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

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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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