Phase I/II trial of sitagliptin, bortezomib and post-transplant cyclophosphamide for GvHD prophylaxis; IND 158327 (09/03/2021) - PROJECT SUMMARY Acute and chronic graft-versus-host disease (GvHD) remain an important and potentially fatal complications of allogeneic (HSCT). Despite current standard prophylactic regimens based on calcineurin inhibitors, grades II-IV acute GVHD occurs in 34-51% of patients by day 100 after transplantation, and chronic GvHD occurs in up to 60% patients, both major causes of morbidity and mortality. In addition to their partial efficacy, standard GvHD prophylactic regimens target T-cell broadly and indiscriminately, delaying immune reconstitution and hampering graft-versus-tumor effects, have a narrow therapeutic index and multiple drug interactions, requiring frequent drug monitoring, directly contribute to transplant-related complications, and are typically given for 6 moths or more after transplant challenging patient compliance and increasing cost. Approaches that reduce acute and chronic GvHD without increasing relapse, given for a short duration, and avoiding the shortcomings of standard agents may improve survival and reduce cost of HSCT. Post-transplant cyclophosphamide (PTCy) is a recently developed GvHD prevention platform, initially developed to overcome human leukocyte antigen (HLA) barriers in the setting of haploidentical transplantation. PTCy preserves regulatory T-cells (Tregs) promoting immune tolerance and is consistently associated with a low incidence of chronic GvHD in clinical trial. Indeed, PTCy may be an ideal platform for the development of calcineurin inhibitor-free GVHD prevention approaches. Our preliminary data shows that the combination of PTCy and proteosome inhibition is superior to each alone in rescuing mice from experimental GvHD, and in a phase II clinical trial of HLA-matched PBSC transplants the combination of PTCy and bortezomib was well-tolerated, resulted in a low incidence of chronic GVHD (27%), and resulted in an incidence of grade II-IV acute GVHD (35.9%) similar to that expected when calcineurin inhibitors are used. Further, we have also shown that dipeptidylpeptidase (DPP)-4 inhibition, using the specific inhibitor sitagliptin, approved for treatment of type II diabetes mellitus, is a novel, simple and efficacious strategy for prevention of acute GvHD and synergizes with bortezomib in inhibiting alloreactive T cell activation and proliferation. In this project, we propose to test in a phase I/II clinical trial the combination of sitagliptin, bortezomib, and PTCy as a novel GvHD prevention regimen; a calcineurin inhibitor-free prophylaxis regimen that will be completed by day 14 post-transplant. We hypothesize that the combination will be an efficacious, short-term prophylaxis regimen that will result in reducing the incidence of grade II-IV acute GVHD from a baseline of 35% to 20% or less, thereby improving outcomes of HLA-matched related and unrelated donor allogeneic PBSC transplants. Laboratory correlative studies will assess the in vivo effects of the regimen on inflammatory cytokines, GvHD biomarkers, gut microbiota, and immune reconstitution. With only a little over 24,000 allogeneic HSCT performed annually in the United States, GvHD is a “rare disease or condition.” We believe our proposal meets the objectives of the Orphan Product Grants Program (RFA-FD-15-001).
