4859 results for "*oma"

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• Sequential Antigen-loss and Branching Evolution in Lymphoma after Anti-CD19 and Anti-CD20 Targeted T Cell Engaging Immunotherapy

  CD19 CAR T cells and CD20 targeting T cell engaging bispecific antibodies have been approved in B-cell Non-Hodgkin lymphoma lately, heralding a new clinical setting where patients are treated with both approaches, sequentially. The aim of our study was to investigate the selective pressure of CD19 and CD20 directed therapy on the clonal architecture in lymphoma. Using a broad analytical pipeline, we identified truncating mutations in the gene encoding CD20 conferring antigen loss in 80% of patients relapsing from CD20 bispecs. Pronounced T cell exhaustion was identified in cases with progressive disease and retained CD20 expression. We also confirmed CD19 loss after CAR T cell therapy and report the case of sequential CD19 and CD20 loss. We observed branching evolution with re-emergence of CD20 positive subclones at later time points and spatial heterogeneity for CD20 expression in response to targeted therapy. Our results highlight immunotherapy as an evolutionary bottleneck selecting for antigen-loss variants but also complex evolutionary pathways underlying disease progression from these novel therapies.

  Study EGAS00001007561

• Single-cell RNA-seq of peripheral blood mononuclear cells in classic Hodgkin lymphoma

  Classic Hodgkin lymphoma (cHL) is a largely MHC class I-negative tumor with recurrent 9p24.1/ PD-L1/ PD-L2 copy gains and the highest reported response rates to PD-1 blockade. We utilized scRNA sequencing to characterize the peripheral immune response to PD-1 blockade and more broadly define non-CD8+ dependent mechanisms of immune evasion in cHL. Peripheral blood mononuclear cells were obtained from 20 patients with relapsed/refractory (R/R) cHL treated with PD-1 blockade (nivolumab) on the CheckMate 205 clinical trial (paired samples from cycle 1 day 1 [C1D1] and cycle 4 day 1 [C4D1]), 11 patients with newly diagnosed, previously untreated cHL and 13 healthy donors.

  Study EGAS00001007569

• Exploring the cell-free total RNA transcriptome in diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma patients as biomarker source in blood plasma liquid biopsies

  The goal of this study was to investigate cell-free RNA (cfRNA) biomarkers in DLBCL and PMBCL patients. Blood plasma samples (n=168) and matched diagnostic formalin-fixed paraffin-embedded (FFPE) tissue samples (n=69) of DLBCL patients, PMBCL patients and healthy controls were collected between 2016-2021. Plasma samples were collected at diagnosis, at interim evaluation, after treatment, and in case of refractory or relapsed disease. RNA was extracted from 200 µl plasma using the miRNeasy serum/plasma kit and from FFPE tissue using the miRNeasy FFPE kit. RNA was subsequently sequenced on a NovaSeq 6000 instrument using the SMARTer Stranded Total RNA-seq pico v3 library preparation kit.

  Study EGAS00001007585

• PRADO trial - Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab plus nivolumab in stage III melanoma

  The PRADO trial tested a personalized response-directed treatment approach based on the pathologic response after neoadjuvant ipilimumab plus nivolumab in stage III melanoma patients. In patients achieving a major pathologic response, in their index lymph node (the largest lymph node metastasis at baseline), therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. Patients with partial response underwent TLND only, whereas patients with pathologic non-response underwent TLND and adjuvant systemic therapy ± synchronous radiotherapy. Biomarker analyses based on baseline RNA sequencing data were performed in order to find features that are associated with major pathologic response.

  Study EGAS00001007601

• A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1

  Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. The determination of TM-interconnectivity in individual tumors has been challenging and the impact on patient survival unresolved. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells has been established using a dye uptake methodology, confirmed with recording of cellular calcium epochs and validated with clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, network connectivity correlated with the mesenchymal subtype and dismal patient survival. CHI3L1 has been identified and validated as a robust molecular marker of connectivity with functional relevance. The connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients’ prognosis, and serves as a robust prognostic biomarker.

  Study EGAS00001007611

• NOTCH1 fusion genes in pediatric T-cell lymphoblastic lymphoma hallmark a common high-risk subgroup with blood TARC levels as possible biomarker

  T-cell lymphoblastic lymphoma (T-LBL) is a common pediatric malignancy accounting for approximately 20% of the non-Hodgkin lymphomas during childhood. Survival rates of T-LBL are ~80%, but outcome after relapse is dismal, with salvage rates reaching only ~15. Considering the extremely poor prognosis after relapse and absence of clinically relevant high-risk genetics, there is an urgent need for the identification of molecular risk factors and new prognostic biomarkers in T-LBL, as well as identification of new therapeutic strategies. In this study we present a novel entity of high-risk pediatric T-LBL patients characterized by previously unknown NOTCH1 gene fusions and highly elevated blood TARC levels

