A5084250997- HIV Research and Treatment
- Immune Cell Function and Interaction
- CAR-T cell therapy research
- Virus-based gene therapy research
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Circadian rhythm and melatonin
- Nanowire Synthesis and Applications
- Occupational and environmental lung diseases
- CRISPR and Genetic Engineering
- Protease and Inhibitor Mechanisms
- Cytomegalovirus and herpesvirus research
- RNA Interference and Gene Delivery
- Viral Infectious Diseases and Gene Expression in Insects
- Blood Coagulation and Thrombosis Mechanisms
- Peptidase Inhibition and Analysis
- Cancer Research and Treatments
- HIV/AIDS Research and Interventions
- Hematopoietic Stem Cell Transplantation
- Animal Virus Infections Studies
- Pleural and Pulmonary Diseases
- HIV/AIDS drug development and treatment
- Dietary Effects on Health
- Autophagy in Disease and Therapy
- Asthma and respiratory diseases
Royal College of Surgeons in Ireland
2018-2025
Weatherford College
2024
Trinity College Dublin
2013-2020
GlaxoSmithKline (United Kingdom)
2017-2018
University of Pennsylvania
2002-2013
Cancer Research Institute
2002-2011
Cancer Research Institute of the Slovak Academy of Sciences
2002-2011
UPMC Hillman Cancer Center
2004-2011
Philadelphia University
2006
Brigham and Women's Hospital
2006
Persistence of T cells engineered with chimeric antigen receptors (CARs) has been a major barrier to use these for molecularly targeted adoptive immunotherapy. To address this issue, we created series CARs that contain the cell receptor-ζ (TCR-ζ) signal transduction domain CD28 and/or CD137 (4-1BB) intracellular domains in tandem. After short-term expansion, primary human were subjected lentiviral gene transfer, resulting large numbers >85% CAR expression. In an immunodeficient mouse...
Mesothelin is a cell-surface molecule over-expressed on large fraction of carcinomas, and thus an attractive target immunotherapy. A molecularly targeted therapy for these cancers was created by engineering T cells to express chimeric receptor with high affinity human mesothelin. Lentiviral vectors were used single-chain variable fragment that binds mesothelin fused signaling domains derived from T-cell zeta, CD28, CD137 (4–1BB). When stimulated mesothelin, lentivirally transduced induced...
Abstract Active suppression by T regulatory cells plays an important role in the down-regulation of cell responses to foreign and self-Ags. Thus far, potential CD4+CD25+ human tumors has not been reported. In this work we show that lung contain large numbers these they have constitutive high-level expression CD152 (CTLA-4). Furthermore, mediate potent inhibition autologous proliferation. Finally, from patient failed inhibit proliferation allogeneic cells. Together results suggest found...
Redirecting T lymphocyte antigen specificity by gene transfer can provide large numbers of tumor-reactive lymphocytes for adoptive immunotherapy. However, safety concerns associated with viral vector production have limited clinical application cells expressing chimeric receptors (CAR). be modified RNA electroporation without integration-associated concerns. To establish a safe platform immunotherapy, we first optimized the backbone in vitro transcription to achieve high-level transgene...
A variety of innate immune responses and functions are dependent on time day, many inflammatory conditions associated with dysfunctional molecular clocks within cells. However, the functional importance these has yet to be fully characterized. NRF2 plays a critical role in system, limiting inflammation via reactive oxygen species (ROS) suppression direct repression proinflammatory cytokines, IL-1β IL-6. Here we reveal that core clock protein, BMAL1, controls mRNA expression Nrf2 E-box...
Abstract Macrophages undergo metabolic changes during activation that are coupled to functional responses. The gram negative bacterial product lipopolysaccharide (LPS) is especially potent at driving reprogramming, enhancing glycolysis and altering the Krebs cycle. Here we describe a role for citrate-derived metabolite malonyl-CoA in effect of LPS macrophages. Malonylation wide variety proteins occurs response LPS. We focused on one these, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In...
To facilitate the therapeutic application of antigen-presenting cells (APCs), we have developed a cell-based artificial APC (aAPC) system by engineering K562 with lentiviruses to direct stable expression and secretion variety co-stimulatory molecules cytokines. Here report use combinatorial lentiviral gene transfer approach achieve long-term at least seven genes in parental cell line. Expression various combinations on aAPC enables precise determination human T-cell activation requirements,...
The inducible costimulator ICOS is critical for the differentiation and expansion of human T H 17 cells promotes antitumor capacity these cells.
