A5063252921- Immunodeficiency and Autoimmune Disorders
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- CAR-T cell therapy research
- Viral Infections and Immunology Research
- Blood disorders and treatments
- Lymphoma Diagnosis and Treatment
- Advanced Biosensing Techniques and Applications
- Cell Adhesion Molecules Research
- Blood groups and transfusion
- Cytomegalovirus and herpesvirus research
- Biosimilars and Bioanalytical Methods
- T-cell and B-cell Immunology
- Cancer-related molecular mechanisms research
- Hematopoietic Stem Cell Transplantation
- RNA modifications and cancer
- Mesenchymal stem cell research
- Nanowire Synthesis and Applications
- Nanofabrication and Lithography Techniques
- RNA and protein synthesis mechanisms
- Virus-based gene therapy research
- Viral Infectious Diseases and Gene Expression in Insects
- Cancer, Hypoxia, and Metabolism
Roche (Switzerland)
2020-2024
University of Basel
2021-2022
Polytechnique Montréal
2018
T cell engagers represent a novel promising class of cancer-immunotherapies redirecting cells to tumor and have some outcomes in the clinic. These molecules can be associated with mode-of-action related risk cytokine release syndrome (CRS) patients. CRS is characterized by rapid pro-inflammatory cytokines such as TNF-α, IFN-γ, IL-6 IL-1β immune activation eliciting clinical symptoms fever, hypoxia hypotension. In this work, we investigated biological mechanisms triggering amplifying after...
T cell engaging therapies, like chimeric antigen receptor cells and bispecific antibodies (TCBs), efficiently redirect towards tumor cells, facilitating the formation of a cytotoxic synapse resulting in subsequent killing, process that is accompanied by release cytokines. Despite their promising efficacy clinic, treatment with TCBs associated risk cytokine syndrome (CRS). The aim this study was to identify small molecules able mitigate while retaining cell-mediated killing.By screening...
Target-dependent TCB activity can result in the strong and systemic release of cytokines that may develop into cytokine syndrome (CRS), highlighting need to understand prevent this complex clinical syndrome.We explored cellular molecular players involved TCB-mediated by single-cell RNA-sequencing whole blood treated with CD20-TCB together bulk endothelial cells exposed TCB-induced release. We used vitro assay an vivo DLBCL model immunocompetent humanized mice assess effects dexamethasone,...
T cell engagers are bispecific antibodies recognizing, with one moiety, the CD3ε chain of receptor and, other specific tumor surface antigens. Crosslinking CD3 upon simultaneous binding to antigens triggers activation, proliferation and cytokine release, leading killing. Treatment can be associated safety liabilities due on-target on-tumor, off-tumor cytotoxic activity release syndrome (CRS). Tyrosine kinases such as SRC, LCK or ZAP70 involved in downstream signaling pathways after...
Because of their unique ability to modulate the immune system, mesenchymal stromal cells (MSCs) are widely studied develop cell therapies for detrimental and inflammatory disorders. However, controlling final phenotype determining immunosuppressive function following amplification in vitro often requires prolonged culture assays, all which contribute major bottlenecks, limiting clinical emergence therapies. For instance, multipotent Wharton's Jelly stem/stromal (WJMSC), extracted from human...
<h3>Background</h3> T cell bispecific antibodies (TCBs) are extremely potent engagers, harboring a 2+1 format with one binder to the CD3ε chain and two binders specific tumor antigens. Crosslinking of CD3 antigens triggers activation, proliferation cytokine release, leading killing.<sup>1 2</sup> TCB treatment is sometimes associated safety liabilities due on-target on-tumor, off-tumor cytotoxic activity release. Patients treated TCBs may experience Cytokine Release Syndrome (CRS),...