  Study EGAS00001007703

• Myeloid-specific KDM6B inhibition sensitizes Glioblastoma to PD1 blockade

  Glioblastoma (GBM) tumors are enriched in immune-suppressive myeloid cells and are refractory to immune checkpoint therapy (ICT). Targeting epigenetic pathways to reprogram the functional phenotype of immune-suppressive myeloid cells to overcome resistance to ICT remains unexplored. Single-cell and spatial transcriptomic analyses of human GBM tumors demonstrated high expression of an epigenetic enzyme - histone 3 lysine 27 demethylase (KDM6B) in intra-tumoral immune-suppressive myeloid cell subsets. Importantly, myeloid-cell specific Kdm6b deletion enhanced pro-inflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies elucidated that the absence of Kdm6b enhances antigen-presentation, interferon response and phagocytosis in myeloid cells by inhibiting mediators of immune suppression including Mafb, Socs3 and Sirpa. Further, pharmacological inhibition of KDM6B mirrored the functional phenotype of Kdm6b deleted myeloid cells and enhanced anti-PD1 efficacy. Thus, this study identified KDM6B as an epigenetic regulator of the functional phenotype of myeloid cell subsets and a potential therapeutic target to improve response to ICT.

  Study EGAS00001007002

• Genomic and transcriptomic landscape of T-cell lymphoblastic lymphoma compared to T-cell acute lymphoblastic leukemia: similar subtypes and different fusions

  Due to the lower incidence of T-LBL and difficulties in obtaining diagnostic T-LBL material, extensive research on T-LBL has been hampered whereas genetic aberrations in T-ALL are thoroughly characterized. Given the similarities and differences between T-LBL and T-ALL, the question has been raised whether T-LBL and T-ALL represent two different diseases or different manifestations of the same disease. This study aims to identify the genomic and transcriptomic landscape of T-LBL and compare the findings to what is found T-ALL. Comparison of the molecular aberrations between T-LBL and T-ALL can provide insights into the overlap and differences in malignant development between the two entities, which could lead to improved risk stratification in T-LBL in order to eventually adapt T-LBL treatment protocols based on molecular-genetic prognostic factors.

  Study EGAS00001007767

• Pharmacogenomic Analysis Reveals New Therapeutic Options for Pleural Mesothelioma

  Background: Pleural mesothelioma (PM) urgently requires novel effective treatments. Drug repurposing is a relevant strategy to discover new therapeutic options among well-known drugs used in clinical practice. This study aimed to identify new therapies in the context of molecular heterogeneity of PM. Methods: We performed a multi-omics study of the largest cohort of patient-derived primary PM cell lines (n=58) to date, using whole exome sequencing, RNA sequencing and methylome analysis. We also conducted a large-scale drug screening of over 1300 compounds on a subset of cell lines (n=11), as well as an extension screen (n=48) for selected drugs of interest. The best candidates were validated using 3D culture and mouse models. Results: We demonstrated that the molecular landscape of the cell lines cohort recapitulates the main findings in tumours and revealed new specific features of PM. The large-scale drug screening and subsequent validations highlighted notably strong sensitivity to entinostat and fluvastatin. Importantly, both compounds displayed same efficacy in 2D and 3D culture models and single treatment prolonged survival in vivo similarly or even better than standard chemotherapy. Strikingly, combining entinostat treatment with anti-PD1 led to cures in some mice and immunized them against tumour cells. Conclusions: Among several candidates, we identified entinostat, notably in combination with immune checkpoint inhibitor, and to a lesser extent fluvastatin, as promising therapeutic options for patients. We believe our study provides a valuable resource that could contribute to advances in the field and warrants further clinical investigation.

  Study EGAS00001007866

• MethylationEPIC BeadChip samples of pre- and post-5ZA-treated head and neck cancer patients refractory to anto-PD-1 therapy

  Background Immune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with head and neck squamous cell carcinoma (HNSCC); however, most patients are refractory. Methods In a non-randomized, open-label phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC were treated with low-dose 5’azacytidine (5’aza) daily for either 5- or 10-days in combination with fixed doses of durvalumab and tremelimumab after progression on ICB therapy. The primary objective was to assess the biologically effective dose of 5’aza as determined by molecular changes in paired baseline and on-treatment tumor biopsies; the secondary objective was safety. Results Thirty-eight percent (3/8) of participants with evaluable paired tissue samples had a greater than 2-fold increase from baseline in interferon-gamma (IFN-ɣ) signature and CD274 (programmed cell death protein 1 ligand, PD-L1) expression within the tumor microenvironment (TME), which was associated with increased CD8+ T cell infiltration and decreased infiltration of CD4+ T regulatory cells. The mean neutrophil-to-lymphocyte ratio (NLR) decreased by greater than 50%, from 14.2 (SD 22.6) to 6.9 (SD 5.2). Median overall survival (OS) was 16.3 months (95% CI 1.9, NA) and 2-year OS rate was 24.7% (95% CI: 4.5%, 53.2%) with 58% (7/12) of treated participants demonstrated prolonged OS of greater than 12 months. Conclusion Our findings suggest that low-dose 5’aza can reprogram systemic host immune responses and the local TME to increase IFN-ɣ and PD-L1 expression. The increased expression of these established biomarkers correlated with prolonged OS upon re-challenge with ICB.

  Study EGAS00001007998