Summary The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knockdown starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion.

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s iv7NEURO-ONCOLOGY • JUNE 2017 intratumoral immunogenic cell death through infusion of Newcastle Disease Virus (NDV) together with local application of modulated electrohyperthermia (mEHT) and injections of autologous mature monocyte-derived dendritic cells (DCs) loaded with NDV/mEHT-induced serum-derived antigenic microparticles + NDV. Treatment is provided on individual basis. Data were retrospectively collected. 28 DIPG children with median age 6.9y (range 3-19y) were treated with immunotherapy, 18 of them as part of primary treatment (DIPGprim) and 10 at time of progressive disease after first line treatment (DIPGprog). 14/18 DIPGprim children had a Lansky score >70. At start of immunotherapy, 36% of patients had deficient IFN-g expression in the CD4+ T cells. Diminished NK function was observed in 64%. The treatment was feasible without major toxicity. We detected the increase of GBM antigen cross-reacting IFN-g-producing T cells in those patients that could be immunomonitored. Median PFS was 8.26m. Rescue after progression was mainly re-irradiation. Median OS is still undefined with a median follow up of 10.26m (range 4.3-19m). 18m OS is estimated as 55% (asymmetrical 95%CI: +27.39, -39.9). Median OS of the 10 DIPGprog children calculated from last event prior to immunotherapy was 5.55m. These clinical experiences support the concept that immunotherapy can be considered as part of multimodal treatment for patients with DIPG at an early stage of their disease. Its effect is primarily located at an improvement of long-term OS. This read-out, together with the individualized treatment approach, makes the scientific steps towards evidence-based efficacy demonstration very challenging.