A5089356328- Immunotherapy and Immune Responses
- RNA Interference and Gene Delivery
- Peptidase Inhibition and Analysis
- Cancer Immunotherapy and Biomarkers
- CAR-T cell therapy research
- vaccines and immunoinformatics approaches
- Cancer Research and Treatments
- Glycosylation and Glycoproteins Research
- Monoclonal and Polyclonal Antibodies Research
- T-cell and B-cell Immunology
- Immune cells in cancer
- Immune Cell Function and Interaction
- Virus-based gene therapy research
- Rheumatoid Arthritis Research and Therapies
- SARS-CoV-2 and COVID-19 Research
- RNA regulation and disease
- Immune Response and Inflammation
- Autophagy in Disease and Therapy
- Antimicrobial Peptides and Activities
- Endoplasmic Reticulum Stress and Disease
- Glioma Diagnosis and Treatment
- Immunodeficiency and Autoimmune Disorders
- Silk-based biomaterials and applications
- Renal and related cancers
- Retinoids in leukemia and cellular processes
University of Nottingham
2012-2024
Science Oxford
2024
Nottingham City Hospital
2016-2019
Nottingham Trent University
2019
Physical-based gene delivery via biolistic methods (such as the Helios gun) involve precipitation of nucleic acids onto microparticles and direct transfection through cell membranes exposed tissue (e.g. skin) by high velocity acceleration. The glycosaminoglycan (GAG)-binding enhanced transduction (GET) system exploits novel fusion peptides consisting cell-binding, acid condensing, cell-penetrating domains, which enable across multiple types. In this study, we combined chemical physical (gene...
Abstract Stressful conditions in the harsh tumor microenvironment induce autophagy cancer cells as a mechanism to promote their survival. However, also causes post-translational modification of proteins that are recognized by immune system. In particular, modified self-antigens can trigger CD4+ T-cell responses might be exploited boost antitumor defenses. this study, we investigated ability CD4 target tumor-specific citrullination, which converts arginine residues citrulline. Focusing on...
Stress-induced post-translational modifications occur during autophagy and can result in generation of new epitopes immune recognition. One such modification is the conversion arginine to citrulline by peptidylarginine deiminase enzymes.We used Human leukocyte antigen (HLA) transgenic mouse models assess immunogenicity citrullinated peptide vaccine cytokine Enzyme linked immunosorbant spot (ELISpot) assay. Vaccine efficacy was assessed tumor therapy studies using HLA-matched B16 melanoma ID8...
A DNA vaccine, SCIB1, incorporating two CD8 and CD4 epitopes from TRP-2/gp100 was evaluated in patients with metastatic melanoma. Each patient received SCIB1 via intramuscular injection electroporation. The trial designed to find the safest dose of which induced immune/clinical responses or without tumour. Fifteen tumor doses 0.4-8 mg whilst 20 fully-resected 2–8 doses. Twelve elected continue immunization every 3 months for up 39 months. dose-dependent T cell 88% no serious adverse effects...
Checkpoint blockade has demonstrated promising antitumor responses in approximately 10–40% of patients. However, the majority patients do not make a productive immune response to their tumors and respond checkpoint blockade. These may benefit from an effective vaccine that stimulates high-avidity T cell combination with We have previously shown incorporating TRP-2 gp100 epitopes into CDR regions human IgG1 DNA (ImmunoBody®: IB) results significant tumor regression both animal models This...
Targeting post-translationally modified epitopes may provide a new strategy for generating tumor specific immune responses. Citrullination is the post-translational modification of arginine to citrulline catalyzed by peptidylarginine deaminase (PAD) enzymes. Presentation citrullinated peptides on MHC-II has been associated with autophagy. Tumors upregulate autophagy and present in response stresses including nutrient deprivation, oxygen redox stress DNA damage, making them good targets...
A cell needs to maintain a balance between biosynthesis and degradation of cellular components homeostasis. There are 2 pathways, the proteasome, which degrades short-lived proteins, autophagy/lysosomal pathway, long-lived proteins organelles. Both these pathways also involved in antigen presentation or effective delivery peptides MHC molecules for T cells. Autophagy (macroautophagy) is key player providing substantial sources citrullinated loading onto MHC-II stimulate CD4+ responses....
Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these intracranial relatively low toxicity and tumor specificity. Here we show that SCIB1, TRP-2 gp100 directed ImmunoBody® DNA vaccine, generates strong specific immune response, as demonstrated by the high number of TRP2-specific IFNγ spots produced detection pentamer positive T cells in spleen vaccinated mice. Furthermore,...
High avidity cytotoxic T lymphocytes (CTL) are important in viral clearance and anti-tumor immunity, however, mechanisms for their optimal generation maintenance vivo remain unclear. Immunizing mice with an antibody-DNA vaccine encoding a single CTL epitope, induces 100 fold higher response than peptide vaccination the identical epitope. The high is retained into memory can be efficiently reactivated boost. In contrast, reactivation of peptide, stimulated responses significant drop avidity,...
