A new cell therapy for Crohn’s disease aims to treat the root cause of gut inflammation by infusing patients with their own carefully selected regulatory immune cells. Crohn’s disease is a chronic inflammatory bowel condition that causes severe symptoms and often requires surgery, even with existing medications. The problem is that standard treatments don’t work for many patients. This research targets a specific type of regulatory T cell (tTreg) from the patient’s blood that, when expanded in the lab, maintains a stable anti-inflammatory profile and homes to the gut. Earlier attempts using a less pure cell population risked producing cells that actually worsened inflammation. If the clinical trial succeeds, this approach could offer a personalised, long-lasting therapy for patients with refractory Crohn’s disease who currently have few options. Instead of broadly suppressing the immune system with drugs, the treatment would restore the body’s natural ability to control intestinal inflammation. This could reduce the need for repeated surgeries and hospitalisations, and lower the long-term healthcare burden of a disease that quietly disrupts millions of lives.
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Crohn's disease (CD) is a common inflammatory bowel disease, causing significant chronic morbidity and healthcare cost. Despite appropriate use of CD medications, many CD patients have on-going intestinal inflammation or require surgery for their disease. This significant unmet need compels the development of novel, effective therapies. Thymically-derived regulatory T cells (tTregs) are associated with dominant peripheral tolerance in mice and humans. In both species, monogenetic defects affecting Treg function (e.g. FOXP3 or IL-10R defects) result in multi-system inflammation, including the intestine. Syngeneic Tregs prevent or cure multiple murine models of colitis. GMP-expanded human Tregs are safe and show promise in recent phase I studies in GvHD and type 1 diabetes. We have a substantial track record in the pre-clinical investigation and GMP-grade enrichment and expansion of Tregs for cell therapy in transplantation. However, we recently found that a significant proportion of tTregs expanded from a CD8-CD25+ MACS-enriched precursor population obtained from CD patients' blood expressed pro-inflammatory cytokines, which may confer a pro-inflammatory phenotype following adoptive transfer. Our new data show that this phenotype can be avoided by expanding a highly pure subpopulation of Tregs from CD patients' blood, enriched by FACS sorting on the basis of CD4+CD25hiCD127loCD45RA+ expression. In contrast to tTregs expanded from MACS-enriched precursors, or FACS sorted CD4+CD25hiCD127loCD45RA- precursors, tTregs expanded from CD4+CD25hiCD127loCD45RA+ precursors have epigenetically stable FOXP3 expression, which is associated with a stable tTreg phenotype and low likelihood of plasticity to an effector phenotype. These cells also suppress activation of autologous CD blood and mucosal effector T cells, express intestinal homing markers and home to human gut in a humanized mouse bearing human small bowel. Our proposal addresses this unmet medical need by translating our human pre-clinical data into a full clinical-grade GMP FACS solution for the preparation of a pure subpopulation of tTregs from the blood of patients with CD. This will be followed by the pivotal phase I/IIa clinical trial of autologous tTregs expanded from CD4+CD25hiCD127loCD45RA+ precursors for the treatment of refractory CD.
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