Stem Cell Therapy: Preparing for its Closeup in IBD

Research into the use of cell-based therapies as possible treatment options for various diseases exploded over the last several years.

One of the most recent noteworthy examples has been the use of chimeric antigen receptor T-cells to treat various oncologic diseases.

In fact, one of the more breakout moments for cell-based therapies occurred when the 2018 Nobel Prize in Physiology or Medicine was awarded to James Allison, PhD, and Tasuku Honjo, MD, PhD, for their work in analyzing the use of an individual’s T cells to treat and attack cancer.

But not every disease state is as ready for its closeup regarding the use of cell-based therapies.

Healio Gastroenterology and Liver Disease spoke with several surgeons and gastroenterologists about the potential validity and effectiveness cell-based therapies may have in treating gastrointestinal disorders, most notably inflammatory bowel disease.

“There is great potential for cell-based therapies in inflammatory bowel disease. It is truly an exciting evolution, but we’re still in its infancy,” Amy Lightner, MD, an associate professor of surgery in the Department of Colon and Rectal Surgery at Cleveland Clinic, told Healio Gastroenterology and Liver Disease.

Lightner, who is also the primary investigator for the Cleveland Clinic’s surgical IBD translational laboratory, noted some of the challenges of applying cell based therapy to various disease states and phenotypes of IBD.

“People talk about cell-based therapy and expect you can put cells on anything and get it to heal,” she said. “But it’s challenging because we are still using cell therapy in the context of clinical trials, which means that there are strict inclusion and exclusion criteria of each trial. This limits how we can deliver the cells and what types of disease states we can treat. However, as cell-based therapy becomes more widely utilized we will see an expansion in the modes of delivery and indications of use.”

Because cell-based therapies for IBD are still in the infancy stage and most of the testing still involves safety and efficacy, there have not been many people flocking to study the use of these therapies, according to Lightner.

William A. Faubion Jr., MD, a consultant in the Division of Gastroenterology and Hepatology and Mayo Clinic in Rochester, Minnesota, agrees that interest has been rather slow in assessing the potential of cell-based therapies in treating patients with IBD, but has been picking up recently.

“It’s a more active area of research now, probably since the advancement of the program out of Spain and the publication of the ADMIRE trial and then the acquisition of the North American rights to Takeda from TiGenix for a product that has been approved by the European regulatory authorities,” Faubion told Healio Gastroenterology and Liver Disease. “There’s definitely been more interest in the last 3 years, than there has been in the last decade. I think in general however, it’s still an understudied, underserved area.”

Background

Faubion says he remembers being approached by Allan B. Dietz, PhD, co-director of the Human Cell Therapy Lab within Mayo Clinic’s Center for Regenerative Medicine, a little more than 7 years ago about the program and how it was being used to treat a number of other conditions.

“He was an expert in adipose-derived, autologous stem cells in a variety of other conditions for a period of time,” he said. “He approached me about a possible utility in Crohn’s disease, or really any GI disease.”

Along with Eric J. Dozois, MD, program director of colon and rectal surgery at Mayo Clinic, Dietz and Faubion agreed that the best approach for using cell therapy would be for perianal fistulizing Crohn’s disease.

“At that time, there were only a couple of small pilot studies that had been done in Madrid, and so we got into the space then,” Faubion said.

Faubion highlighted the reasoning as to why the team focused on perianal fistulas.

“That’s probably one of the most difficult scenarios that we deal with in Crohn’s disease; the highly morbid situation of perianal fistulas,” he said. “We felt like there was terrific need. Second, there was an opportunity to innovate in the space because the best effective therapies at that point were at best effective in only about 40% of patients.”

Additionally, Faubion noted the fact that a fistula requires more than just alterations of immune signals, it requires tissue regeneration and tissue healing, was another reason to get into the space.

For James Lindsay, PhD, FRCP, professor of Inflammatory Bowel Disease at Barts and the London School of Medicine and Dentistry, Queen Mary University of London and a consultant gastroenterologist at Barts Health NHS Trust, his interest in cell therapy for treating IBD started much earlier.

“My interest has always been in autologous stem cell transplantation, which is effectively a bone marrow transplant to reset the immune system and get rid of the autoreactive memory T cells that drive inflammation in Crohn’s disease,” Lindsay told Healio Gastroenterology and Liver Disease. “The initial first reports first came from the United States; however, it has become less popular over there with the advent of more biologic therapy treatments for disease.”

Lindsay noted his group participated in a trial after there were reports coming from studies in the early 2000s that the process could possibly cure Crohn’s disease.

Although the trial was negative in nature and demonstrated cell therapy did not cure the disease, the researchers felt that individual patients did quite well within the trial. As a result, a new trial was established to evaluate it further.

