5246 results for "*oma"

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• Phase 1/2 Study of the Indoleamine 2,3-Dioxygenase 1 Inhibitor Linrodostat Mesylate Combined With Nivolumab or Nivolumab and Ipilimumab in Advanced Solid Tumors or Hematologic Malignancies

  Purpose: To evaluate the safety, efficacy, pharmacokinetics, pharmacodynamics, and biomarker data of linrodostat mesylate, a selective, oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, combined with nivolumab ± ipilimumab in advanced solid tumors and hematologic malignancies. Patients and Methods: In this phase 1/2 study, patients received once-daily (QD) linrodostat (part 1 [escalation], 25-400 mg; part 2 [expansion], 100 or 200 mg) plus nivolumab (480 mg every [Q] 4 weeks [W] or 240 mg Q2W) or triplet therapy (part 3, linrodostat 20-100 mg QD; nivolumab 360 mg Q3W or 480 mg Q4W; ipilimumab 1 mg/kg Q6W or Q8W). Endpoints included safety and efficacy (co-primary; parts 2, 3), pharmacokinetics, pharmacodynamics, biomarkers, and efficacy (part 1). Results: Fifty-five, 494, and 41 patients were enrolled in parts 1, 2, and 3, respectively. Linrodostat exposures exceeded predicted therapeutic target concentrations starting at 50 mg. Rates of grade 3/4 adverse events were 50.1%-63.4%. The maximum tolerated linrodostat dose was 200 mg; dose-limiting toxicities were primarily immune related. Responses were observed across different cohorts, study parts, and tumor types, particularly in immunotherapy-naive patients. Kynurenine decreased with linrodostat + nivolumab, regardless of response. In contrast, interferon gamma (IFN-γ) gene expression signature was associated with response; in nonmelanoma patients, a composite of low tryptophan 2,3-dioxygenase (TDO2) gene expression plus high IFN-γ signature was associated with response. Conclusions: Linrodostat + nivolumab ± ipilimumab demonstrated a manageable safety profile. Kynurenine changes supported IDO1 pathway inhibition but did not correlate with response. A composite biomarker of low TDO2 expression plus high IFN-γ gene expression may predict response to linrodostat + nivolumab.

  Study EGAS50000000710

• Epstein-Barr Virus status drives morphological and molecular intra-tumour heterogeneity in gastric cancer: insights from a case report and literature review

  This case report describes a rare case of bi-phenotypic gastric cancer with two distinct, but clonally related, histological components. The first component, associated with Epstein-Barr virus (EBV) infection, exhibited the morphological features of gastric carcinoma with lymphoid stroma, suggesting that EBV, as an effective immunogenic factor, may trigger a prominent immune response within the tumour microenvironment. The second component, which was EBV-negative, displayed tubular/papillary morphology and features of increased biological aggressiveness, such as high-grade areas and lymphatic invasion. Immunohistochemical and molecular studies confirmed that, despite the differing morphologies and immunophenotypes, both components were clonally related, with especially the EBV-negative area showing more complex DNA aberrations, reminiscent of Chromosomally instable (CIN) lesions. This case describes clonally related EBV-positive and negative components within a single gastric cancer, contributing to a better understanding of EBV role in tumour heterogeneity and progression and highlighting the impact of EBV loss on tumour behaviour.

