Regulatory T cell therapy for IBD

Inflammatory bowel disease (IBD) affects more than 300,000 people in the UK, with an annual cost to the NHS in 2016 of over £900 million. It presents predominantly in young people, resulting in disruption of education and impaired career progression and work productivity, as well as affecting both social and personal activities. Despite the advent of several highly targeted biological therapies as well as new small molecules, approximately 30% of patients fail to have a meaningful response to treatment and develop complications including bowel perforation, colorectal cancer and intestinal failure. Furthermore, current therapies are associated with significant risk including side effects such as serious infection, malignancy and demyelination. There is, therefore, a pressing need to explore novel therapeutic techniques.

It is thought that IBD is caused by inappropriate activation of the immune system within the intestine, which triggers chronic inflammation of the gut. Regulatory T cells (Tregs) and effector T cells (Teffs) are important mediators of the immune response seen in the gut of IBD patients. Tregs suppress immune activity in the intestine and over-active Teffs are thought to be critical in driving the inflammation seen in IBD. Therefore, the balance and interaction between Treg and Teff cells in the intestine represents a potential therapeutic target.

There is growing interest in the use of cellular therapy in a wide range of chronic inflammatory diseases. In particular, the ability of Treg-targeted therapy and of Tregs themselves to be used as a treatment is growing. At King's College London / Guy's and St Thomas' we have developed a system that allows us to remove Tregs from people and then grow them in the laboratory before infusing them back into the same patient. We are imminently starting an early phase study of the use of Tregs to treat Crohn's disease which we hope will allow us to understand how Tregs work as a treatment and will help us plan later phase studies that will allow the treatment to be used on an everyday basis.

This proposal has two main aims. First, we intend to explore how we can manipulate Tregs to make them more effective anti-inflammatory agents whilst minimising their side effects. IBD represents an excellent model to understand how Tregs work as a treatment and how they can be manipulated to make them more effective as well as how they can be targeted to specific organs. There are several ways in which this might be achieved, such as using Tregs in combination with drugs that either change the way that Tregs work or, alternatively, help them to target specific organs. This should make them more effective as well as minimising the chance of them causing side effects in other parts of the body which are unaffected by inflammation. In addition, work from our department has identified a change in the genetic code of a proportion of people with Crohn's disease that might change the way their Tregs and Teffs respond to drugs which we might use in combination with Tregs. This will allow us to identify patients who may be more or less likely to respond to treatment, i.e. allowing us to use personalised medicine in Treg therapy. Finally, it is potentially possible to use this knowledge to alter the way Tregs work by changing their genetic code which, again, could make them more effective when used in combination with specific drugs.

The second aim of the proposal is to investigate how we can expand the use of Tregs beyond Crohn's disease. Initially, we aim to investigate their use in ulcerative colitis which is a similar, yet distinct condition from Crohn's disease. The ultimate aim, however, which has the potential to help many more people, will be to use the results of this research programme to understand how we might be able to use Tregs in other conditions affecting different parts of the body, for example, the nervous system, the joints or the skin.

Ulcerative colitis (UC) and Crohn's disease (CD) , together IBD, are chronic, incurable diseases of the GI tract resulting in significant morbidity and potentially life threatening complications. IBD affects more than 300,000 people in the UK and incurs costs to the NHS in the region of £1bn per year. Current therapies have limitations in terms of occasionally life-threatening side effects and also limited effectiveness; steroid-free remission rates for individual therapies tend to be 30-40% at best.
Regulatory T cells (Tregs) have been identified as a potential therapy for patients with a range of disorders including CD. However, the ability to use them therapeutically has been limited by difficulties including performing ex vivo expansion, maintaining a non-inflammatory phenotype, delivery to the target organ and optimising treatment. In this program, I aim to research the mechanism of action of Treg therapy in patients with CD, the ability of Tregs to target the gut, the optimisation of Tregs as a treatment, the importance of a genetic variant, rs61839660, on Treg function and the potential to apply Treg therapy to another disease, UC, potentially paving the way for expansion to other disease areas.
We are starting a Phase 1b/2a trial using ex vivo expanded CD4+CD25hiCD127loCD45RA+Tregs, optimised for gut homing using RAR568 and rapamycin, as a treatment for treatment-refractory Crohn's disease. Using samples from this, we will explore the phenotype of Tregs, after re-infusion, in both the peripheral blood and in the gut using techniques including ELISA, flow cytometry and TCR sequencing. In addition, we shall track the deuterated Tregs to investigate distribution and kinetics. Treg therapy optimisation will be investigated focussing on the effects of IL-2 co-therapy, initially in blood from UC patients, to inform the design of a clinical trial. In collaboration with the UK IBD Bioresource, gene editing may allow further optimisation of Treg therapy.

This research has the potential to impact in several ways. First, researchers and clinicians working in the field of IBD will gain knowledge of how Tregs might work therapeutically in IBD as well as how they might be used as a therapy whether alone or in combination with other drugs. There are key gaps in our knowledge of Treg biology and this research will help to fill them. The programme looks to move Treg therapy from early to later phase studies and from beyond the confines of Crohn's disease to ulcerative colitis. Most importantly, this work is necessary if Treg therapy is going to impact upon the people who stand to gain most, namely people with IBD; this condition affects more than 300,000 people in the UK and has direct healthcare costs to the NHS of more than £900,000 per year. The costs to society are, of course, much greater due to the impact of IBD on work and education and the effects on individuals' lives are significant and wide ranging.

In addition, the results of this research are likely to be applicable across several disease areas and may address some of the limitations that we see with currently available drug treatments. As such, the research is also likely to benefit the research and development arms of the pharmaceutical industry, whose expertise will be important in making novel treatments such as Treg therapy widely available. Whilst the timescale for translating this potential therapeutic into something that is available in everyday practice is probably in the order of a decade, partnering with industry will accelerate this process and, inevitably, the results of this research will be applicable to other disease areas and will allow more rapid translation to a clinically available therapeutic beyond IBD.

In addition, the scientific outputs will improve the understanding of the importance of Tregs and their interaction with IL-2 in vivo expanding on the work that has already been performed both in vitro and ex vivo as well as in animal models. Again, this knowledge will have broad ranging impact beyond the field of gut inflammation.

The institutions supporting this work include the Biomedical Research Centre (BRC) at Guy's and St Thomas' Hospital and Kings College London (KCL) will benefit through ongoing use of their advanced immune monitoring facilities. We hope that undertaking cutting-edge translational research will lead to high impact publications and presentations, which will contribute to the university's excellent academic reputation and the hospital's reputation as a leading academic health centre.
Finally, personally, this award would allow me to develop the academic side of my career. Having trained in research whilst studying for my MD, having a full time clinical role has limited my research to collaboration with colleagues in KCL. I would relish the opportunity to bring the clinical expertise I have to benefit my collaborators more directly and to allow me to develop as a researcher in order to further our understanding of IBD