“Our interest stemmed from previous observations, patients who were refractory to current therapies actually did get meaningful reduction in their disease activity after a transplant and so that’s why we started with a new trial,” he said in an interview.

Lindsay emphasized that an autologous stem cell transplant is a very different process that aims to treat severe intestinal inflammation that has not responded to any currently available therapy. In a stem cell transplant, a patient’s own stem cells are mobilized from their bone marrow, harvested and frozen. The patient then receives immune modifying and ablative chemotherapy to remove their current immune system before their thawed stem cells are reinfused. These them populate the bone marrow and differentiate into a naive immune system.

Lindsay highlighted that his focus is different than many of quoted studies of stem cell therapy in Crohn’s disease, which involves mesenchymal stem cells which are directly injected into a fistula.

Promising Results

The most noteworthy results to date demonstrating the efficacy of cell therapy were presented at Congress of European Crohn’s and Colitis Organisation in 2017.

Results from the double-blind, randomized controlled, phase 3 ADMIRE-CD trial demonstrated that patients with Crohn’s disease achieved sustained remission of treatment-refractory complex perianal fistulas through 52 weeks after treatment with Alofisel (darvadstrocel; TiGenix/Takeda) stem cell therapy.

At week 24, a greater proportion of patients treated with darvadstrocel achieved clinical and radiological combined remission (51.5% vs. 35.6% for controls; P = .021), and these benefits were maintained through week 52 (56.3% vs. 38.6%; P = .01) in the modified intention-to-treat population. A greater proportion also maintained clinical remission at week 52 (59.2% vs. 41.6%; P = .013).

Cell therapy, as Faubion noted, is probably best used as a last-ditch effort for patients.

“All the patients that have enrolled in clinical trials to date are already failing other therapies, so we don’t really have a study to look at where cell therapy is being used as a primary therapy,” he said. “Most of these patients have failed biologics, multiple drainage procedures and even diversion treatment. The fact that it is efficacious at all, the fact that the ADMIRE trial was statistically significantly effective, is meaningful.”

Faubion was a part of a study that demonstrated that autologous mesenchymal stem cells, applied in a bioabsorbable matrix, were able to heal fistulas.

At 6 months, 10 of 12 patients (83%) had complete clinical healing and radiographic markers of response.

“The fact that our study, much smaller and prospective, yet not controlled, showed an 80% healing rate, the fact that these therapies had been so productive with such refractory patients I think is what holds so much promise for regenerative techniques,” he said.

Lightner, who participated in the same study published in Gastroenterology, acknowledged that results from these various trials are promising.

“The results [show] efficacy ranging from 50% to 90%. That is encouraging that most refractory patients are having better results than conventional medical and surgical options,” she said. “Even in rectovaginal fistulas efficacy is again around 60% to 80%, also better than our conventional therapy options. Those are the only two types of Crohn’s fistulas with published results; trials for enterocutaneous and pouch fistulas have not yet been initiated.”

Stem cell therapy, as Lightner notes, offers a different treatment option with a possibly better side effect profile.

“This has the potential to be more effective than current treatment options. If this proves to be the case, we could prevent the potential morbidity from conventional surgical intervention including the risk for incontinence.”

Faubion expanded further on the side effect profile of stem cells for IBD and highlighted something he considered a “beauty of cell therapy.”

“In the whole of the patients treated to date with a regenerative technique there have been no adverse events related to the cells themselves,” he said. “That’s one of the beauties of a cell therapy; it’s not an advanced immunotherapeutic, so it’s not immunosuppressing. There is no published malignant potential to these cells, no published experience demonstrating a malignant event and other than patients not responding and therefore developing separate complications related to their known perianal fistulas we haven’t really seen a risk to the cell as a medication.”

Slowing Down

Although available data for stem cell therapy have been promising in terms of safety and efficacy in IBD, there are still some significant limitations.

There are three main limitations to getting stem cell therapy research off the ground, according to Lightner.

Those limitations include costs of cell-based therapy, time to conduct clinical trials, and most importantly, assembling the right team of physicians and scientists and regulatory experts.

“People are studying stem cell therapy for a whole variety of disease states,” Lightner said. “But the process can be slow. Clinical trials can get very expensive mandating the need to acquire ongoing funding. Federal and institutional approvals can take months in order to ensure safety for our patients. Even more than the time and funding is the importance of the right team and key collaborations with other physicians and scientists. These trials take many active players.”

Faubion expanded on Lightner’s sentiment about finding the right collaborators, noting that a multidisciplinary team is needed to study cell-based therapies effectively.

