Exploring Mechanisms and Approaches for Graft-Versus-Host Disease Prophylaxis

Ernst Holler, MD, University Medical Center Regensburg, Regensburg, Bavaria, Germany, provides insights and analyses regarding the latest mechanisms and approaches for graft-versus-host disease (GVHD) prophylaxis, explaining the latest evolution of T-cell interaction methods. 

Transcript:

Hello, I'm Professor Ernst Holler. I'm a senior physician, currently performing research and translational research on pathophysiology of graft-versus-host disease, on early recognition of graft versus host disease, and on the role of microbiota in GVHD. I have a longstanding experience in GVHD. I started my work in 1982, and I have been the head of the transplant unit at the University of Ravensburg in Germany in the last 20 years.

Now today I will introduce you about the mechanisms of GVHD prophylaxis. As we know, the T-cells are at the center of GVHD. Most of our approaches to prophylaxis of GVHD try to interact with the T-cells. And very old approach was of course, if T-cell are the bad guys, you have to remove them—so this was complete T-cell depletion, or selection of stem cells and removing all the T-cells.

This worked, this reduced graft-versus-host disease. However, we also had to learn that the donor T-cells are also involved in a major positive effect of transplantation, and that's a graft versus leukemia effect. And with complete T-cell depletion, we lose, also, some of the graft versus leukemia effect. And we also need donor T-cells for anti-infectious defense, and we get more infections if we deplete T-cells. So, complete T-cell depletion is not used anymore, and there are more sophisticated approaches for prophylaxis. 

For instance, we can selectively deplete some T-cell populations. One approach is either better T-cell depletion, which is used mainly in pediatric patients. Another approach would be to not mechanistically remove the T-cells from the graft, but to give, treat the patients with antibodies against T-cells, which are not as complete, depleting T-cells.

One very broadly used approach in Europe, is to give patients serotherapy with anti-thymocyte globulin, induced by immunization with thymocytes and prepared as a serum. The serum is given pre-transplant, and then persisting after transplant, and reducing the donor T-cell activity. 

This reduces acute and chronic GVHD, but not to a larger extent, the graft-versus-leukemia effect. Now this is still a very broad approach of suppression. The standard way is to use drugs which suppress T-cell activation, mainly [ ] inhibitors.

Now, if we talk about new developments of GVHD prophylaxis, there 2 important developments. One approach recognizes that we can use selectivity by a very simple approach. We infuse the donor T-cells in the patients without any immunosuppression. This will result in early activation of the most aggressive T-cells. And at day 3 and 4 after transplantation, post-transplant cyclophosphamide is given as a drug, which is not stem cell toxic, but which deletes activated T-cells. So, you delete selectively those T-cells which are most aggressive and attacking the patient.

This is a very broadly used approach. Nowadays, currently there are randomized trials between classical T-cell depletion, post-transplant cyclophosphamide, and the maturity of trials shows some beneficial effect of post-transplant cyclophosphamide. We know that the balance of T-cell reaction is largely influenced by a specific cell population, the regulatory T-cells. We have the GVH-reactive alloreactive T-cells, and we have regulatory T-cells. We keep them in balance. 

Now, methods are developed of selectively isolating regulatory T-cells, and there is 1 approach which is currently tested in the randomized trial, where patients’ stem cells are separated into stem cells, then regulatory T-cells and conventional T-cells. 

And patients receive, at the day of transplantation, transplant the stem cells, and in the first infusion of regulatory T-cells, and 2 days later, they receive a small proportion of classical T-cells. But by this sequential application, the regulatory T-cells can expand, and they are now then able to stop and block the reactive alloreactive T-cells given 2 days later.

And this approach gave, in phase 2 trials, very promising results, with almost only 5% acute and chronic GVHD. If this turns out and turns true in the phase 3 trials, we will have a new standard of GVH prophylaxis. I talked about GVH prophylaxis in general T-cell depletion, T-cell manipulation, and as I mentioned, it is always affecting both acute and chronic GVHD. So there's no selective mechanism to prevent chronic GVHD, and it doesn't make sense to prevent only one of these manifestations of GvHD.

Of course, again, we have to be aware that GVHD is not only T-cells, but it's also the repair capacity of the tissue, which is called tissue tolerance. And there are supplementary mechanisms stabilizing the tissues, like, again, giving beneficial microbiota or giving [interleukin-22] (IL-22), which protects the stem cells, which protects intestinal epithelial tolerance. 

So, these could be additional approaches, but the center of GVHD prophylaxis is T-cell modulation, mainly sophisticated, as I mentioned, with the [] approach. And I think this is the big chance for the future. Thank you for your attention.