  Study EGAS50000000706

• Bladder cancer subtyping study across 4 atezo clinical trials

  Checkpoint inhibitors targeting the PD-1/PD-L1 interaction have revolutionized cancer therapy across many indications. In urothelial carcinoma (UC), several PD-1/PD-L1 inhibitors have been approved for treatment in localized and metastatic disease. While these agents provide durable clinical benefit in a number of patients, the majority do not respond. A better understanding of the molecular mechanisms underlying response and resistance is needed to tailor existing treatments and develop new therapeutics in UC. We profiled tumors from 2803 patients from four late-stage randomized clinical trials evaluating the PD-L1 inhibitor atezolizumab in metastatic UC and muscle-invasive bladder cancer by RNA-seq, a targeted DNA panel, immunohistochemistry, and digital pathology. A machine learning algorithm identified four UC transcriptional subtypes, representing luminal desert, stromal, immune, and basal tumors. Overall survival benefit from atezolizumab over standard-of-care was observed in immune and basal tumors (45% of patients). Digital pathology showed enrichment of human interpretable features in specific molecular subtypes, and a self-supervised approach could classify molecular subtypes from H&E slides with high accuracy, suggesting that machine-based image interpretation could accelerate tumor molecular profiling. Somatic alterations showed limited capacity to identify responders. Finally, mechanisms of benefit with PD-L1 blockade appeared different in immune and basal tumors, with immune tumors benefiting from B/plasma cell enrichment, while basal tumors benefited from granulocyte enrichment. This study represents the largest integration of UC molecular and curated clinical data in randomized clinical trials to date, paving the way for prospective clinical studies tailoring treatment regimens to specific tumor molecular subtypes in UC and other indications.

  Study EGAS50000000497

• MET amplification in gastric cancer

  Targeting MET in gastric and gastroesophageal junction adenocarcinoma (GC) with monoclonal antibodies or tyrosine kinase inhibitors has had limited success. We hypothesize that other prognostic and response determining genetic alterations explain the poor outcome and lack of response to MET-targeted therapies.

  Study EGAS50000000744

• The genetic footprint of the European Roma diaspora: Evidence from the Balkans to the Iberian Peninsula

  Our genomic approach focuses on: (i) the internal genetic structure of Roma and its correlation with geography; (ii) the relationships between Iberian Roma and other non-Roma populations to explore possible contacts during the period of population upheaval following the Roma’s arrival on the Iberian Peninsula; (iii) estimation of the admixture events in the Iberian Roma before and after their arrival to the Iberian Peninsula; and (iv) the assessment of endogamy patterns and assortative mating of the European Roma. Our study provides a detailed analysis of the intricate population history of the Iberian Roma, offering insights from both micro-geographical and large-scale perspectives on the population history of European Roma.

  Study EGAS50000000746

• Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: CheckMate 649 biomarker analyses

  First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) versus chemotherapy for advanced gastroesophageal adenocarcinoma (CheckMate 649). Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein Bar Virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T-cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma.

  Study EGAS50000000747

• Development of a fully human glioblastoma-in-brain-spheroid model for accelerated translational research

  In glioblastoma (GBM) the intricate interplay between tumor cells and the surrounding microenvironment plays a crucial role in tumor progression, invasion, and therapeutic resistance. So far, studying these interactions in a controlled and representative model system has been challenging. Here, we report the development of hGliCS, a human glioma-cortical spheroid model that allows the elucidation of the biology of GBM cells and their interactions with a human-specific brain-like microenvironment and neurons. GBM cells efficiently invade the cortical spheroids, forming a well-connected network of communicating cells. The heterogeneous cellular states of the GBM cells within this model closely resembled findings previously observed in glioblastoma patients and in mouse xenografts. We observed a transition from predominantly mesenchymal-like cells to heterotopic states with a high diversity. In contrast to the substantial changes observed in the tumor cell population, the impact of the GBM cells on the neurons was minimal. We further demonstrate the suitability of hGliCS to test compounds targeting tumor-specific neurobiological features.

