A5018589623- CAR-T cell therapy research
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Virus-based gene therapy research
- Cancer Mechanisms and Therapy
- Myasthenia Gravis and Thymoma
- Influenza Virus Research Studies
- Inflammatory Myopathies and Dermatomyositis
- NF-κB Signaling Pathways
- Muscle Physiology and Disorders
- Nanowire Synthesis and Applications
- Dermatology and Skin Diseases
- Peptidase Inhibition and Analysis
- Synthesis and Biological Evaluation
- Biosimilars and Bioanalytical Methods
- PI3K/AKT/mTOR signaling in cancer
- Metabolism, Diabetes, and Cancer
- Respiratory viral infections research
- Cancer Genomics and Diagnostics
- Signaling Pathways in Disease
- Cutaneous lymphoproliferative disorders research
- Monoclonal and Polyclonal Antibodies Research
- Sarcoma Diagnosis and Treatment
Adaptimmune (United Kingdom)
2016-2019
Memorial Sloan Kettering Cancer Center
2019
Princess Margaret Cancer Centre
2019
Dana-Farber Cancer Institute
2019
City Of Hope National Medical Center
2019
City of Hope
2019
Cornell University
2019
Merck & Co., Inc., Rahway, NJ, USA (United States)
2015
Albert Einstein College of Medicine
2012-2014
National Institute of Allergy and Infectious Diseases
2014
The forkhead family protein FOXP3 acts as a repressor of transcription and is both an essential sufficient regulator the development function regulatory T cells. molecular mechanism by which FOXP3-mediated transcriptional repression occurs remains unclear. Here, we report that involves histone acetyltransferase-deacetylase complex includes acetyltransferase TIP60 (Tat-interactive protein, 60 kDa) class II deacetylases HDAC7 HDAC9. N-terminal 106-190 aa are required for TIP60-FOXP3,...
We evaluated the safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) recognizing HLA-A2-restricted NY-ESO-1/LAGE1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred 50% (6/12) were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T present postinfusion all persisted for at least 6 months responders. Most infused exhibited effector...
Abstract Muscle-specific tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disease that causes life-threatening muscle weakness due to anti-MuSK autoantibodies disrupt neuromuscular junction signaling. To avoid chronic immunosuppression from current therapies, we engineered T cells express a MuSK chimeric autoantibody receptor with CD137-CD3ζ signaling domains (MuSK-CAART) for precision targeting of B expressing autoantibodies. MuSK-CAART demonstrated similar efficacy as anti-CD19...
Abstract Addition of rapamycin to cultures expanding natural CD4+CD25+Foxp3+ T regulatory cells (Tregs) helps maintain their suppressive activity, but the underlying mechanism is unclear. Pim 2 a serine/threonine kinase that can confer resistance. Unexpectedly, pim was found be constitutively expressed in freshly isolated, resting Tregs, not CD4+CD25− effector cells. Introduction Foxp3, Foxp3Δ2, into induced expression and conferred preferential expansion presence rapamycin, indicating Foxp3...
Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified expansion and changes within tumor microenvironment (TME) following infusion remain unclear. These studies address immunological mechanisms of response...
Chimeric antigen receptor (CAR) T cells targeting CD19+ B have demonstrated efficacy in refractory systemic lupus erythematosus (SLE). Although initial clinical data suggest that anti-CD19 CAR cell therapy is well tolerated and highly effective, the immunologic consequences of SLE patients remain unclear. We profiled serum six prior to 3 months following infusion. Three post infusion, inflammatory cytokines IL-6 TNFα decreased patient sera. This was accompanied by elevations IL-7 BAFF....
Abstract Regulatory T cells (Tregs) play a critical role in maintaining immune tolerance and preventing autoimmune disease. Tregs express the transcription factor Foxp3, which acts as master regulator of their differentiation controls capacity to suppress cell responses. have an intrinsically anergic phenotype do not produce IL-2 or proliferate upon stimulation ex vivo. Recent studies identified that Helios, member Ikaros family factors, is expressed Tregs. However, its specific function...
CD4(+)CD25(+)Foxp3(+) Tregs have a diminished capacity to activate the PI3K/Akt pathway. Although blunted Akt activity is necessary maintain Treg function, consequences of this altered signaling are unclear. Glut1 cell-surface receptor responsible for facilitating glucose transport across plasma membranes, whose expression tightly coupled costimulatory signals and phosphorylation. Freshly isolated human were unable up-regulate in response TCR compared with Tconv. Consequently, ability use...
Abstract In this study, we demonstrate that malignant mature CD4+ T lymphocytes derived from cutaneous cell lymphomas (CTCL) variably display some aspects of the regulatory phenotype. Whereas seven lines representing a spectrum primary lymphoproliferative disorders expressed CD25 and TGF-β, expression FOXP3 and, to lesser degree, IL-10 was restricted two CTCL are dependent on exogeneous IL-2. IL-2, IL-15, IL-21, all which signals through receptors containing common γ chain, induced in...
Abstract Thymic-derived CD4+CD25+Foxp3+ T regulatory cells (Tregs) have a diminished capacity to activate the PI3K/Akt pathway. Although blunted Akt activity is necessary maintain Treg suppressive function, other consequences of decreased signaling are unclear. Glucose transporter 1 (Glut1) cell surface receptor responsible for facilitating glucose transport across plasma membranes and expression Glut1 tightly coupled co-stimulatory signals phosphorylation. Freshly isolated human Tregs were...
Abstract Pembrolizumab (MK-3475), a humanized monoclonal IgG4 antibody against programmed death receptor 1 (PD-1), is currently being studied in clinical trials across more than 30 types of cancers. To further support the development pembrolizumab and to aid mechanistic understanding anti-PD-1 immunotherapy, we generated surrogate PD-1-blocking (muDX400). We have used muDX400 determine antitumor activity, pharmacokinetics, pharmacodynamics PD-1 inhibition multiple preclinical syngeneic tumor...
Addition of rapamycin to cultures expanding T regulatory cells helps maintain their suppressive activity, but the mechanism behind this observation is unclear. Human pim 2, similar murine a serine/threonine kinase that can confer resistance. Unexpectedly, 2 was found be constitutively expressed in freshly isolated, resting not CD4 effector cells, explaining why addition prior cell activation favors expansion. Introduction FoxP3, FoxP3Ä2, into induced expression and conferred preferential...
Abstract Background: NY-ESO-1c259T-cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 (SPEAR T-cells) are being studied in ongoing multi-cohort clinical trial synovial sarcoma (NCT01343043). We compared safety, efficacy and cell persistence between two cohorts using different doses of lymphodepleting chemotherapy. Methods: There four separated by differing antigen expression levels lymphodepletion regimens, this assessment compares 1 (closed) 4 (ongoing). In both, ≥50%...