EBMT 2018 | Targeting T-cell, B-cell & APC activation to treat chronic GvHD

Steven Pavletic

By understanding the pathogenesis of chronic graft-versus-host disease (GvHD), treatments can be better targeted to improve patient outcomes. In this video, Steven Pavletic, MD, MS, from the National Cancer Institute, Bethesda, MD, talks about targeting T-cell, B-cell and APC activation to treat chronic GvHD, in order to derive alternative therapies to corticosteroid treatment. Dr Pavletic was speaking from the European Society for Blood and Marrow Transplantation (EBMT) 2018 Annual Meeting, held in Lisbon, Portugal.

Transcript (edited for clarity):

Because of a number of new, improved animal models and the great work of many people, including colleagues like Bruce Blazer, Stefanie Sarantopoulos, Robert Isan and many others, we have better understanding of biology and the ornament, and puzzle is coming together.
We know better now where to interfere much cleverly in the disease process.
We know that there are points to interfere with the T cell activation, the B cell activation, with antigen presenting cells activation, with neutrophils, with thalamic function and immune reconstitution, with antigen presentation in the lymph nodes, so different points now due to advances in our technologies in defining and developing new molecules. They can much more cleverly target that process, we are now in the position of testing new drugs.
So, we now aim not to shoot with big guns, and blanket approach like steroids, they’re very broad, very ineffective and very damaging. We try to interfere at certain points in this system where we can interfere with the process, maybe use combinations of drugs, interfering at a of couple points, but avoiding terrible side effects of steroids, and avoiding even more so, interfering with the beneficial effects of transplants that is curing leukemia.
So one of the high interest targets is what emerged from those that preclinical research is targeting the B cells, and the targeting the aberrant dysregulated B cell activation through the B cell receptor.
So the first in class, the first type of drug in that sector is ibrutinib. It’s been developed originally for treating B-cell hematological malignancies, primarily a number of lymphomas, so it’s been for several years approved in the US for treatment of those diseases, there’s vast experience with the safety of that agent, but now we are applying here in targeting B cells in chronic graft versus host disease.
There is another way how ibrutinib interferes with the chronic graph versus host disease, and we learned this especially from clever, chronic GVHD animal models that they’re targeting function of T cells as well.
So those concepts, having a drug that has a good biological rationale, that has vast clinical experience in other diseases, that has a well described side-effect profile, this is a perfect storm and setting, with a growing understanding of B cells in chronic graph versus host disease, to take it to clinical trials in chronic graft-versus-host disease.

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