  Study EGAS50000000757

• Djerroudi et al., E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular carcinoma

  Invasive lobular breast carcinoma (ILC) shows specific stromal features, T lymphocyte infiltration (TIL) being associated with poor prognosis. Here, we reveal the involved mechanism by performing single cell RNA sequencing, combined immunohistochemistry, deconvolution of bulk RNA sequencing from large retrospective ILC series, and functional assays using primary cells. We show that ILC accumulate FAP+ inflammatory cancer-associated fibroblasts (iCAF) through a previously undescribed mechanism mediated by E-cadherin/CDH1 on CAF plasticity. Indeed, CDH1 inactivation in ILC cancer cells prevents differentiation of iCAF into myofibroblastic CAF (myCAF), leading to iCAF accumulation. In turn, iCAF increase TIL infiltration and shape their spatial organization in ILC. Subsequently, CDH1-inactivated ILC cancer cells promote immune escape by lack of retention and activation of ITGAE-expressing resident memory CD8+ T lymphocytes (TRM). Hence, our study uncovers reciprocal interactions between CDH1-inactivated cancer cells, iCAF and CD8+ TRM, revealing why and how TILs have a poor prognosis in ILC patients, a mechanism extrapolated to other CDH1-mutated cancer types.

  Study EGAS50000000761

• Analysis of T cells in follicular lymphoma

  This study aimed to identify new heterogeneities in human T cells of follicular lymphoma. To do so, we performed scRNA-seq of human lymph node and follicular lymphoma samples. We identified minor T cell subsets expanding in follicular lymphoma.

  Study EGAS50000000778

• Genomic Profiling of an anti-PD-L1 treated cohort of Newly Diagnosed GBM patients

  Checkpoint inhibitor therapy has limited efficacy in the outcomes of patients with glioblastoma (GBM). This study involves whole exome sequencing of newly diagnosed glioblastoma patients treated with concurrent atezolizumab, radiation therapy, and temozolomide. By analyzing 29 tumor-normal pairs, the study aims to explore the correlation between tumor genomics and the efficacy of PD-L1 blockade treatment outcomes and further identify which patients may benefit more from such therapy.

  Study EGAS50000000783

• Transcriptomic Profiling of an Anti-PD-L1 Treated Cohort of Newly Diagnosed GBM Patients

  Checkpoint inhibitor therapy has limited efficacy in glioblastoma patient outcomes. This study involves RNA sequencing (RNA-seq) of newly diagnosed GBM patients treated with concurrent atezolizumab, radiation therapy, and temozolomide. By analyzing RNA-seq data from 39 tumors, the study aims to explore tumor transcriptomic features, including immune-based transcriptomic programs and immune infiltration, to understand their influence on PD-L1 blockade treatment efficacy and to identify which patients may benefit more from such therapy.

  Study EGAS50000000784

• Single-cell Analysis of Neoplastic Plasma Cells Identifies Novel Myeloma Pathobiology Mediators and Potential Targets

  Newly diagnosed symptomatic and relapsed/refractory myeloma is a clonal plasma cell (PC) dyscrasia that arises from precursors which have been studied utilizing bulk or single-cell (sc) techniques. By combining scRNA-sequencing with scB-cell receptor (BCR)-sequencing, we found more dysregulated genes in monoclonal PCs compared with analyses of the entire CD138+ population, which includes non-neoplastic/polyclonal PCs. Paired tumor and non-tumor WGS was performed to evaluate the presence of IgH-associated translocations and hyperdiploidy events, initially detected by FISH, in a subset of samples included in this study.

  Study EGAS50000000801

• Genomic analysis of head and neck squamous cell carcinoma upon acquired resistance to cetuximab

  Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab) remain the only FDA-approved targeted therapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Unfortunately, most patients develop acquired resistance to cetuximab and there is currently no further therapeutic option for these patients (unmet clinical need), thereby highlighting the need to better understand resistance-causing mechanisms. Here, we carried out whole-exome sequencing on 2 cetuximab-sensitive and -resistant patient-derived xenograft models of HNSCC. Our data reveal several genetic alterations (mutations and copy number variations) associated with acquired resistance to anti-EGFR therapy.

