IMMU-13. TRANS-SPECIES STUDY OF IDH-MUTANT REPLICATION-REPAIR DEFICIENT HIGH-GRADE GLIOMAS (RRD-HGG) AND RESPONSE TO COMBINED TARGETED AND IMMUNOTHERAPY: AN IRRDC STUDY
Authors: Anirban Das, Vienna Mazzoli, Nicholas Fernandez, Zoya Aamir, Nuno Nunes, Katharine O’Flaherty, Hope Friedman, Kevin Bielamowicz, Gadi Abebe-Campino, Shani Caspi, Per Nyman, Richard Graham, John Kim, Mari Wilhelmsson, Mette Jorgensen, Orli Michaeli, Maria Fernandez, Alyssa Reddy, Nicholas Llosa, Amanda Li, Adrian Levin, Lucie Stengs, Logine Negm, Vanessa Bianchi, Melissa Edwards, Birgit Ertl-Wagner, Julie Bennett, Peter Dirks, Eric Bouffet, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND AND AIMS IDH-mutant gliomas comprise &amp;lt;10% of HGG in children. RRD-HGG comprise 5-10% of childhood HGG, demonstrate high mutation burden (TMB) and respond to immune-checkpoint inhibition (ICI). The impact of RRD within childhood IDH-mutant gliomas, and effective therapeutic options for these patients are not well-established. METHODS Clinical and multi-omic analyses were performed on IDH mut -RRD-HGG registered to the IRRDC and the Toronto glioma taskforce. Tumor development and genomic data were studied from a novel IDH mut -RRD-HGG immunocompetent mouse model. Outcome following ICI and targeted therapy were evaluated. RESULTS RRD was detected in &amp;gt;60% of childhood IDH mut -HGG. IDH1-mutations were detected in 20% of RRD-HGG. All patients with IDH mut -RRD-HGG (n=49) harboured germline variants in MMR genes (CMMRD: 65%, Lynch: 35%). Contrary to sporadic IDH mut -gliomas, &amp;gt;91% were WHO-grades 3/4. Diffuse/multifocal disease involving the frontal lobe was frequent. TMB (median: 28 mutations/Mb) was lower than IDH-wildtype RRD-HGG (p&amp;lt;0.05). POLE/POLD1 mutations were absent. TP53 and ATRX were frequent somatic hits. Copy number changes, particularly CDKN2A/2B loss, were common. IDH-mutation contributed to an immune-suppressed microenvironment, with lower CD8-T-cell infiltration (immunohistochemistry) and tumor-inflammation scores (transcriptome; p&amp;lt;0.05). A novel mouse model (Olig2-Cre+/Msh2LoxP/LoxP/LSL-Idh1R132H/+) demonstrated similar TMB, diffuse cerebral involvement, slower growth, and lesser immune infiltrates as compared with IDH-wildtype RRD-HGG models, and provided opportunity for therapeutic testing. RRD contributed to poor survival in IDHmut-gliomas (p&amp;lt;0.001). Despite hypermutation, ICI monotherapy resulted in inferior survival in IDH mut -RRD-HGG vs IDH-wildtype RRD-HGG (p&amp;lt;0.05). Five patients developed metachronous IDH mut -RRD-HGG while on anti-PD1 treatment for IDH-wildtype RRD-HGG, suggesting intrinsic ICI-resistance. Ivosidenib (IDH-inhibitor) demonstrated objective response in 4/8 IDH mut -RRD-HGG. Furthermore, for IDH mut -RRD-HGG on ICI treatment, the addition of ivosidenib prolonged survival at 12-months in comparison to those without IDH-inhibition (p=0.01) CONCLUSIONS Hypermutant RRD-HGG with IDH1;p.R132H harbour unique immuno-biology and do not respond to anti-PD1 monotherapy. The addition of IDH-inhibition demonstrated favourable responses, supporting need for evaluation of the combination in clinical trials.