Faculty of Medical Sciences

Staff Profile

Professor John Isaacs

Institute Director

Background

My team’s work is focussed in two major areas:

· The development and testing of novel immunotherapies for autoimmunity, with a particular interest in therapeutic tolerance induction.

· Rheumatoid arthritis – immunopathogenesis, biomarkers and novel therapeutic strategies including treatment stratification


Major current therapeutic projects include the development of an autologous tolerogenic dendritic cell therapy for rheumatoid arthritis (AUTODECRA, funded by Arthritis Research UK); the first ever clinical trial of a drug targeted at the synovial fibroblast in rheumatoid arthritis (TRAFIC, funded by the Medical Research Council); an experimental medicine study to identify the biological factors that underpin disease flare in rheumatoid arthritis (BIO-FLARE, funded by the Medical Research Council); we are also part of an EU Innovative Medicines Initiaitive, Rheumatherapy-Cure (RT-CURE), which aims to prevent rheumatoid arthritis by targeting ‘at risk’ individuals with tolerogenic therapies.


Therapeutic tolerance induction remains a ‘holy grail’ for human autoimmunity although there is now a concerted international effort to demonstrate that this is an achievable aim. A major limitation is a lack of understanding of the immune dysregulation inherent in most human autoimmunity, and consequent lack of ‘tolerance biomarkers’. These are essential in order to conduct rational therapeutic tolerance trials. This is a key aim of the MRC/ABPI Immunology and Inflammation Initiative for inflammatory arthritis, RA-MAP, for which I am Chief Investigator. By performing a systems immunology analysis of a cohort of patients with early rheumatoid arthritis, we will dissect the immunopathogenesis of the disease which, in turn, will provide key biomarkers.


All of our work is supported by cutting edge facilities, including the state-of-the art Wilson Horne Immunotherapy Centre and Arthritis UK Experimental Arthritis Treatment Centre, a clinical research facility dedicated to the investigation of novel immunotherapies which incorporates arthroscopy and high resolution ultrasound scanning. We are a member of the NOCRI Translational Research Collaboration for inflammatory arthritis, for which I was the inaugural national lead. Our laboratory is based in recently refurbished, open plan laboratory facilities alongside other internationally renowned immunology researchers. I am also a principal investigator of the Arthritis Research UK Centre of Excellence in Rheumatoid Arthritis Pathogenesis, alongside colleagues in Glasgow (PI Iain McInnes) and Birmingham (PI Chris Buckley)


Local roles:

  • Director, Institute of Cellular Medicine
  • Professor of Clinical Rheumatology
  • Deputy Director NIHR Newcastle Biomedical Centre for Ageing and Long-Term Conditions.
  • Director, Newcastle Biomedicine Arthritis Research UK Experimental Arthritis Treatment Centre
  • Director, Wilson Horne Immunotherapy Centre
  • Consultant Rheumatologist, Newcastle upon Tyne Hospitals NHS Foundation Trust
  • Academic lead, Musculoskeletal Directorate, Newcastle upon Tyne Hospitals NHS Foundation Trust


National and International roles:


2018-20: Scientific Chair, European League Against Rheumatism (EULAR)

2018 - MRC Stratified Medicine Assessment Panel

2017 – Arthritis Research UK ‘Disease’ Sub-Committee

2017 - Chairperson, Pfizer ASPIRE research awards funding panel

2016 – Member, NIHR/NOCRI Translational Research Collaboration for Inflammatory Disease

2014 - Member, MRC Translational Research Group


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Research


CURRENT MAJOR RESEARCH PROJECTS:


TRAFIC


This project aims to repurpose a small molecule anti-cancer drug as an anti-fibroblast drug for RA. The past 20 years have seen major advances in RA therapy; more aggressive use of conventional drugs, and biological targeted therapies have each made a significant impact. However, disease remission remains uncommon and around 20% of patients remain refractory to all therapies. This represents a significant unmet need and suggests key aspects of RA pathogenesis remain untargetted.


In health, a delicate nutritive synovial membrane (SM) lines joint cavities. This comprises a few macrophages and fibroblasts in a loose connective tissue stroma. In RA the SM is the focus of autoimmune attack but, in addition to inflammatory cell infiltration, resident synovial fibroblasts (SF) become hyperplastic, forming a vascularised, inflammatory, quasi-malignant pannus which invades articular cartilage and bone. The resultant joint damage underlies the disability and reduced quality of life that characterise RA.


Cell proliferation relies on the coordinated activation of specific regulatory proteins: orderly progression through the cell cycle is tightly controlled by the formation and activation of complexes comprising cyclin proteins and cyclin-dependent kinases (CDK). These complexes are in turn regulated by endogenous CDK inhibitors (CDKI). The concept of inhibiting CDKs to correct uncontrolled cell proliferation has led to the evaluation of small molecule CDKI in cancer.


RA SF have reduced endogenous CDKI levels, and correction of the deficit normalises their dysregulated phenotype. Indeed, small molecule CDKI ameliorate synovitis in pre-clinical arthritis models. In partnership with the SME Cyclacel, we propose a phase IIa repurposing study of a CDKI in patients with refractory RA. Stage 1 will focus on safety and tolerability, to determine an appropriate dose to progress to stage 2, where we will seek evidence of potential therapeutic activity alongside PK and PD biomarkers.