  Study EGAS50000000800

• Blood-based monitoring of relapsed/refractory cHL patients predict responses to PD-1 blockade treatment

  Hodgkin lymphoma (cHL) patients are uniquely susceptible to treatment with programmed cell death-1 (PD-1) treatment. However, monitoring with FDG-PET/CT, the current response detection standard, is challenging. Here, we address the potential applicability of tissue biomarkers and blood-based biomarkers in PD-1 treated cHL patients. We evaluated 9p24.1/PD-L1/PD-L2 alterations, and expression of PD-L1 and antigen presentation molecules (HLA class I/II) in 9 tissue biopsies of 4 patients. In addition, we assessed circulating tumor DNA (ctDNA), extracellular vesicle associated miRNAs (EV-miRNAs), soluble PD-L1 and serum TARC (sTARC) in 26 longitudinal blood samples of these patients during PD-1 treatment. We found that the predictive power of tissue biomarkers is dependent on the timing of the biopsy . The dynamics of blood-based biomarkers: sTARC, EV-miRNAs and ctDNA corresponded well immunotherapy treatment response. Therefore, blood-based biomarkers are promising monitoring strategies in PD-1 treated cHL patients and should be further explored in clinical trials or observational studies.

  Study EGAS00001005894

• Diagnostic Genomic Analysis is Prognostic in AYA ALL Patients Treated on a MRD-Stratified Paediatric Protocol

  Background: Over the last decade, next generation sequencing has enabled classification of multiple new recurrent genomic drivers of acute lymphoblastic leukemia (ALL). We provide a comprehensive genomic survey of adolescent and young adult (AYA) patients treated on the Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study. ALL06 clinical trial described the efficacy and tolerability of AYA ALL patients aged 15-39 years treated on a single minimal residual disease (MRD)-stratified platform. In this study we have taken the ALL06 cohort and retrospectively performed comprehensive genomic analyses assessing response of AYA patients with various genomic subtypes treated with a paediatric approach. Methods: Genomic risk classification of B- and T-ALL patients (n=57) enrolled to the study was based on mRNA-Sequencing, MLPA, immunophenotyping and cytogenetics. Results: Using this approach, 36/40 (90%) B- and 13/17 (76.5%) T-ALL patients were classified according to genomic risk. We have linked outcome data with each patient’s genomic risk and found a strong correlation between adverse genomic risk and MRD at the end of consolidation, translating to inferior overall and relapse free survival. Patients with adverse risk genomics who achieved negative MRD status had improved responses compared to those with persistent MRD. Patients with standard risk genomics had excellent responses regardless of their MRD status. Conclusion: Our data argue strongly for incorporation of a genomic risk classification into future ALL treatment paradigms at the time of diagnosis.

  Study EGAS50000000752

• Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing

  High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls. This confirms enrichment for nearly all previously identified genes. Additionally, one-hundred-and-eleven HGSOC tumours from variant carriers were sequenced alongside other complementary studies, seeking evidence of biallelic inactivation as supportive evidence. PALB2 and ATM validate as HGSOC predisposition genes, with 6/8 germline carrier tumours exhibiting biallelic inactivation accompanied by characteristic mutational signatures. Among candidate genes, only LLGL2 consistently shows biallelic inactivation and protein expression loss, supporting it as a novel HGSOC susceptibility gene. The remaining candidate genes fail to validate. Integrating case-control analyses with tumour sequencing is thus crucial for accurate gene discovery in familial cancer studies.

  Study EGAS50000000770

• A Phase Ib/II Study of Regorafenib and Paclitaxel in Beyond First-line Advanced Esophagogastric Carcinoma (REPEAT)

  Regorafenib showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in advanced esophagogastric cancer (EGC) patients refractory to first-line treatment and explore potential biomarkers.. We performed enzyme-linked immunosorbent assay measurements of galectin-1, RNA sequencing, and shallow wholegenome sequencing of metastatic tumor biopsies for biomarker analyses.

