MICA: Targeted Regulatory T Cell Therapy for Inflammatory Bowel Disease

Lead Research Organisation: King's College London
Department Name: Transplantation Immunology & Mucosal Bio


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.

Technical Summary

Crohn's disease (CD) is a chronic, immune-mediated inflammatory bowel disease (IBD) with no known cure, resulting in significant morbidity. Goals of therapy include resolution of symptoms and mucosal healing. Many patients have sub-optimal responses to currently available therapies. This represents a significant unmet medical need.
"Thymus-derived" regulatory T cells (tTreg) are effective in modulating immune responses in many pre-clinical models of IBD. Our recent data shows that the starting population for tTreg expansion from the peripheral blood (PB) of CD patients has a critical effect on the phenotype of the expanded cell population. In CD patients, tTregs expanded from a highly pure FACS-sorted "naïve" CD4+CD25hiCD127loCD45RA+ tTreg precursor population have substantial advantages over tTregs expanded from FACS-sorted CD4+CD25hiCD127loCD45RA-, or MACS-enriched CD8-CD25+ precursor populations. These include:
1. Median 98.2% (IQR 97.1-98.4%, n=12) CD4+CD25hiCD127lo purity after 24d expansion, allowing precise definition of each clinical preparation, and increased in vitro suppressive ability in comparison to the other cell preparations described above.
2. 100% FOXP3 TSDR demethylation and reduced Th17 plasticity in vitro, in comparison to other cell preparations, reducing the risk of in vivo conversion to an effector phenotype.
3. A demonstrated ability to traffic to human intestine in vivo, in a humanised mouse model.
4. A demonstrated ability to suppress activation of mucosal T cells in vitro, obtained from inflamed CD intestinal resections.
This proposal addresses this unmet need by translating our pre-clinical and patient studies into a clinical-grade GMP flow cytometric sorting solution for the enrichment of highly pure CD45RA+ tTregs from CD patients with GMP cell expansion. This builds on our track record in GMP-Treg manufacture for transplantation and will enable the pivotal Phase Ib/IIa trial of autologous tTregs (TR004) for treatment of CD.

Planned Impact

Academic: The translational and immunological datasets will be made available to the clinical and academic community and will be of use to immunologists and other specialities that are investigating mucosal biology, immune homeostasis and autoimmunity.

Public sector: Understanding the mechanisms that underpin the maintenance of a healthy mucosal immune system has potentially huge impacts across the NHS. If it is possible to develop a greater understanding of the pathogenesis and treatment of IBD, this would be of great importance. We are well placed to translate these findings into relevant clinical impacts as this project is taking place in the context of the NIHR Biomedical Research Centre at Guy's and St Thomas' Hospital. In this environment, we are well placed to contribute to multidisciplinary programmes in the diagnosis and therapeutics of autoimmunity. This will ensure that useful discoveries are rapidly translated for maximum patient benefit.

Industry: Manipulation of immune function has been shown to hold therapeutic promise, with candidate drugs now entering Phase III clinical trials. The potential for developing a novel therapeutic intervention to maintain healthy mucosal immunity would be of significant interest to UK industry. This work has the potential for substantial economic impact.

General public: Understanding how to measure mucosal immunity at all stages of life would benefit the general public in many ways. As a specific example of this, it may be possible to enhance the efficacy of oral tolerance induction, which would be of significant public health impact.

Societal impact: Being able to address the issues of mucosal immunity and the more general aspects of this in relation to societal functions would enhance the awareness of the general population to this aspect of normal human pathophysiology that is generally overlooked. This could have important ramifications as to how society perceives the value of disease focussed research as it relates to their health and wellbeing.

Staff training: This grant will directly lead to the training of several staff members. Staff will gain expertise in a number of cutting-edge research areas that will expand the skills base of the UK and lead to further discoveries and technological advances as this expertise is propagated through the workforce. Staff will also gain training in skills transferable to the wider economy, including time management, communication, presentation, IT skills and university teaching.


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