A5007240984- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Neuroblastoma Research and Treatments
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Hematopoietic Stem Cell Transplantation
- Glycosylation and Glycoproteins Research
- Monoclonal and Polyclonal Antibodies Research
- RNA Interference and Gene Delivery
- Virus-based gene therapy research
- IL-33, ST2, and ILC Pathways
- Receptor Mechanisms and Signaling
- Cancer Immunotherapy and Biomarkers
- Chemokine receptors and signaling
- Radiopharmaceutical Chemistry and Applications
- Lung Cancer Research Studies
- Advancements in Semiconductor Devices and Circuit Design
- Nanowire Synthesis and Applications
- Endoplasmic Reticulum Stress and Disease
- Renal and related cancers
- Adrenal Hormones and Disorders
- Antimicrobial Peptides and Activities
- Psoriasis: Treatment and Pathogenesis
- Toxin Mechanisms and Immunotoxins
- Eosinophilic Esophagitis
University College London
2010-2022
Great Ormond Street Hospital
2018-2022
Great Ormond Street Hospital for Children NHS Foundation Trust
2020
King's College London
2012-2013
NIHR Moorfields Biomedical Research Centre
2012
The Royal Free Hospital
2011
Innate lymphoid cells (ILCs) are increasingly appreciated as key regulators of tissue immunity. However, their role in human homeostasis and disease remains to be fully elucidated. Here we characterize the ILCs skin from healthy individuals inflammatory psoriasis. We show that a substantial proportion IL-17A IL-22 producing blood normal psoriasis patients CD3-negative innate lymphocytes. Deep immunophenotyping ILC subsets showed statistically significant increase frequency circulating NKp44+...
Psoriasis is an inflammatory disease of the skin affecting 2–3% population, characterized by a thickening epidermis and immune infiltrates throughout dermis epidermis, causing lesions that can seriously affect quality life. The study psoriasis has historically been hampered lack good animal models. Various genetically induced models exist, which have provided some information about possible mechanisms disease, but these rely mostly on intrinsic imbalances homeostasis. However, mouse model...
Gamma delta T (γδT) lymphocytes are primed for rapid function, including cytotoxicity toward cancer cells, and a component of the immediate stress response. Following activation, they can function as professional antigen-presenting cells. Chimeric antigen receptors (CARs) work by focusing cell on defined surface tumor antigens provide essential costimulation robust activation. Given natural tropism γδT cells microenvironment, we hypothesized that their transduction with CARs might enhance...
Patients with neuroblastoma infused GD2-directed CAR-T cells experienced immune activation and transient tumor regressions without neurotoxicity.
Genome editing of allogeneic T cells can provide "off-the-shelf" alternatives to autologous chimeric antigen receptor (CAR) cell therapies. Disruption α chain (TRAC) prevent graft-versus-host disease (GVHD) and removal CD52 (cluster differentiation 52) for a survival advantage in the presence alemtuzumab have previously been investigated using transcription activator-like effector nuclease (TALEN)-mediated knockout. Here, we deployed next-generation CRISPR-Cas9 linked CAR expression...
The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; “Hu-PBMC mice”) are important tools to study immune function in vivo. recent introduction targeted deletions at the interleukin-2 common gamma chain (IL-2Rγnull), notably NOD-scid IL-2Rγnull...
The majority of circulating human γδT lymphocytes are the Vγ9Vδ2 lineage, and have T-cell receptor (TCR) specificity for nonpeptide phosphoantigens. Previous attempts to stimulate expand these cells therefore focused on stimulation using ligands receptor, whereas relatively little is known about variant blood subsets their potential role in cancer immunotherapy.
Chimeric antigen receptors (CARs) combine T cell activation with antibody-mediated tumor specificity, bypassing the need for receptor (TCR) ligation. A limitation of CAR technology is on-target off-tumor toxicity caused by target expression on normal cells. Using GD2 as a model cancer antigen, we hypothesized that this could be minimized using cells expressing Vγ9Vδ2 TCR, which recognizes transformed in major histocompatibility complex (MHC)-unrestricted manner, combination co-stimulatory...