BIO-FLARE


Flares of immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA), are a major burden for patients. They occur unpredictably, adding to the physical and psychological burden of the condition, and contribute to joint damage and comorbidities, such as cardiovascular disease. Flares are difficult to study, precisely because of their unpredictable timing. However, we have established a human model that generates a 'synchronized' population of RA patients in clinical remission, of whom about 50% flare within 6 months, the remainder maintaining remission. We propose to carefully study such a population to better understand the factors that determine disease flare.


Up to a third of patients with RA achieve disease remission with aggressive therapy. Many wish to discontinue therapy at this point and, if they do, about 50% flare in the subsequent 6 months. We will follow such a population pr ospectively, to study the biological processes underpinning flare. We will study 150 patients in clinical remission for at least 6 months, and prepared to discontinue treatment. After treatment cessation patients will be studied intensively, with blood sampling at weeks 2, 4, 6, 12 and 24. Patients will also undergo ultrasound-guided biopsy of 'flaring' synovium before reinstatement of previous treatment (with which patients readily regain remission). We will also obtain biopsies from consenting patients at baseline and in remission at 6 months.


In blood we will study immune cell subsets and their activation status; autoantibody profiles; and epigenetic profiles. Synovial biopsies will allow us to examine the cell lineages present, including stromal cell subtypes, as well as inflammatory mediators. We will additionally examine metabolic profiles in blood, urine and synoivum.


Using multivariate statistical techniques we will develop a model that predicts impending flare in RA, highlighting tractable therapeutic pathways and informative biomarkers.


AUTODECRA-2


AuToDeCRA-2 addresses two critical aspects of tolDC therapy: the route of tolDC administration and the demonstration of specific immune modulation. Our hypothesis is that tolDC will need to access seondary lymphoid tisses in order to modulate the autoreactive immune response.


We wish to identify an optimal route for tolDC administration. This should be technically practical, and enable tolDC to reach spleen, liver or lymph nodes (alone or in combination). TolDC will be labelled with a 'dye' that is visible by MRI, and loaded with cirullinated peptides prior to administration. We will then apply cutting edge immunological assays, using MHC-peptide tetramers, to identify and phenotype autoreactive T-cells, ultimately associating tolDC distribution with immune modulation.


We will study 16 patients with anti-citrullinated peptide autoantibody (ACPA) positive RA. They will be HLADR*0401 or *0404 positive and receiving non-biologic) DMARD therapy. TolDC will be manufactured according to the protocols we have developed over the past ten years, and used for AuToDeCRA-1. However, tolDC will be labelled with 19F, a stable and non-radioactive isotope that can be sensitively tracked using MRI. Additionally, tolDC will be loaded with a mixture of citrullinated peptides. 19F-cit-tolDC will be injected via three distinct routes: intradermal; intra-articular; and intra-nodal. Control groups will receive intra-nodal 19F-tolDC that have not been loaded with citrullinated peptides.


MRI will be performed immediately after tolDC administration, 24 and 72 hours later. Blood for immune monitoring will be taken at baseline, 1, 2, 6 and 13 weeks after treatment. Specific immune monitoring will utilise anti-citrullinated peptide autoantibody profiling, alongside enumeration and functional analysis of antigen-specific T-cells, identified by appropriate MHC-peptide tetramers (derived from the peptides used to load tolDC). We will study autoreactive T-cell proliferation, surface phenotype, cytokine production and transcriptional profiling. Our final analysis will compare the distribution of tolDC after administration with evidence of subsequent immune modulation. We will also record disease activity and carefully document potential adverse effects.


RA-MAP


Our primary aim is to identify clinical, molecular and cellular biomarkers of prognosis and therapeutic response in patients with early rheumatoid arthritis (RA). Clinical predictors will be identified principally from meta-analysis of data derived from the placebo arms of completed clinical trials, seeking baseline parameters that associate with subsequent clinical response. Additional clinical predictors will be identified from an inception cohort of patients with early RA, followed longitudinally (the TACERA study). These patients will also provide the substrate to identify molecular and cellular biomarkers of prognosis and therapeutic response: participants will donate blood and urine at 3 monthly intervals for transcriptomic, flow cytometric, epigenetic, proteomic and metabolomic analyses. A systems based immunology approach will be adopted to identify baseline parameters that predict 6 month outcomes. By comparison with equivalent molecular profiles obtained from healthy individuals we will seek to define elements of immune dysregulation in RA and address whether the immune system of patients who subsequently achieve remission reverts to normal or continues to manifest immune dysregulation. A parallel study will similarly analyse blood samples from vaccinated healthy individuals, to compare the immune dysregulation in RA with the evolving response to vaccination. Ultimately, molecular or cellular biomarkers that inform prognosis or therapeutic response will be developed into a data warehouse and ‘polyomic toolkit’ describing the hallmarks of RA in blood, to enable the development of in vitro assays for patient monitoring.


A secondary aim of the programme is to identify individuals at high risk of developing RA, in order to evaluate immunological factors associated with the ‘pre-RA’ state.



Publications