Taking a Second Look at Placental-Derived Mesenchymal-Like Adherent Stromal Cell Therapy for Crohn Disease

Adrian Kilcoyne, MD, MPH, MBA

In the past, while a subsidiary of Celgene, Celularity carried out several early phase clinical trials evaluating a placental-derived mesenchymal-like adherent stromal cell (MSC) therapy for the treatment of Crohn disease (CD). The studies utilized short-term time points, such as 12 weeks or 3 months, for assessment of the therapy’s efficacy. With reference to more recent research on the mechanism of action of MSC therapies, Celularity, now operating independently, chose to conduct a new analysis in order to determine whether the time points used in the legacy clinical trials may have been too short-term to give a full picture of the therapy’s efficacy. The new findings, based on an evaluation of gene and protein signatures from participants in these trials, were presented by Adrian Kilcoyne, MD, MPH, MBA, the chief medical officer of Celularity, at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16 to 20, in Los Angeles, California.

Shortly after the conference, CGTLive™ spoke with Kilcoyne about the new findings and their implications for the potential of MSC therapy in CD. He touched on unmet needs in CD and emphasized the promising results of the new analysis.

CGTLive: What unmet needs remain with treating CD that your research aimed to address?

Adrian Kilcoyne, MD, MPH, MBA: CD is a difficult condition to manage. There have been significant advances; however, regardless of the significant advances, there's still a significant unmet need. If we look from a US perspective, notwithstanding the global problem, about 500,000 patients a year are diagnosed with CD. While there are good biologics, one of the fundamental and persistent problems remains: the requirement for surgical intervention, and importantly, the requirement for surgical intervention for fistulae. Now, fistulae occurr in about 50% of patients and despite all the advances in treatments, it remains a rather stubborn problem. Surgical rates appear to be plateaued but they certainly haven't come down; some data may even suggest they have gone up for whatever reason. But nonetheless, it remains a big problem and we need to look at strategies in order to deal with it. That's really why we looked at our legacy data and said: Given that we now have a greater understanding of the pathophysiology of fistulae, is there something within the mode of action and the responses we've seen that may suggest fistulae as an outcome? And improvement of fistulae is something that we may be able to address. So that was really what we wanted to look at.

Could you tell us about the MSC therapy and the previous legacy studies?

Just as a way of background, Celularity uses placental-derived material. From that we have a natural killer (NK) cell platform, we have a T-cell platform, we have a biomaterials platform, but we also have a mesenchymal-like adherent stromal cell—some call them mesenchymal stem cells (MSCs)—and we have done a lot of investigation into MSCs. Some of the results across the literature have been mixed. MSCs have a very broad mode of action in terms of anti-inflammatory, but also importantly, pro-repair, mechanisms of action. In the phase 1 legacy studies—and it's important to say legacy studies because we've looked back at treatment of patients, but actually looking at those patient samples with a rather modern approach in terms of understanding the pathophysiological changes—in those patients we treated, we've seen good results [in the initial studies]. Now, I would preface that the primary outcome of the studies was looking at early outcomes of these patients: 12 weeks or 3 months outcomes. But with the passage of time, we got to understand that the mode of action of MSCs is somewhat different and often it can take longer to see those outcomes. So, when we see some mixed results in MSCs, my view is that a lot of the issues we've seen is that our endpoints are early, whereas our impact is later.

Can you give an overview of the new findings you presented at ASGCT’s 2023 conference?

When we followed up some of our patients and looked at the 2-year timepoint we could see that despite there being reasonably good, but not overly compelling early data at 6 weeks, what we're seeing is a 50% complete clinical remission rate at 2 years. That made us wonder: “Well, what's going on here?”

We think there's probably an element of reprogramming—and I use that word in the broadest sense—of the immune system. Taking patients from these trials, 12 patients in each group, and looking at their protein and gene signatures, we were able to show that we were moving from a proinflammatory to an anti-inflammatory state and some of the key markers of fistulae appeared to be reducing. That was really of interest to us. This made us think that treatment with MSCs resulted in a shift in the gene signature away from the inflammatory state and away from the fistulizing state to a more regenerative state. 

We did the legacy studies a few years ago, when we were still part of Celgene Cellular Therapeutics under the umbrella of Celgene. At that time, there were multiple options in terms of going into the inflammatory bowel space and this approach was probably deprioritized somewhat from a cell therapy perspective. Now with our newfound—dare I say it—independence as a publicly-listed company, we were wondering if there was merit in proceeding further and developing further in this area? These data have now given us some view that this is probably something that should be explored further. I have said repeatedly that I don't believe the MSC studies have failed, I believe the study designs have failed the MSCs. I think now with our understanding of the mode of action, we can design the end points a lot better [and] we can design the time points a lot better so what we may have are longer studies, but with the appropriate end points. It's allowed us to rethink our approach to inflammatory bowel disease, specifically CD. Also, we've seen some more positive news for MSCs now when we look at mesoblasts in terms of graft versus host disease, etc. I think the academic and indeed the pharma community have started to figure out exactly where they should be and how to use them optimally.

Transcript edited for clarity.

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REFERENCE
Kilcoyne A, Koppisetti S, GloverB, et al. Placental-derived mesenchymal-like adherent stromal cell (MLASC) therapy results in alterations in gene and protein signatures associated with inflammation and fistula formation in patients with Crohn’s disease. Presented at: American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting. May 16-20, 2023; Los Angeles, CA. Abstract #1111