ID #863 Dendritic-cell treated matched primary-relapse PDHGG patient-derived xenograft models to identify TME shift and therapy resistance profiles

Background Paediatric-type diffuse high-grade glioma (PDHGG) carries a dismal prognosis despite multimodal therapy. Profound intra- and intertumoral heterogeneity,an immunosuppressivemicroenvironment, and adaptive resistance drive treatment failure and rapid progression. Improved understanding of tumor-intrinsic and therapy-induced molecular alterations is thereforerequiredto enable rational, personalizedcombinationstrategies integrating immune-based therapies. Methods A clinical study in adult and children with high-grade glioma was conducted in a swedish cohort with autologous tumor-lysate-pulsed DC vaccinations. Primary outcomes weretoxicityand secondary outcomes included progression-free survival (PFS) and overall survival (OS), alongsideimmuno-monitoringof peripheral T-cell and regulatory T-cell (Treg) activation.Toidentifyrelapse-associated pathways and therapeutic targets, the therapy-associated molecular changes were assessed in bulk and single-cell RNA sequencing ofmatched primary–relapse tumors from one pediatric patient. Results The vaccinations were feasible and well tolerated. Immunomonitoringrevealed heterogeneous CD4+, CD8+, and T-reg responses. From longitudinal transcriptomic profiling and single-cell analysis we could show thatthe majority oftumor cells displayed an oligodendrocyte precursor-like (OPC-like) phenotype andat relapse,multipleradiation- andtherapy-responsesignatureswereidentifiedaspotential driversinrelapsebiology,whereOPC-likecellsdisplayed upregulation ofIGFBP2,as well as loss ofCDKN2Aexpressionsuggesting a complex SV signature including increasing MYC enhancer mutations among other oncogenes. The plasticity of these tumors, their aggressivnessand the evolution of treatmentresistance through time must be takenintoconsiderationwhenidentifyingtargetsfordrugrepurposing. Conclusion DC vaccination patients showed immunologicallyactivitybutshowedlimitedclinicalbenefit. Atrelapsetherapy-drivenreprogrammingsupportedintegratedimmunogenomicstrategiesandrationalcombinationtherapiesforrecurrentPDHGGs.