<h3>Background</h3> Cytokine Release Syndrome (CRS) is one of the main safety concerns associated with on-target activity T cell Bispecific antibodies (TCBs). While dexamethasone widely used for CRS mitigation, its effects on TCB controversial when at high clinical doses. This highlights need to explore synergy and Tyrosine Kinase Inhibitors (TKIs) lower dose needed reduce cytokine release retain anti tumor efficacy<sup>1–4</sup> (figure 1). <h3>Methods</h3> We first explored cellular...
<p>Supplementary Figure S9. Single cell RNA-sequencing of whole blood treated with 0.2 μg/mL CD20-TCB was performed using the BD Rhapsody platform</p>
<p>Supplementary Figure S8. Single cell RNA-sequencing of whole blood treated with 0.2 μg/mL CD20-TCB was performed using the BD Rhapsody platform.</p>
<p>Supplementary Figure S7. Overview of average expression and fraction positives per cell type, timepoint treatment condition for cytokines that are differentially expressed in neutrophils, monocytes, pDC, cDC, B cells, CD4+ T CD8+ MAIT cells and/or NK vs. control any timepoint. The untreated corresponds to the pooled baseline samples incubation samples. Mean n= 4 donors (baseline, 20 hrs) n=2 (2 hrs, hrs 6 hrs).</p>
<p>Supplementary Methods</p>
<p>Supplementary Figure S12. Individual tumor growth curves for each treatment group. OCI-Ly18 (DLBCL)-bearing humanized NSG mice were pre-treated with 30 mg/kg Gazyva (Gpt, grey arrow) and treated weekly escalating doses of CD20-TCB (0.5 mg/kg, 1 2 red arrows). Adalimumab (25 orange arrow, TNF-α blockade) tocilizumab (10 green IL-6R given day hour before the first infusion. Dexamethasone (1 blue was prior therapy. Anakinra purple IL-1R NLRP3 inhibitor (20 light administered before, 4...
<p>Supplementary Figure S1. Levels of cytokines were measured by Luminex in serum from whole blood assay with CD20-TCB. 1 donor.</p>
<p>Supplementary Figure S13. A. 3D in vitro experimental setup. Human PBMCs and SU-DHL-8 tumor cells were co-cultured a ratio of 5:1 treated with 0.01 nM CD20-TCB the presence or absence 5 μg/mL adalimumab for 24 hrs. Supernatant from co-cultures was transferred to bottom channel Mimetas OrganoPlate®. derived same donor as co-cultures, are fluorescently labeled seeded upper OrganoPlate®, where endothelial tubules have been previously formed. OrganoPlate® then imaged Operetta System...
<p>Supplementary Figure S3. Identification of an interacting B and T cells cluster by scRNA sequencing human whole blood treated with 0.2 μg/mL CD20-TCB using the BD Rhapsody platform.</p>
<p>Supplementary Figure S2. Proportions of T cells, monocytes and neutrophils in human whole blood after treatment with 0.2 μg/mL CD20-TCB</p>
<p>Supplementary Figure S10. Single cell RNA-sequencing of whole blood treated with 0.2 μg/mL CD20-TCB was performed using the BD Rhapsody platform</p>
<p>Supplementary Figure S11. Single cell RNA-sequencing of whole blood treated with 0.2 μg/mL CD20-TCB was performed using the BD Rhapsody platform. A. UMAP plots neutrophils colored by treatment. B. showing IL-1β (IL1B), IL-1Ra (IL1RN), IL-6 (IL6), IP-10 (CXCL10), IL-8 (CXCL8), TNF-α (TNF), MCP-1 (CCL2), MIP-1α (CCL3), MIP-1β (CCL4) gene expression within neutrophil clusters identified above. C. Violin kinetics distribution in neutrophils. The cytokine and receptor genes are listed on...
<p>Supplementary Figure S5. Overview of GO Biological process pathways found enriched in A. CD4+ T cells (6 hrs), B. CD8+ C. monocytes hrs) and D. neutrophils (4 after treatment with 0.2 μg/mL CD20-TCB.</p>