  Study EGAS00001006054

• Tumor-reactive heterotypic CD8 T cell clusters from clinical samples

  Emerging evidence suggests a correlation between CD8+ T cell-tumor cell proximity and anti-tumor immune response. However, it remains unknown whether these cells exist as functional clusters that can be isolated from clinical samples. By conventional and imaging flow cytometry, we show here that from 21/21 human melanoma metastases, we could isolate heterotypic clusters, comprising CD8+ T cells interacting with one or more tumor cells and/or antigen-presenting cells (APCs). Single-cell RNA-sequencing revealed that T cells from clusters were enriched for gene signatures associated with tumor reactivity and exhaustion. Clustered T cells exhibited increased TCR clonality indicative of expansion, while TCR-matched T cells showed more exhaustion and co-modulation when conjugated to APCs than to tumor cells. T cells that were expanded from clusters ex vivo exerted on average 9-fold increased killing activity towards autologous melanomas, which was accompanied by enhanced cytokine production. Upon adoptive cell transfer into mice, T cells from clusters showed improved patient-derived melanoma control, which was associated with increased T cell infiltration and activation. Together, these results demonstrate that tumor-reactive CD8+ T cells are enriched in functional clusters with tumor cells and/or APCs and that they can be isolated and expanded from clinical samples. Typically excluded by single cell gating in flow cytometry, these distinct heterotypic T cell clusters serve as a valuable source to decipher functional tumor-immune cell interactions, while they may also be therapeutically explored.

  Study EGAS50000000785

• Single-cell Analysis of Neoplastic Plasma Cells Identifies Novel Myeloma Pathobiology Mediators and Potential Targets

  Newly diagnosed symptomatic and relapsed/refractory myeloma is a clonal plasma cell (PC) dyscrasia that arises from precursors which have been studied utilizing bulk or single-cell (sc) techniques. By combining scRNA-sequencing with scB-cell receptor (BCR)-sequencing, we found more dysregulated genes in monoclonal PCs compared with analyses of the entire CD138+ population, which includes non-neoplastic/polyclonal PCs. We identified a panel of genes that were over- or under-expressed in symptomatic states that could be putative oncogenic drivers or tumor suppressors, respectively.

  Study EGAS50000000803

• Measles oncolytic virus as an immunotherapy for recurrent/refractory pediatric medulloblastoma and atypical teratoid rhabdoid tumor

  Pediatric recurrent medulloblastoma (MB) and atypical teratoid rhabdoid tumor (ATRT) are largely incurable and warrant novel therapies. We investigated a) the safety of a measles virus variant, MV-NIS, in a pediatric phase 1 study and b) the mechanisms of MV-NIS and potential benefit of combination with immune checkpoint inhibition (ICI). Pediatric patients with recurrent MB or ATRT were treated with intratumoral injections for local recurrence or via lumbar puncture for disseminated recurrence. We evaluated local immune responses to MV-NIS with and without ICI via single-cell and bulk RNA sequencing in an intracranial, immunocompetent, syngeneic murine model. MV-NIS given intratumorally or via repeat intrathecal dosing was safe. MV-NIS prolonged survival in murine models but did not demonstrate additive benefit with ICI. No changes in tumor-infiltrating immune-cell composition or activation were observed in response to MV-NIS treatment; however, MV-NIS induced local expression of neutralizing antibodies, complement cascade, and phagocytosis-related genes.

  Study EGAS50000000811

• Integrative analysis reveals a macrophage-predominant, immunosuppressive immune microenvironment and subtype-specific therapeutic vulnerabilities in advanced salivary gland cancer

