Project description:Personalized neoantigen cancer vaccine plus pembrolizumab for newly diagnosed glioblastoma patients treated with standard radio-chemotherapy
Project description:Personalized neoantigen cancer vaccine plus pembrolizumab for newly diagnosed glioblastoma patients treated with standard radio-chemotherapy
Project description:Patients diagnosed with glioblastoma (GBM) with sustained synthesis of the DNA repair enzyme, O6-methyl guanine DNA methytransferase (MGMT), are rendered resistant to Temozolomide (TMZ) chemotherapy. Here, we hypothesized that pretreatment with the proteasome inhibitor Bortezomib (BTZ, Velcade) might sensitize these GBM to TMZ by depleting MGMT.
Project description:Glioblastoma (GBM) is the most common primary brain tumor in adults with a median survival of 11-12 months. Standard therapy consists of radiotherapy (RT) plus chemotherapy with Temozolomide (TMZ), and no alternative treatment is available. We assessed changes in tumor microenvironment (TME) after RT associated with TMZ and metformin (MET) in a syngenic murine GBM model using single-cell RNA-sequencing (scRNA-seq). RT induced an enrichment of GO annotation related with cell cycle, translation and ribosome biogenesis in all tumor clusters, except the radio resistant one where an increase in the inflammatory phenotype was observed. Resident GAM were reduced after RT alone and differentially modulated by RT-drug combinations. After RT alone, we detected an increase in GAM markers and a downregulation of glycolytic metabolism in both microglial and peripheral macrophage subclusters. Association of TMZ increased the pro-inflammatory phenotype of some GAM clusters in comparison to RT. A different signature was observed for the TMZ-MET association but limited to peripheral infiltrating GAM.
Project description:To determine whether gene expression profiles from peripheral whole blood could be used to determine therapeutic outcome in a cohort of children with newly diagnosed polyarticular JIA.
Project description:We report the application of RNA-based sequencing technology for high-throughput profiling of T cell enriched peripheral blood mononuclear cells. By sequencing in total of 12 pairs GBM patient samples, we extracted TCRαβ V(D)J sequences from the deep RNA-seq of T cells isolated from the 24 PBMCs to determine if TTFields treatment affected TCR diversity, using the Simpson’s diversity index (DI), which is the average proportional abundance of TCR clones based on the weighted arithmetic mean. Of the 12 patients, 9 exhibited negative log fold change (logFC) of TCR DI after TTFields, indicating clonal expansion. Notably, in all but 1 patient, the top 200 most abundant clones post TTFields, which accounted for 38.1% to 100% (median 67%) of detectable clones, showed substantial expansion compared to pre-TTFields T cells, and inversely correlated with the DI. Thus, TTFields treatment is associated with adaptive immune activation as evidenced by clonal expansion of peripheral T cells.
