ID #863 Dendritic-cell treated matched primary-relapse PDHGG patient-derived xenograft models to identify TME shift and therapy resistance profiles
Thale Olsen, Nelly Franzén, Srijita Banerjee, Amanda Håkansson, Molly Gustafson, Miao Zhao, Gabriela Rosén, Tobias Bergström, Anders Sundström, Teresita Díaz de Ståhl, Johanna Sandgren, Lars Adamson, Anna Segerman, Brinton Seashore-Kudlow, Wojciech Michno, Nikolas Herold, Jan-Inge Henter, Giuseppe Stragliotto, Chris Jones, Angeliki Stamtsis-Datsi, Rüdiger Sorg, Stefan Holm, Fredrik Swartling, Géraldine GiraudAbstract
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.