Background The enzymatic conversion of arginine to citrulline is involved in gene and protein regulation alerting the immune system stressed cells, including tumor cells. Nucleophosmin (NPM) a nuclear that plays key roles cellular metabolism ribosome biogenesis, mRNA processing chromatin remodeling regulated by citrullination. In this study, we explored if same citrullinated arginines within NPM are activation. Methods HLA-DP4 HLA-DR4 transgenic mice were immunized with 22 overlapping...
We have previously shown that supraoptimal signaling of high avidity T cells leads to expression PD-1 and inhibition proliferation. This study was designed see if this effect could be mitigated by combining a vaccine stimulates with blockade.We investigated the anti-tumor huIgG1 antibody DNA (SCIB1) blockade.Vaccination HLA-DR4 transgenic mice SCIB1 induced frequency cell responses resulted in survival (40%) established B16F1-DR4 tumors. vaccination associated increased infiltration CD4 CD8...
Post-translational modifications are induced in stressed cells which cause them to be recognised by the system. One such modification is citrullination where positive charged arginine modified a neutral citrulline. We demonstrate most healthy donors show an oligoclonal CD4 response vitro at least one citrullinated vimentin or enolase peptide. Unlike rheumatoid arthritis patients, these T cell responses were not restricted HLA-DRB1 shared epitope (SE) alleles, suggesting they could presented...
Background Somatic mutations or post-translational modifications of proteins result in changes that enable immune recognition. One such modification is citrullination, the conversion arginine residues to citrulline. Citrullinated peptides are presented on MHC class II (MHCII) via autophagy which upregulated by cellular stresses as tumourigenesis. Methods Peptides were eluted from B16 melanoma expressing HLA-DP4 and analysed mass spectrometry profile citrullinated repertoire. Initially, seven...
DNA technology has emerged as a promising route to accelerated manufacture of sequence agnostic vaccines. For activity, vaccines must be protected and delivered the correct antigen presenting cells. However, physicochemical properties vector carefully tuned enhance interaction with immune cells generate sufficient response for disease protection. In this study, we have engineered range polymer-based nanocarriers based on poly(beta-amino ester) (PBAE) polycation platform investigate role that...
Background Homocitrullination is the post-translational modification of lysine that recognized by T cells. Methods This study identified homocitrullinated peptides from aldolase, enolase, cytokeratin and binding immunoglobulin protein used human leukocyte antigen (HLA) transgenic mice to assess immunogenicity enzyme-linked immunosorbent spot assay. Vaccine efficacy was assessed in tumor therapy studies using HLA-matched B16 melanoma expressing constitutive or interferon γ (IFNγ)-inducible...
Many cancers, including myeloid leukaemia express the cancer testis antigen (CTA) DDX43 (HAGE) and/or oncogene Wilms’ tumour (WT1). Here we demonstrate that HAGE/WT1-ImmunoBody ® vaccines derived T-cells can kill ex-vivo human CML cell lines expressing these antigens and significantly delay B16/HHDII + /DR1 /HAGE /WT1 growth in HHDII/DR1 mice prolonged mouse survival prophylactic setting comparison to non-immunised control mice. We show immunisation of with HAGE- WT1-ImmunoBody DNA a...
Homocitrullination is the post translation modification (PTM) of amino acid lysine to homocitrulline also referred as carbamylation. This PTM has mainly been studied in relation autoimmune diseases including rheumatoid arthritis. lysines alters their charge which can lead generation neoepitopes that are differentially presented by MHC-II and induce modification-specific immune responses. often considered a process triggers disease bypassing self-tolerance however, we suggest...
Abstract Citrullination and homocitrullination are stress induced post‐translational modifications (siPTMs) which can be recognized by T cells. Peripheral blood mononuclear cells isolated from healthy donors rheumatoid arthritis (RA) patients were stimulated with nine siPTM‐peptides. CD45RA/CD45RO depletion was employed to determine if peptide‐specific responses naïve or memory. Human leucocyte antigen (HLA)‐DP4 HLA‐DR4 transgenic mice immunized siPTM‐peptides immune determined ex vivo...
Introduction Post translational modification of proteins plays a significant role in immune recognition. In particular the arginine to citrulline which is mediated by PAD enzymes increased during cellular stress (autophagy) permits presentation modified epitopes upon MHC class II molecules for recognition CD4 T cells. Citrullination also occurs tumour cells as result continuous environmental stresses and autophagy. We have shown animal models efficient stimulation citrullinated epitope...
Background Post-translational modification of proteins has the potential to alter ability T cells recognize major histocompatibility complex (MHC) class -I and class-II restricted antigens, thereby resulting in altered immune responses. One such is carbamylation (homocitrullination) that results formation homocitrulline (Hcit) residues a non-enzymatic reaction cyanate with lysine polypeptide chain. Homocitrullination occurs tumor microenvironment CD4-mediated responses Hcit epitopes can...
Summary Complex cellular interactions between the immune system and cancer can impact tumour development, growth, progression. T cells play a key role in these interactions; however, challenge for is to recognize antigens whilst minimizing cross-reactivity with associated healthy tissue. Some cells, including those viral infections, have clear, tumour-specific that be targeted by cells. A high mutational burden lead increased numbers of neoantigens allow very specific responses generated but...