A5075336471- Cancer Immunotherapy and Biomarkers
- Immune cells in cancer
- Histone Deacetylase Inhibitors Research
- Neuroscience and Neuropharmacology Research
- Cytokine Signaling Pathways and Interactions
- Melanoma and MAPK Pathways
- Monoclonal and Polyclonal Antibodies Research
- interferon and immune responses
- Synthesis and biological activity
- Radiopharmaceutical Chemistry and Applications
- Memory and Neural Mechanisms
- Cancer Research and Treatments
- Schizophrenia research and treatment
- Pancreatic and Hepatic Oncology Research
- Functional Brain Connectivity Studies
- Epilepsy research and treatment
- Immunotherapy and Immune Responses
- Ion channel regulation and function
- Cancer Cells and Metastasis
- Systemic Lupus Erythematosus Research
- Cancer Mechanisms and Therapy
- Macrophage Migration Inhibitory Factor
- S100 Proteins and Annexins
- HER2/EGFR in Cancer Research
- Inflammatory Biomarkers in Disease Prognosis
Novartis (United States)
2021-2025
Novartis Institutes for BioMedical Research
2024
Novartis (Switzerland)
2023-2024
Boston Biomedical Research Institute
2023
Royal College of Physicians and Surgeons of Canada
2017
University of Alberta
2017
Merck & Co., Inc., Rahway, NJ, USA (United States)
2012-2013
Health Sciences Centre
2013
Biogen (United States)
2003-2011
McGill University
1998-2010
The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective and MAP-ERK (MEK) inhibitors have shown clinical efficacy patients with melanoma. However, majority responses are transient, resistance is often associated pathway reactivation extracellular signal-regulated (ERK) signaling Here, we describe identification characterization SCH772984, a novel selective inhibitor ERK1/2 that...
Abstract Purpose: This phase I study assessed the safety, pharmacokinetics (PKs), and efficacy of MIW815 (ADU-S100), a novel synthetic cyclic dinucleotide that activates stimulator IFN genes (STING) pathway, in patients with advanced/metastatic cancers. Patients Methods: (n = 47) received weekly i.t. injections MIW815, 50 to 6,400 μg, on 3-weeks-on/1-week-off schedule. Results: A maximum tolerated dose was not reached. Most common treatment-related adverse events were pyrexia (17%), chills,...
Abstract Despite the increasing interest in targeting stromal elements of tumor microenvironment, we still face tremendous challenges developing adequate therapeutics to modify landscape. A major obstacle this is our poor understanding phenotypic and functional heterogeneity cells tumors. Herein, perform an unbiased interrogation mesenchymal cells, delineating co-existence distinct subsets cancer-associated fibroblasts (CAFs) microenvironment murine carcinomas, each endowed with unique...
Abstract Purpose: The stimulator of IFN genes (STING) is a transmembrane protein that plays role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed safety and tolerability plus spartalizumab (PDR001), humanized IgG4 antibody against PD-1, 106 patients with advanced solid tumors or lymphomas. Patients Methods: were treated weekly intratumoral...
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated cancer characterized by a poor prognosis and high level of lymphocyte infiltrate. Genetic hallmarks NPC are not completely known but include deletion the p16 (CDKN2A) locus mutations in NF-κB pathway components, with relatively low total mutational load. To better understand genetic landscape, integrated genomic analysis was performed using large clinical cohort treatment-naïve tumor specimens. This generally concordant...
Immune-stimulator antibody conjugates (ISAC) combining tumor-targeting monoclonal antibodies with immunostimulatory agents allow targeted delivery of immune activators into tumors. NJH395 is a novel, first-in-class ISAC comprising Toll-like receptor 7 (TLR7) agonist conjugated to an anti-HER2 via noncleavable linker payload. Preclinical characterization showed ISAC-mediated activation myeloid cells in the presence antigen-expressing cancer cells, antigen targeting and TLR7 agonism...
BAFF (B cell activating factor of the TNF family, also known as BlyS and TALL-1), a family cytokine critical for development function B cells, has been reported to bind three receptors, BCMA maturation protein), TACI (transmembrane activator CAML [calcium-modulator cyclophilin ligand] interactor), BAFFR (BAFF receptor), but with widely conflicting values affinity selectivity binding. additionally APRIL (a proliferation-inducing ligand), ligand most homologous BAFF. Using soluble, monomeric...
