A5036760632- Cancer Immunotherapy and Biomarkers
- Ferroptosis and cancer prognosis
- Bladder and Urothelial Cancer Treatments
- Lung Cancer Diagnosis and Treatment
- Systemic Sclerosis and Related Diseases
- Lung Cancer Treatments and Mutations
- Immune cells in cancer
- Cancer-related molecular mechanisms research
- Immune Cell Function and Interaction
- CAR-T cell therapy research
- IL-33, ST2, and ILC Pathways
- MicroRNA in disease regulation
- Autoimmune Bullous Skin Diseases
- Radiomics and Machine Learning in Medical Imaging
- RNA Interference and Gene Delivery
- Asthma and respiratory diseases
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Esophageal Cancer Research and Treatment
- Cancer, Hypoxia, and Metabolism
- Systemic Lupus Erythematosus Research
- Cancer Treatment and Pharmacology
- Clusterin in disease pathology
- Eosinophilic Disorders and Syndromes
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
AstraZeneca (United States)
2021-2022
AstraZeneca (Brazil)
2020
Abstract Purpose: To identify a predictive biomarker for durvalumab, an anti–programmed death ligand 1 (PD-L1) mAb. Experimental Design: RNA sequencing of 97 advanced-stage non–small cell lung carcinoma (NSCLC) biopsies from nonrandomized phase Ib/II clinical trial (1108/NCT01693562) were profiled to signature; 62 locally advanced or metastatic urothelial cancer tumors the same study confirm utility signature. Thirty NSCLC patients provided pre- and posttreatment messenger (mRNA) analysis....
Innate lymphoid cells recirculate through peripheral lymph nodes and contribute to early IFN-γ production after immunization.
Myeloid-derived suppressor cells (MDSCs) are major negative regulators of immune responses in cancer and chronic infections. It remains unclear if regulation MDSC activity different conditions is controlled by similar mechanisms. We compared MDSCs mice with lymphocytic choriomeningitis virus (LCMV) infection. Chronic LCMV infection caused the development monocytic (M-MDSCs) but did not induce polymorphonuclear (PMN-MDSCs). In contrast, both populations were present models. An acquisition...
Production of pathogenic autoantibodies by self-reactive plasma cells (PCs) is a hallmark autoimmune diseases. We undertook this study to investigate the prevalence PCs and their relationship known pathways increase our understanding role in disease progression treatment response.We developed sensitive gene expression-based method overcome challenges measuring using flow cytometry. Whole-genome microarray analysis sorted cellular fractions identified panel genes, IGHA1, IGJ, IGKC, IGKV4-1,...
B cells impact the progression of systemic sclerosis (SSc; scleroderma) through multiple pathogenic mechanisms. CD19 inhibition in mice reduced skin thickness, collagen production, and autoantibody levels, consistent with expression on plasma (PCs), source antibody production. PC depletion could effectively reduce deposition inflammation SSc; therefore, we investigated effects SSc disease activity.A gene signature was evaluated biopsy samples 2 phase I clinical trials. We assessed microarray...
Lung fibrosis is an unabated wound healing response characterized by the loss and aberrant function of lung epithelial cells. Herein, we report that extracellular Clusterin promoted cell apoptosis whereas intracellular maintained epithelium viability during repair. Unlike normal COPD lungs, IPF lungs were significantly increased inverse was evident for Clusterin. In vitro in vivo studies demonstrated while intercellular modulated expression DNA repair proteins, MSH2, MSH6, OGG1 BRCA1. The...
3036 Background: Biomarkers may help to identify non-small cell lung cancer (NSCLC) patients (pts) more likely have improved outcomes anti-PD-L1 therapy. From 112 durvalumab (D)-treated pts, we previously reported that high pretreatment levels of PD-L1 protein and IFNγ mRNA expression in tumor biopsies were associated with higher objective response rates. We extend this analysis mature survival outcome data includes additional available pts; addition, examined changes gene from on-treatment...
The heterogeneous clinical phenotypes of chronic obstructive pulmonary disease (COPD) challenge successful drug development. To identify COPD subgroups beyond phenotypes, we interrogated blood immune cell profiles and ex-vivo responses current former smokers, with or without COPD, in the longitudinal Genetic Epidemiology study (COPDGene) cohort. CD4+ CD8+ T cells monocytes were profiled by flow cytometry. Microarray analysis was performed on RNA from aforementioned isolated cells. T-cell...
3037 Background: PD-L1 can be induced by IFNG in tumor cells (TC) and immune (IC). TC expression prevalence UC is low the relevance of scoring (in addition to IC) not fully understood. We recently reported a positive correlation between high levels an IFNGS outcome cohort 30 pts treated with D. Here, we assessed potential predictive value additional 32 (total N = 62) further explored relationship and/or IC IHC patterns. Methods: Study CP1108 was phase 1/2 trial evaluating D solid tumors; 191...
