We developed an MHC-haploidentical allogeneic bone marrow transplantation model that parallels human treatment and is being used to decipher the immunologic impact of post-transplantation cyclophosphamide (PTCy). We are studying the impact of this therapy on clinical endpoints (survival, graft-versus-host disease, weight); accompanying these studies is a detailed characterization of the immunologic and histopathologic changes associated with this approach. We have found that the mechanisms thought to underlie GVHD prevention by PTCy were not responsible for GVHD prevention by PTCy, but instead have provided the basis for a new mechanistic model which we are working on elaborating and more fully developing. Once the mechanisms by which PTCy prevents GVHD are fully understood, we will use this understanding as a basis to explore how to refine this BMT approach clinically towards the clinical goals of further reducing graft-versus-host disease, ensuring reliable engraftment with minimal conditioning, and serving as a platform for other therapies to reduce relapse. Some of these findings are already beginning to be translated clinically with the opening of a new clinical trial this month at the NIH Clinical Center which seeks to optimize the exposure of PTCy clinically. We also are exploring the impact of PTCy on human T cells in mixed lymphocyte cultures with the goal of improving our understanding of the immunologic impact of PTCy in order to improve clinical outcomes. Lastly, we have been working over the past two years on a way of integrating antigen-specific cellular therapy safely and effectively with haplo BMT using PTCy in our murine models. We are now exploring the clinical translation of this approach and expect by the end of the next fiscal year to have a clinical study open to translate that approach..