T cell–dependent reprogramming of intratumoral macrophages by cIAP1/2 inhibition leads to control MHC class I–negative pancreatic cancer in mice.
Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development characterization of sabatolimab.Sabatolimab was tested for binding to its target TIM-3 blocking properties. The functional effects sabatolimab were in killing myeloid cell cytokine assays. Antibody-mediated phagocytosis (ADCP) by also assessed.Sabatolimab shown (i) enhance inflammatory production dendritic cells...
Abstract High levels of IL1β can result in chronic inflammation, which turn promote tumor growth and metastasis. Inhibition could therefore be a promising therapeutic option the treatment cancer. Here, effects blockade induced by mAbs canakinumab gevokizumab were evaluated alone or combination with docetaxel, anti–programmed cell death protein 1 (anti–PD-1), anti-VEGFα, anti-TGFβ syngeneic humanized mouse models cancers different origin. Canakinumab did not show notable efficacy as...
Abstract Objective To determine whether receptors for B lymphocyte stimulator (BLyS) are altered on cells of patients with systemic lupus erythematosus (SLE). Methods Total available BLyS were measured by analysis binding recombinant soluble to peripheral blood in 36 SLE patients, 29 healthy controls, and 10 disease controls. Antibodies the BAFF‐R, BCMA, TACI used define expression individual subsets blood, spleen, tonsils. Two different antibodies which differentially sensitive BAFF‐R...
Background NIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-β). This first-in-human study investigated plus spartalizumab treatment in patients with advanced solid tumors. Methods Patients received (0.3–1 mg/kg every 3 weeks (Q3W)) monotherapy; following evaluation of two dose levels, escalation continued (NIS793 0.3–30 Q3W and 300 mg or 20–30 2 [Q2W] 400 4 (Q4W)). In expansion, non-small cell lung cancer (NSCLC) resistant prior anti-programmed...
Abstract Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Herein, we report clinical and translational results from a phase Ib trial testing whether IL1β blockade pancreatic cancer would alleviate myeloid immunosuppression reveal antitumor T-cell responses to PD1 blockade. Patients with treatment-naïve advanced ductal adenocarcinoma (n = 10) were treated canakinumab, high-affinity monoclonal...
BAFF is considered a therapeutic target because dysregulated production of can induce systemic lupus erythematosus-like phenotype in mice, and elevated levels are associated with disease severity erythematosus rheumatoid arthritis patients. Fc fusion decoy receptors, BCMA-Fc BAFF-R-Fc, candidates for blocking BAFF. While studying their interactions BAFF, we found that BAFF-R-Fc more effective than binding to its receptors. We also trimeric bind one but only BCMA-Fc. Moreover, show that,...
Chronic (18 h) exposure of cultured hippocampal slices to the type-A GABA receptor blocker, bicuculline methiodide (BMI) 10 micro m increased levels connexin 43 (Cx43) and 32 (Cx32) mRNAs, but not 26 36, as demonstrated by RNase protection assays. The Cx43 Cx32 proteins in membrane fractions detected western blotting were also significantly increased. Immunoblotting indicated that BMI promoted a significant expression transcription protein c-fos. rate fluorescence recovery after...
Despite exhibiting oncogenic events, patient's leukemia cells are responsive and dependent on signals from their malignant bone marrow (BM) microenvironment, which modulate survival, cell cycle progression, trafficking resistance to chemotherapy. Identification of the signaling pathways mediating this leukemia/microenvironment interplay is critical for development novel molecular targeted therapies. We observed that primary B-cell precursors aberrantly express receptors BAFF-system, BAFF-R,...
Abstract Purpose: Preclinical studies have shown that interleukin (IL)-1β blockade can modulate the tumor microenvironment (TME) to activate antitumor immunity and, in combination with immune checkpoint inhibitors (ICIs), prevent cancer growth. Our study investigates if biomarkers TME impact outcomes patients non–small cell lung (NSCLC) treated IL-1β inhibitor canakinumab plus an ICI-based therapy and describes effects on TMEs of these patients. Methods: Exploratory analyses were conducted...