Abstract Durvalumab (D) is a human IgG1 monoclonal antibody which inhibits PDL1 binding to PD-1 and CD80, restoring antitumor immunity. In D-treated (tx) NSCLC patients (pts), we previously reported high baseline levels of tumoral PD-L1 protein IFNγ mRNA expression associated with improved ORRs, PFS OS. Here, gene signature tumors associates outcomes on D. CP1108/NCT01693562 was nonrandomized phase 1/2 trial evaluating D in advanced tx or other solid tumors. By 29APR2016, 304 pts received 10...
Abstract Delta-like ligand 4 (DLL4)-Notch signaling regulates several key stages of angiogenesis. MEDI0639 is a human IgG1 antibody that blocks the binding DLL4 to Notch receptor and being developed as potential anticancer therapy for patients with solid tumors. Cynomolgus monkeys were selected pharmacologically relevant species toxicologic evaluations MEDI0639. The results these studies showed dose-dependent MEDI0639-related serious adverse effects associated possible gastrointestinal...
4087 Background: Study 22, a phase 2 clinical study (NCT02519348) evaluating T (anti-CTLA-4) and D (anti-PD-L1) as monotherapies in combination indicated the best efficacy-safety profile with novel regimen containing single, priming dose of (T300+D). Additionally, an expansion proliferative CD8+ lymphocytes at Day 15 was observed T300+D that associated improved response. Here, exploratory molecular analysis peripheral blood cell receptors is presented. Methods: Immune-checkpoint...
<h3>Background</h3> MEDI1191 is an investigational therapy composed of mRNA encoding bioactive interleukin-12 (IL-12p70) in a lipid nanoparticle optimized for intratumoral injection. We hypothesized that injection will reprogram the immunosuppressed tumor microenvironment (TME) and increase cytotoxic T-cell recruitment, proliferation activation. <h3>Methods</h3> In ongoing phase 1 dose escalation study (NCT03946800), patients with C/SC lesions received 0.1-12µg sequentially (Part 1A) or...
The rapid development of immune checkpoint blockade (ICB) therapies has revolutionized the cancer treatment landscape and brightened long-term forecast for many patients. However, specific genomic proteomic changes in tumors treated with different ICB treatments have yet to be fully characterized. We four non-small-cell lung carcinoma (NSCLC) tumor digests ex vivo anti-PD-L1 antibody durvalumab (D) alone or combination anti-CTLA-4 tremelimumab (T) explore gene protein expression associated...
<h3>Background</h3> Production of pathogenic autoantibodies by self-reactive plasma cells (PC) is a hallmark autoimmune diseases; thus, PC levels could be associated with efficacy B-cell depleting therapies. Additionally, investigating the prevalence in disease and their relationship known pathways may increase our understanding role progression treatment response. <h3>Objectives</h3> Flow cytometry methods that are commonly used to enumerate describe difficult implement routinely clinic...
<b>RATIONALE:</b> We sought biomarkers to identify asthma patients (pts) likely benefit from tralokinumab, an anti–IL-13 IgG4 monoclonal antibody. <b>METHODS:</b> Airway epithelial cells grown in air-liquid interface cultures were stimulated with cytokines with/without dexamethasone for 24 hrs. Bronchial brushings matched BAL and serum samples collected healthy volunteers (N=20) pts on ICS/LABA (N=68) or ICS/LABA+OCS (N=22). Serum DPP-4 was assessed a new immunoassay (Abbott Diagnostics)....
<h3>Background</h3> Systemic sclerosis (SSc) is characterized by excessive extracellular matrix (ECM) deposition in the skin, as well autoantibody production, release of various cytokines, and T-cell activation. Several lines evidence indicate a potential role for B cells pathogenesis SSc through effects on activation, fibrosis, among others. Accordingly, targeting could effectively reduce ECM inflammatory background this disease. <h3>Objectives</h3> In animal models SSc, decreased B-cell...
<p>Supplemental Figure S2. Association of IFNγ+ signature with ORR at higher cutoffs in NSCLC and UC patients.</p>
<p>Supplemental Material</p>
<p>Supplemental Figure S4. Association of IFNγ mRNA signature status and survival in patients with TCGA UC (BLCA), NSCLC adenocarcinoma (LUAD), squamous (LUSC).</p>
<p>Supplemental Figure S3. Association of IFNγ+ signature with OS and PFS at higher cutoffs in NSCLC (A) UC (B) patients.</p>
<p>Supplemental Figure S4. Association of IFNγ mRNA signature status and survival in patients with TCGA UC (BLCA), NSCLC adenocarcinoma (LUAD), squamous (LUSC).</p>
<p>Supplemental Material</p>