Deciphering the efficacy of posttransplant cyclophosphamide in BMT

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Over the past several years, we have been using our murine transplant models to dissect the mechanisms underlying the efficacy of PTCy and have found that these diverge widely from the prior dogma in the field. We are actively working across several projects to better define a new mechanistic model, which will inform rational translation of new approaches or modifications to improve outcomes for patients. Indeed, in the course of these studies, we have determined that the optimal dose of PTCy is an intermediate dose rather than a very high dose. We have now completed enrollment of the primary cohort of a phase I/II study that has shown that reduced dosing PTCy allows for excellent prevention of acute GVHD while allowing lower early transplant-associated toxicity and better hematopoietic and immune recovery and function. Pharmacokinetic modeling studies by Jeannine McCune accompanying this trial are funded by an R01. We have three other clinical trials that are accruing or will begin accruing soon that are stemming from the work performed in the laboratory. Our goals with these clinical studies and ongoing laboratory research are to use our developing 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. 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 5 years on a way of integrating engineered antigen-specific cellular therapies safely and effectively with haplo BMT using PTCy in our murine models. We are now developing a protocol to clinically translate this approach and expect within the next 12-18 months to have this clinical study open.