Hematopoietic stem cell transplantation (HSCT) often represents the only chance for cure for patients diagnosed with aggressive leukemias and other hematologic malignancies. However, HSCT is a treatment that is plagued with complications. These complications result in a high rate of transplant-related mortality, with approximately 30% of recipients of unrelated donor transplants dying of transplant-related complications. The two most prominent of these complications are severe infection and acute graft-versus host disease (aGVHD). Post-transplant infections comprise the gamut of opportunistic organisms, with the greatest morbidity and mortality arising from viral disease. aGVHD arises due to the activation and proliferation of engrafting donor T cells, triggered by histocompatibility disparities between donor and recipient. These activated T cells can cause devastating damage to host tissues, with the most severe clinical manifestations occurring in the skin, the liver and the gastrointestinal tract. Importantl, the risks of aGVHD and infection are reciprocal: while potent immunosuppression can decrease the risk of aGVHD, it results in an increased risk of infection due to the attendant defects in protective immunity that immunosuppression creates. It is perhaps because of the reciprocal risks of aGVHD and of post-transplant immune incompetence that there have been no broadly successful additions to standard aGVHD prophylaxis regimens in many years, despite the unacceptably high rate of death due to aGVHD that occurs each year. Thus, there is an unmet clinical need to develop strategies that more effectively prevent aGVHD while preserving the transplant recipient's protective immune response. There is growing evidence from preclinical models that a new class of immunomodulatory agents, targeting the CD28:CD80/86 T cell costimulation pathway, has significant activity in inhibiting aGVHD. One of these agents, abatacept, is FDA approved for use in rheumatoid arthritis. In this application, the investigators propose a 'first-in-disease'Phase 2 trial to determine whether the addition of abatacept to a standard aGVHD prophylaxis strategy could increase survival after HSCT by reducing rates of aGVHD, while preserving anti-viral protective immunity. This will be done through the conduct of the following two Specific Aims: (1) To conduct a multicenter Phase 2, randomized, double-blind, placebo controlled trial to assess the impact of abatacept on the incidence of aGVHD after unrelated donor HSCT;(2) To assess the impact of abatacept on post-transplant reconstitution of T cell protective immunity against viruses.
The proposed research aims to improve clinical outcomes for patients that are undergoing hematopoietic stem cell transplantation (HSCT) as a curative therapy for hematologic malignancies, and thus is relevant to public health. It does this by investigating the efficacy of a novel biologic therapy (CD28:CD80/86-directed T cell costimulation blockade with abatacept) to reduce Graft-versus-Host Disease (GvHD), which is one of the most deadly complications of HSCT. To rigorously evaluate this question, we will conduct a multicenter phase II, randomized, double-blind, placebo controlled trial, that will assess both the efficacy and safety of abatacept in this patient population.
| Rogatko, André; Cook-Wiens, Galen; Tighiouart, Mourad et al. (2015) Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding. Entropy (Basel) 17:5288-5303 |
| Suessmuth, Yvonne; Mukherjee, Rithun; Watkins, Benjamin et al. (2015) CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCR? repertoire. Blood 125:3835-50 |