Surgeons, imaging technicians, cell therapy researchers and clinicians are all involved in the process, he said.

“That probably makes it a challenge to integrate research teams across a variety of academic institutions, because you have to have not just medical clinicians that want to treat a perianal fistula, but you have to have qualified surgeons capable in treating these diseases, and you also have to have imaging technicians that have the appropriate equipment and are able to monitor patients.”

Additionally, Faubion noted that as clinical trials develop in this area of treating patients with perianal fistulas, researchers are still searching for the right outcome measures.

“MR pelvis is probably emerging as one of the better objective qualifiers of fistulizing disease and trying to put together a really highly responsive and reproducible measurement of response has been a bit of a challenge, that might have slowed things down,” he said.

Other concerns, according to Lightner, include the infrastructure needed for the production of cells.

“There’s a lot of infrastructure required for cell production, which isn’t feasible in every hospital or clinic,” she said. “A good manufacturing practice laboratory (GMP-grade lab) is required for cell manufacturing of cells used in human clinical trials. This is a huge cost and requires significant regulatory oversight. If a hospital doesn’t have a GMP-grade lab, and cells need to be shipped for patient administration, the challenge is the short half-life of cells. When shipped fresh, the cells have to be used within 24 to 48 hours. If they’re shipped frozen, you have to have a receiving person who knows how to thaw and suspend the cells. All of this can get quite costly.”

Cost is always a consideration when evaluating a possible therapeutic option, according to Faubion.

“What regulatory agencies are going to be looking for is a health care economic evaluation,” he said. “When one talks about cost, I don’t think you can just look at the cost of developing the product and transferring the cells into a patient. But rather, you have to look at the cost all-in, which is the number of exams and/or anesthesia that this patient has experienced over the prior two years, as well as the cost of missing work and the cost of the medications they may be taking to treat their perianal fistula.”

Faubion said that the cost of most biologic therapy’s hovers around $40,000 per year, and that the cost of a surgery is significantly more than that.

That’s why, according to Faubion, an entire health care economic quantification is needed to rationally compare cost of one therapy to another.

For Lindsay, there is a way to justify the potential cost of the treatment.

“It’s always going to be a low volume procedure that can only ever be performed in a small number of centers because of the complexity of doing the transplant,” he said. “It’s a very expensive intervention, although if you say people require hospitalization and surgery and save some of the biologic drugs, it probably does work out to be cost effective, but there is a higher upfront cost. If you save someone 2 years’ worth of drug and a hospitalization, you have recouped the cost of the process.”

Looking Ahead

The time for cell-based therapies for IBD is now, according to Faubion.

He noted that it is already in large, registration, phase 3 trials in Europe and the researchers are trying to recruit in North America.

Additionally, Faubion mentioned his program is near the beginning of their own phase 2 program where the goal is to complete within the next 4 years.

“We’re really just at the very beginning of cell therapy for wound healing and tissue regeneration broadly,” he said. “Right now, most folks are using unmanipulated cells because it’s probably going to be safer using a cell that is unmanipulated, and it’s certainly a lower bar for regulatory approval, but I do think there is going to be a future in ex vivo manipulation of cells either to produce a certain wound healing phenotype, or produce a certain protein expression pattern that is particularly useful in a disease of interest.”

Lightner believes there will be even more developments over time as more research delves into cell-based therapies for IBD.

“I think we will see different routes of administration whether they’re intravenous or intraarterial or we’re delivering them endoscopically, but I think that we’ll certainly see more cell-based therapies,” she said. “Perhaps in the future they will be engineered to be more immunosuppressive or engineered to carry a drug to a certain area. The other thing that we’re starting to see more of is acellular therapy, or portions of cells that carry the whole function of the cell. With all the promising and innovative research being done we are likely to see an explosion in regenerative medicine. This is a really exciting time for our patients.” – by Ryan McDonald

• References:
• Dave M, et al. Inflamm Bowel Disease. 2015;doi:10.1097/MIB.0000000000000543.
• Dietz AB, et al. Gastroenterology. 2017;doi:10.1053/j.gastro.2017.04.001.
• Panes J, et al. Abstract OP009. Presented at: ECCO Congress; February 15-18, 2017; Barcelona.
• Snowden JA, et al. BMC Gastroenterol. 2019;doi:10.1186/s12876-019-0992-2.

• For more information:
• Amy Lightner, MD, can be reached through Caroline Auger at augerc@ccf.org.
• William A. Faubion Jr., MD, can be reached at faubion.william@mayo.edu.
• James Lindsay, PhD, FRCP, can be reached at james.lindsay8@nhs.net.

Disclosures: Faubion and Lindsay report no relevant financial disclosures. Lightner reports consulting for Takeda.