The State of Play of Stem Cells in Inflammatory Bowel Disease

A conversation with researcher and surgeon Amy Lightner, MD

The introduction of infliximab in 1998 and the subsequent addition of more biologic products marked a new era in the treatment of inflammatory bowel disease (IBD), significantly improving medical management.

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However, all biologics have side effects that limit their use, and they are effective in no more than half of IBD patients. Patients who become refractory to medical management eventually need surgery; one-third of patients with ulcerative colitis and about two-thirds of patients with Crohn’s disease still require a major abdominal operation, with the inherent prospect of complications and reduced quality of life.

There is a clear need for improved IBD treatments. Stem cell therapy, with its potential for suppression of overactive immune response and for healing inflamed tissue, is emerging as a promising IBD treatment alternative.

Amy Lightner, MD, is a leading translational researcher and clinical trials director in stem cell therapy for Crohn’s disease, as well as an expert in regenerative surgery and its application to IBD. In 2019, she was recruited from the Mayo Clinic to become an Associate Professor of Surgery and Associate Chief of Surgical Research in Cleveland Clinic Digestive Disease & Surgery Insitute’s Department of Colon and Rectal Surgery. Dr. Lightner also is the Primary Investigator of the surgical inflammatory bowel disease translational laboratory.

Dr. Lightner spoke with Consult QD about her work and the state of play of stem cells in IBD.

Why do stem cells particularly show promise for IBD?

We’ve done a lot of phase I, II and III clinical trials in perianal fistulizing Crohn’s disease, and stem cells have shown superior efficacy to conventional therapy with medications and surgical intervention. There have been no safety issues to date. We don’t know exactly why stem cells work, but they seem to migrate to sites of inflammation or injury. They then seem to release cytokines that recruit other cells to treat inflammation and immunity. This kind of action seems to increase T regulatory cells and interleukin 10, which is important in Crohn’s disease. It probably alters the macrophage ratio, which also helps healing in Crohn’s disease. So there seems to be something on a cellular level that’s happening that certainly makes stem cells effective, particularly for Crohn’s.

Do mesenchymal or hematopoietic stem cells have a particular advantage or efficacy?

All the stem cell trials to date in IBD have used mesenchymal stem cells. Access to mesenchymal stem cells is easier. You can harvest adipose tissue or bone marrow tissue. It can be autologous or allogeneic.

Does the tissue donation site make a difference in efficacy?

They’ve never been directly compared. There have been clinical trials using both, but the clinical trial design was different, so we can’t really compare across trials. There’s probably easier access to adipose tissues, so it’s more often used. Fistulas are in ischiorectal fat, so the thought would be that if you inject stem cells derived from fat tissue, you could potentially signal to the local micro environment in a superior way than when using bone marrow-derived stem cells.

Does localized injection of stem cells have an advantage over systemic administration?

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All of the perianal Crohn’s disease trials have used local delivery of stem cells, and that’s clearly safe and effective. The challenge with delivering stem cells intravenously is they have pulmonary trappings, so they get trapped in the lung when we inject them into the venous system. Arterial delivery is likely effective, but you need interventional radiology for targeted delivery. There have only been two small pilot studies done on that. So we’re going to be rolling out a phase I trial doing arterial delivery for intestinal Crohn’s disease.

Do stem cells have the same potential in ulcerative colitis as in fistulizing Crohn’s disease?

I imagine that they would, given that ulcerative colitis involves an aberrant immune response or level of inflammation. So stem cells theoretically should also be effective for ulcerative colitis, but it hasn’t been studied yet.

What areas of research is your lab working on?

We’re working on two things. One is donor characterization of stem cells, to see who would be the optimal allogeneic donor for treating Crohn’s disease patients. Is it men, women, young, old, smoker or nonsmoker, different disease states? Are there various donor characteristics that affect mesenchymal stem cell function? And the main thing we’re working on is mesenchymal stem cell secretions called extracellular vesicles. They’re a lot less expensive than whole stem cells, easier to transport to different facilities for multicenter trials, and have a longer shelf life. And we can grow our mesenchymal stem cells in certain conditions that make these vesicles more immunosuppressive. So what we’re working on is engineering these extracellular vesicles as an alternative treatment to giving the whole cell.

What stage is that research?

It is in pre-human clinical models. We’re gathering the extracellular vesicles and doing all the in vitro work, and now we’re going into a mouse model to look at arterial delivery for ulcerative colitis.

What human clinical trials are you involved in?

We have stem cell trials for perianal fistulizing Crohn’s disease, recto-vaginal fistulizing Crohn’s disease, fistulizing disease of the ileal pouch, and arterial delivery of stem cells for luminal Crohn’s disease. Then later we’re replicating those with the extracellular vesicle products. These are all phase I safety trials.

It sounds like at some point there will be a need to compare the efficacy of stem cells with other IBD therapies.

I think we’ll be able to randomize medical therapy versus stem cell therapy. Throwing surgery into the mix would be hard. But I think we could eventually do a trial that looked at placebo, stem cell and medical therapy and see what works best. Crohn’s patients are tricky because there are a lot of confounding variables, but it certainly is worth comparing for efficacy’s sake.

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You’re a colorectal surgeon and a researcher. Can you imagine a time when surgery is much less necessary —or even perhaps unnecessary — in IBD, or specifically in Crohn’s disease?

That will take figuring out the pathophysiology of the disease — understanding what’s causing it, to be able to prevent it and adequately treat it. The challenge now with medical therapy and surgery for Crohn’s is we’re basically treating the symptoms. We’re not addressing the underlying problem. It would be much, much better for the patients if that happened, certainly, but it probably won’t in the next decade.

How do you balance your time between clinical and research obligations?

It’s a challenge. Patients always come first. The clinical work usually seeps into the research world. I try to protect my mornings on research days. It’s a lot of nights and weekends doing research.

Why not choose one or the other track?

That’s a good question. I think if you only do research, it becomes a challenge to see the unmet treatment needs, unless you have some strong collaborations with clinicians. And then on the clinical side, it’s very rewarding to treat a patient at a time. But I think as you see these problems that are affecting thousands of patients, it becomes a desire to be able to work on how can I treat things on a bigger scale or a larger level. So that’s why I like doing both.

Why did you join Cleveland Clinic?

Mostly the people in the GI and colorectal departments, the leadership that’s here. I really liked the colleagues that I would be working with. And there’s definitely a strong sense at the Clinic for innovation, for clinical trials, and for making sure that we’re thinking about both research and clinical work to serve the mission of Cleveland Clinic – the patient comes first.

Mesenchymal stem cells image credit: Chun Yang, Hao Ma, Anouk Killaars, University of Colorado Boulder