Because stimulation of CD4 + lymphocytes leads to activation human immunodeficiency virus-type 1 (HIV-1) replication, viral spread, and cell death, adoptive T therapy has not been possible. When antigen CD28 receptors on cultured cells were stimulated by monoclonal antibodies (mAbs) CD3 that had immobilized, there was an increase in the number polyclonal from HIV-infected donors. Activated predominantly secreted cytokines associated with helper type function. The HIV-1 load declined absence...
Cytotoxic T lymphocytes (CTLs) modified with chimeric antigen receptors (CARs) for adoptive immunotherapy of hematologic malignancies are effective in preclinical models and being tested several clinical trials. Although CTLs bearing stably expressed CARs generated by integrating viral vectors efficacious have potential long-term persistence, this mechanism CAR expression can potentially result significant toxicity. cells were electroporated an optimized vitro transcribed RNA encoding a...
Activation of CD4 + T lymphocytes from human immunodeficiency virus–type 1 (HIV-1)–infected donors with immobilized antibodies to CD3 and CD28 induces a virus-resistant state. This effect is specific for macrophage-tropic HIV-1. Transcripts encoding CXCR4/Fusin, the fusion cofactor used by cell line–tropic isolates, were abundant in CD3/CD28-stimulated cells, but transcripts CCR5, viruses, not detectable. Thus, CD3/CD28 costimulation an HIV-1–resistant phenotype similar that seen some highly...
Abstract The costimulatory requirements required for peripheral blood T regulatory cells (Tregs) are unclear. Using cell-based artificial APCs we found that CD28 but not ICOS, OX40, 4-1BB, CD27, or CD40 ligand costimulation maintained high levels of Foxp3 expression and in vitro suppressive function. Only the presence rapamycin consistently generated Tregs suppressed xenogeneic graft-vs-host disease immunodeficient mice. Restimulation after 8–12 days culture with resulted >1000-fold...
Abstract Purpose: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-β gene transfer using an adenoviral vector (Ad.IFN-β) in patients with malignant pleural mesothelioma (MPM) metastatic effusions (MPE). Experimental Design: Ad.IFN-β was administered through indwelling catheter doses ranging from 9 × 1011 to 3 1012 viral particles (vp) two cohorts MPM (7 patients) MPE (3 patients). Subjects were for (a) toxicity, (b) transfer, (c)...
Highlights•Parkin activation can result in mitophagy or apoptosis•Bcl-2 family proteins regulate Parkin-dependent apoptosis•Parkin and PINK1 promote Mcl-1 degradation•Parkin sensitizes toward apoptosis response to mitochondrial impairmentSummaryMitochondrial depolarization promotes Parkin- PTEN-induced kinase 1 (PINK1)-dependent polyubiquitination of multiple on outer membranes, resulting the removal defective mitochondria via mitophagy. Because Parkin mutations occur Parkinson's disease, a...
We previously showed that a single intrapleural dose of an adenoviral vector expressing interferon-β (Ad.IFN-β) in patients with malignant pleural mesothelioma (MPM) or effusions (MPE) resulted gene transfer, humoral antitumor immune responses, and anecdotal clinical responses manifested by modified Response Evaluation Criteria Solid Tumors (RECIST) disease stability 3 10 at 2 months additional patient significant metabolic response on positron emission tomography (PET) imaging. This phase I...
Since HIV requires CD4 and a co-receptor, most commonly C-C chemokine receptor 5 (CCR5), for cellular entry, targeting CCR5 expression is an attractive approach therapy of infection. Treatment CD4+ T cells with zinc-finger protein nucleases (ZFNs) specifically disrupting coding sequences induces resistance to infection in vitro vivo. A chimeric Ad5/F35 adenoviral vector encoding CCR5-ZFNs permitted efficient delivery transient following anti-CD3/anti-CD28 costimulation lymphocytes. We...
Abstract Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E 2 (PGE ) inhibits caspase-11-dependent pyroptosis murine human macrophages. PGE suppreses expression macrophages the airways of mice with allergic inflammation. Remarkably, caspase-11-deficient are strongly resistant to developing experimental airway inflammation, where is known be protective. Expression elevated lung wild type Blocking production...
Abstract Dendritic cells play a key role in processing and presenting antigens to naïve T prime adaptive immunity. Circadian rhythms are known regulate many aspects of immunity; however, the circadian dendritic cell function is still unclear. Here, we show greater responses when mice immunised middle their rest versus active phase. We find rhythm antigen that correlates with both mitochondrial morphology metabolism, dependent on molecular clock gene, Bmal1 . Using Mdivi-1, compound promotes...