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).
