Safety and efficacy of Belatacept in heart transplantation

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Project Summary: Although calcineurin inhibitors (CNIs), including tacrolimus have led to excellent 1-year outcomes in heart transplantation, long-term survival remains limited by cardiac allograft vasculopathy, driven by donor-specific-antibodies (DSA), and by CNI-associated morbidity, dominated by chronic kidney disease. Belatacept, a selective costimulation blocker, is FDA approved for use in kidney transplantation as a CNI- alternative. By inhibiting CD28/CD80/CD86 interactions belatacept prevents activation of both naïve T cell and T follicular helper cells associated with the development of DSA, but less effectively inhibits memory T cells. In kidney transplant recipients, this has translated to sustained improvement in kidney function, suppression of DSA, and improved graft/patient survival, albeit at the cost of more early rejection which has since been markedly reduced by using a delayed CNI substitution strategy. Building on these findings, we propose a randomized controlled trial of belatacept in first-time heart transplant recipients, in conjunction with gradual tacrolimus withdrawal over 9-months to achieve a CNI-free immunosuppressive regimen (with mycophenolate mofetil and prednisone). We hypothesize that the gradual approach to CNI withdrawal will promote quiescence in graft-reactive T cells, thereby preventing rejection, inhibiting the development of DSA, and eliminating CNI- related morbidity, together increasing survival after heart transplantation. The specific aims are: Aim 1. Clinical trial to determine safety of belatacept in heart transplantation. We will perform a multicenter clinical trial in EBV seropositive heart transplant recipients randomized 2:1 to receive belatacept with gradual tacrolimus withdrawal (9-months) post-heart transplant or standard-of-care tacrolimus (control). The objectives are to a) establish safety of the protocol based on stopping criteria defined by the composite of historical control event rates and b) test efficacy for kidney sparing and DSA. Aim 2. Impact of CNI withdrawal under costimulation blockade on graft-reactive immune responses. We will serially analyze donor reactive, and autoantigen reactive T cell and B cell subsets using state-of-the-art phenotypic and functional assays and will quantify DSA and autoantibodies. Results will be compared between study arms and the kinetics of responses will be evaluated in individual subjects over time. Aim 3. Other mechanistic/biomarker studies relevant to primary and secondary endpoints in the trial. We will use molecular approaches to define differences in the intragraft response, explore markers of kidney injury and fibrosis, and test donor derived cell-free DNA as a potential biomarker of impeding rejection during CNI withdrawal. If successful, belatacept has the potential to transform the heart transplant field, removing CNI-morbidities and preventing DSA as major barriers to improving long-term survival. The comprehensive mechanistic studies will provide novel information, regardless of outcomes of the trial.