNA replication-repair deficient, IDH mutant gliomas unravels unique genomic and immune landscape, leading to successful translation to combined immune and targeted therapy

Key Points

The research aims to explore the biology and vulnerabilities of IDH mutant gliomas characterized by DNA replication-repair deficiency.
Multi-omic analyses on IDH mutant gliomas registered with the International RRD Consortium.
Development of an immunocompetent mouse model to study tumor behavior.
Evaluation of treatment efficacy through the addition of an IDH-inhibitor after previous anti-PD1 therapy.
Lower tumor mutation burden was observed in mIDH RRD-gliomas compared to IDH-wildtype (113 vs 28 mutations/Mb, p < 0.05).
Adding the IDH-inhibitor ivosidenib after anti-PD1 treatment led to objective responses and prolonged survival (p = 0.01) in refractory patients.
The study provided evidence for superior efficacy and CNS-penetration of comparison treatments, supporting future trials.

Abstract

Abstract Background IDH mutant (mIDH) gliomas are the most common primary brain tumors in age 50 years. Checkpoint-inhibitors have historically failed to demonstrate responses after their inevitable malignant transformation. We identified that primary DNA replication-repair deficiency (RRD) drives 60% of malignant mIDH malignant gliomas in age 40 years and have an exceptionally poor outcome. We aimed to decipher their biology and identify novel vulnerabilities. Methods Multi-omic analyses were performed on mIDH RRD-glioma registered to the International RRD Consortium and a novel immunocompetent mouse model was generated. Results mIDH RRD-glioma was frequent in older children and young adults with CMMRD and Lynch syndrome, majority were high-grade, with diffuse frontal lobe or multifocal distribution. Mutation burden was lower than IDH-wildtype RRD-glioma (TMB, 113 vs 28 mutations/Mb; p 0.05). Loss of TP53, ATRX and CDKN2A/2B, and global hypomethylation were observed. CD8-T-cell infiltration (immunohistochemistry) and tumor inflammation score (transcriptome) were lower than IDH-wildtype RRD-glioma (p 0.05), contributing to extremely poor survival, even after anti-PD1 monotherapy (p 0.05). A novel mouse model (Olig2Cre+/Msh2LoxP/LSL-Idh1R132H) demonstrated similar lower TMB, diffuse involvement and low immune infiltrate, mimicking human disease. Cell lines demonstrated high levels of 2-hydroxyglutarate, an immuno-suppressive oncometabolite, that was reduced following IDH-inhibition. Adding a 1st-generation IDH-inhibitor (ivosidenib) after progression on anti-PD1 demonstrated objective responses and prolonged survival in refractory human patients (n = 13; p = 0.01). Conclusion Tumors in patients with hypermutant mIDH RRD-glioma that do not respond to anti-PD1 monotherapy harbor an immune-suppressed microenvironment that can be overcome by IDH-inhibition. Additional data demonstrating superior efficacy and CNS-penetration of vorasidenib (2nd-generation IDH1/IDH2 inhibitor), and higher sensitivity of RRD-gliomas to combined PD1+LAG3 inhibition, have now provided the rationale for developing a prospective international clinical trial in adolescents and young adults with mIDH RRD-glioma spanning five countries.

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