17th Congress of EHA, Amsterdam, 14-17 June 2012

Use of mesenchymal stromal cells against graft-versus-host disease

Professor Willem Fibbe – Lieden University Medical Centre Holland


In cancer medicine we’re very interested in early cells – stem cells, progenitor cells – that can grow into other cells and Willem Fibbe, you’re working at Lieden on this very subject, in particular mesenchymal stromal cells and you’ve got a form of therapy. Now could you tell me, first of all, why these are important cells to be looking at?

The reason we are using these cells in clinical application is because of their ability to modulate and suppress immune responses. So we’re using the cells to suppress a particular form of disease called graft-versus-host disease which occurs after allogeneic stem cell transplantation and is due to differences in tissue antigens between a donor and a host. This graft-versus-host disease can be suppressed by the administration of mesenchymal stromal cells, that’s our main interest.

What is it that MSCs do to suppress immunity?

That’s a difficult point, it’s not fully clarified. There’s a whole range of in vitro studies that show that these cells produce soluble factors that are able to suppress the proliferation of certain immune cells like T cells, for instance, but also NK cells and B cells. Then the other side is that they are able to produce immune suppressive molecules, like interleukin 10, that are immune suppressive by itself. They can also induce degeneration of so-called regulatory T cells and these are T cells that are able to suppress T cell responses. Then finally they can also inhibit the differentiation of monocytes towards dendritic cells and that inhibition results in the formation of an immature cell type that is associated with what we think are tolerogenic T cell responses.

It sounds as if we could do with these in all sorts of clinical settings but where do you normally find them and how do you get your hands on more of them?

Yes, that’s a good point. We normally take them now from the marrow because the marrow contains, in addition to haematopoietic cells also non-haematopoietic stromal cells that constitute the microenvironment, the stem cell niche, where the haematopoietics can grow. So we harvest them, they adhere to plastic surfaces, we can easily exponate them multiple times and then we get the numbers required for clinical application. We can also take other tissue sources such as adipose tissue; we’re currently working on Wharton’s jelly derived stromal cells, this is the cord tissue, so there are various sources.

Now do you have to get them from each patient or can you mass produce them and put them in a bottle for the doctor to use?

That’s also a good point. We use patient designated products so we take an individual donor for each one, or sometimes two, patients because the number of cells that you can generate from a single marrow aspirate of approximately 100ml is around 200-300 million cells and we can treat one or two patients. There are biotech companies that have a different strategy, they use bioreactors and low density plating and they can generate a large number of cells for many patients so this is called an off the shelf product, our product is a patient designated product.

But in principle you’re doing the groundwork which could show whether the MSCs are going to be useful. One of the settings I know you’re looking at is allogeneic transplantation; you’ve published on this in The Lancet some time ago. Remind me of your data then because I know you’re continuing it now.

This was a pilot study in 55 patients, both adults and children, where we have administered these cells, between one and four injections with about a week or several weeks interval, and we got an overall response rate of around 70%; 60% in adults, 80% in children and, more importantly, we could show that those who responded to the treatment had a better survival than the non-responders.

Right, so you got tolerance induction from these cells?

Well we think that it may be indirectly tolerance induction but it may also be directly suppression of on-going immune responses. We think that the cells need to be activated in the body, so in the case of graft-versus-host disease can be seen as an inflammatory response and that will activate these cells and then they will start producing these soluble mediators.

OK, so more work needs to be done and that work is indeed being done. You’ve got an on-going study – what are you up to now?

We’re now up to a truly randomised study which will be a pivotal study because there have been a few randomised studies that did not reach their primary endpoint. We think that patient selection may be an important factor here so we will focus on a group of patients that have severe graft-versus-host disease which is not skin only but skin and in addition either gut or liver. So these are really the severe forms and we will treat them with steroids first and if they do not respond in five days they will get two infusions of MSCs one week apart.

But there are other standard therapies for patients who fail steroids at the moment, but how well do they work?

There are many therapies available and there are many opinions about that also but nothing has been standardised. So there are many individual centre preferences here, there’s no standard treatment. What we will do is to treat all patients who are refractory to steroids with a standard second line treatment and then we will randomise between patients receiving additional MSC treatment or not.

So you’re not going to deny the patients any of the treatments they would have got anyway.

No, that would not be ethically justified to have a control group without any form of treatment.

Quite, even though those treatments are not very effective as far as you know.

Right, I mean this is severe condition so you have to do something.

Yes, so obviously the message isn’t there yet but what are the provisional clinical implications for doctors to bear in mind because already doctors have patients undergoing allogeneic transplantation who are compromised.

Yes.

So is there a provisional clinical message?

The provisional clinical message is it might work for patients with severe graft-versus-host disease; that pilot data, not only our pilot data but other data, clearly indicate that the main point is to identify a well-defined subgroup of patients that will benefit from this disease. Then we can register MSCs as a cellular therapy for these patients.

Overall what do you see coming out of this very intriguing approach of actually getting right into the nuts and bolts of the immunity and hopefully preventing it with fewer side effects than other agents?

Yes, well we know already that there is little or no infusional toxicity, long-term side effects are uncertain but we don’t think that they will live very long. The cells are pretty safe, there is very little evidence that they are able to transform into malignant tumour cells; there have been rumours about it initially but it has never occurred over several thousands of patients that have been treated so far. So I think the first phase will be that we have to register cellular therapy with cells; we have to simplify the exponation procedures using bioreactors. Thereafter it may be that once we know the soluble mediators that they make that we can use these. Another possibility would be that we can engineer the cells to promote their properties that are involved in these beneficial effects.

Now busy doctors have a lot of stress on their thinking time, they have a lot to think about, is this something that they should dedicate some thinking time to for potentially practical benefit?

Yes, it’s a little bit early still but I would say in the area of allo-immune responses, so either organ transplantation or allogeneic stem cell transplantation or also to modulate autologous immune responses in the setting of autoimmune disorders such as multiple sclerosis, Crohn’s disease, that could be promising as well. But it will take a number of years to really find out.

So there could potentially be a number of less dangerous treatments but very common treatments which could benefit from this approach?

Absolutely.

Willem, thank you very much for joining us on ecancer.tv.

Thank you very much, a pleasure.