Novel-Based Approaches in Treating GVHD

Transcript:

Joseph H. Antin, MD: There are a number of other drugs that may have some value in graph-versus-host disease. My group studied bortezomib a number of years ago and published that work, and it does seem to have some activity, particularly in hepatic chronic graph-versus-host disease, although the notion of proteasome inhibition for GvHD has really not been well accepted. And I think we’ll need to see much more definitive data to adopt it into clinical practice.

Alpha-1 antitrypsin is actually quite an interesting drug. Many years ago the Minnesota group led by Dan Weisdorf, MD, demonstrated that blood levels of Alpha-1 antitrypsin were quite low in people with intestinal graph-versus-host disease. This was thought, and probably is to some extent, an epiphenomenon, reflective of protein losing enteropathy. However, the question can be raised of whether low levels of alpha-1 antitrypsin actually contribute to the pathophysiology of graph-versus-host disease.

And a number of murine studies have really demonstrated that it’s not just an antitrypsin; first of all, it’s an antiprotease that inhibits a number of different enzymes, some of which may be important in cellular cytotoxicity. So it’s possible that the use of a drug like that will reduce some degree of tissue damage. But it also has a very interesting feature of increasing regulatory T-cells.

One of the areas I think that is most promising in controlling both acute and chronic GvHD is to increase regulatory T-cells. That is really an effort to recruit the normal component of the immune system that downregulates inflammation to our benefit. And an increase in regulatory T-cells of course is not likely to result in long-term toxicity such as corticosteroid toxicity, and yet may be extremely effective in helping control graph-versus-host disease.

Low-dose interleukin-2 can do that, and there are a number of studies that are ongoing about modifications of interleukin-2, mutants of interleukin-2, which either have longer half-lives so you don’t have to give the drug every day, or have different specificities for interleukin-2 receptor that might selectively stimulate natural killer cells to try and prevent leukemic relapse, or stimulate regulatory T-cells selectively over conventional T-cells to modulate the immune response, and therefore prevent graft-versus-host disease.

Monoclonals have not been all that effective in graph-versus-host disease as a rule, certainly in therapy. There are some interesting data in prophylaxis using abatacept. Much of this was generated by Leslie Kean, MD, PhD, at Boston Children’s Hospital in both mismatched and matched patients and does seem to substantially reduce the incidence of acute GvHD without increasing the risk of infection, and without increasing the leukemic relapse rate.

I think this is a very promising approach; we’ll require additional studies, including randomized trials, to see where really it fits into our armamentarium. But it’s really the one monoclonal antibody that I’m familiar with that seems to have all the characteristics that we’re looking for in terms of preventing the clinical manifestations of GvHD without interfering with the useful components of the immune system.

Transcript Edited for Clarity