Abstract Exhaustion of chronically stimulated CD8+ T cells is a significant obstacle to immune control chronic infections or tumors. Although coinhibitory checkpoint blockade with anti–programmed death ligand 1 (PD-L1) Ab can restore functions exhausted cell populations, recovery often incomplete and dependent upon the pool size quiescent T-bethigh subset that expresses lower levels PD-1. In model in which unhelped, HY-specific gradually lose function following transfer male bone marrow...
Allogeneic blood or BM transplantation (BMT) is the most commonly applied form of adoptive cellular therapy for cancer. In this context, ability donor T cells to respond recipient antigens coopted generate graft-versus-tumor (GVT) responses. The major reason treatment failure tumor recurrence, which linked eventual loss functional, host-specific CTLs. study, we have explored role antigen expression by nonhematopoietic in sustain effective CTL immunity. Using clinically relevant models, found...
A key predictor for the success of gene-modified T cell therapies cancer is persistence transferred cells in patient. The propensity less differentiated memory to expand and survive efficiently has therefore made them attractive candidates clinical application. We hypothesized that redirecting specialized niches BM support differentiation would confer increased therapeutic efficacy. show overexpression chemokine receptor CXCR4 CD8+ (TCXCR4) enhanced their migration toward vascular-associated...
Antibodies (Abs) have been engineered into small antigen‐binding fragments and rebuilt multivalent high‐avidity molecules for improving in vivo pharmacokinetics efficacy clinical use. To increase the avidity of a T‐cell receptor‐like single‐domain Ab (sdAb) specific HLA‐A2 complex, we fused sdAb to coiled‐coil peptide derived from human cartilage oligomeric matrix protein (COMP48) make an multimer, termed combody. The combody improved binding significantly, whereas specificity targeted cells...
Gamma delta T lymphocytes (γδT cells) have pleiotropic properties including innate cytotoxicity, which make them attractive effectors for cancer immunotherapy. Combination treatment with zoledronic acid and IL-2 can activate expand the most common subset of blood γδT, express Vγ9Vδ2 cell receptor (TCR) (Vδ2 cells). cells are equipped antibody-dependent cell-mediated cytotoxicity (ADCC) through expression low-affinity FcγR CD16. GD2 is a highly ranked tumor associated antigen immunotherapy...
Adoptive transfer of ex vivo expanded tumor infiltrating lymphocytes (TILs) has led to clinical benefit in some patients with melanoma but not demonstrated convincing efficacy other solid cancers. Whilst the presence TILs many types cancer is often associated better prognosis, their function been systematically evaluated across types. Responses immunological checkpoint inhibitors a wide range cancers, including those for which adoptive shown benefit, clearly delineated number type...
Abstract Background: Treatment of high risk neuroblastoma remains challenging; current multimodal treatment regimens achieve long term survival in <50% patients and are associated with significant morbidity. Ganglioside GD2 is abundantly expressed on almost all neuroblastomas whilst expression normal tissue highly limited, providing a suitable CAR target. Here, we report the preliminary results Phase I clinical study GD2-CART for refractory/relapsed (NCT02761915). Trial design: The...
B7-H3 (CD276) has emerged as a target for cancer immunotherapy by virtue of consistent expression in many malignancies, relative absence from healthy tissues, and an emerging role driver tumor immune inhibition. Recent studies have reported to be suitable chimeric antigen receptor-modified T cell (CAR-T) therapy using CARs constructed established anti-B7-H3 antibodies converted into single-chain Fv format (scFv). We screened binders scFv library generate new CAR-T with favorable properties....
Abstract We have examined how the host environment influences graft-vs-leukemia (GVL) response following transfer of donor T cells to allogeneic chimeras. Donor induce significant GVL when administered in large numbers established mixed chimeras (MC). However, using limiting cells, we found that late MC induced less than did early freshly irradiated recipients. Late cell was associated with marked accumulation anti-host CD8 within spleen, but delayed kinetics differentiation, reduced...