  Background Salivary gland cancers (SGC) are rare and heterogeneous malignant tumors. Advanced SGC lack established treatment options and show poor response to immunotherapy. Here, an integrative multi-omics analysis in a large cohort of advanced SGC revealed insights into the tumor immune microenvironment (TIM) and distinct mechanisms of immune evasion. Methods A total of 104 patients with recurrent/metastatic SGC from the DKTK MASTER program were included in this study. Whole-exome or whole-genome sequencing and RNA-sequencing was performed on fresh frozen tumor tissue. The tumor immune microenvironment was analyzed using CIBERSORT deconvolution analysis and immune gene expression scores in bulk RNA-sequencing data. Single-nuclei sequencing and immunohistochemistry analyses were performed in selected samples. Results were validated in bulk RNA-sequencing data of a previously published independent dataset. Results Bulk transcriptome analysis revealed an immune-deserted TIM in the majority of advanced SGC samples. Immune exclusion was most prominent in adenoid cystic carcinoma (ACC) subgroup 1 exhibiting a downregulation of the antigen processing machinery. Only a small subset of advanced SGC, including few adenoid cystic carcinoma, exhibited T-cell inflammation, which was correlated with tumor mutational burden in Non-ACC samples. Subtype specific expression of immune checkpoints as well as cancer testis antigens were identified with prominent expression of VTCN1 in luminal cells within ACC. Single-cell RNA-sequencing and bulk RNA-seq deconvolution analysis validated immune cell exclusion and revealed a TIM that was dominated by M2 macrophages across SGC subtypes. Among evaluable patients treated with immune checkpoint inhibitors, a high T-cell to macrophage ratio was associated with clinical benefit. Conclusions These data support biomarker-based development of immune-checkpoint inhibition and the development of novel immune-checkpoint inhibitors and cellular therapies in SGC.

  Study EGAS50000000809

• Whole Exome Sequencing of a Lung Adenocarcinoma Patient Across Three Time Points

  A 65-year-old female patient with a significant smoking history (40 pack-years) was first diagnosed with lung adenocarcinoma (LUAD) in the left lung in May 2020 (L1-T1). One year later, in May 2021, the patient progressed with a new LUAD in the right lung (L1-T2) and in May 2024, another LUAD emerged in the right lung (L1-T3). Whole Exome Sequencing (WES) analysis was conducted on three tumor biopsies obtained at different time points from the same patient to investigate clonal trajectories.

  Study EGAS50000000812

• Single Cell RNA Transcriptomics of Mantle Cell Lymphoma Reveals the Presence of Treatment-Resistant Subclones at the Time of Diagnosis

  Mantle cell lymphoma is a chronically relapsing B cell neoplasm characterized by clonal heterogeneity. We implemented single cell RNA sequencing of paired tumor samples from four patients with an aggressive nodal MCL at diagnosis and after failure of standard immunochemotherapy. Clustering the cells based on the inferred CNVs showed small subclones present at diagnosis with a CNV profile similar to the major subclone at relapse. Comparison of these subclones to major subclones present at diagnosis revealed 119 upregulated pathways common for the four patient with an aggressive MCL, including NF-kappaB and PTEN signaling pathways. Additionally, we sequenced a patient with an indolent to blastoid MCL transformation with intestinal tissue involvement. In contrast to other compartments at relapse, the cells in the intestine showed strikingly different CNV profile and presence of new driver mutations including NOTCH1. In conclusion, our study demonstrates that scRNAseq can potentially detect therapy resistant subclones at diagnosis.

  Study EGAS50000000825

• Tumor-resident T-cell regulate responses to checkpoint blockade immunotherapies

  In cancer models, CD103+CD8 TRM cells are implicated in the response to anti-PD-1 immunotherapy, and a subset of CD4 TRM cells expressing the integrin CD49a is required for response to anti-CTLA-4 immunotherapy. We performed single-cell RNA sequencing on tumour-infiltrating T lymphocytes (TILs) isolated from colon carcinoma et unsupervised analyses reveal several TRM populations.

  Study EGAS50000000826

• Molecular biomarkers for stratification periheral T cell lymphoma

  Peripheral T cell lymphoma (PTCL) is a diverse group of rare lymphoid malignancies with overall poor prognosis. Diverse biological mchanisms behind these diverse disease groups make targeted treatment challenging. Based on molecular biomarkers, more , the aim is to characterise more specific features for the different clinically defined PTCL for new future prognostic therapies.

  Study EGAS00001006691