While the last decade has seen improvements in survival following heart transplant, long-term outcomes remain suboptimal with an unacceptably high burden of comorbidities contributing to morbidity and mortality. Amongst these, renal dysfunction remains at the forefront with underlying pre-transplant renal impairment perpetuated by chronic calcineurin inhibitor (CNI) exposure leading to severe chronic kidney disease (creatinine > 2.5mg/dL, dialysis, or transplant) in almost one-quarter of heart transplant recipients within 10-years. Simultaneously, cardiac allograft survival is limited by the relentless immunological processes, both innate and adaptive that drive the development of cardiac allograft vasculopathy (CAV), fibrosis, and graft failure. The appearance of de novo donor specific antibodies (dnDSA) in particular portend a worse outcome5- 7. Clinically, hypertension, hypercholesterolemia and diabetes further contribute to renal dysfunction and adverse allograft outcomes. Thus, there is an urgent need for therapies that more favorably modulate the immune response while simultaneously reduce the comorbidity profile. Belatacept (CTLA4-Ig; NULOJIX) is a fusion protein comprised of the extracellular domain of human CTLA4 and the Fc domain of a human immunoglobulin (Ig) G1. By binding to CD80 and CD86 on antigen presenting cells (APCs), belatacept prevents CD28 mediated signaling critical for i) T cell activation and proliferation, ii) T follicular helper cell (Tfh) differentiation, iii) cognate T/B cell interactions and iv) both effector and regulatory mechanisms responsible for the balance between acceptance and rejection. Belatacept is FDA approved for use in kidney transplant recipients on the basis of two randomized controlled trials, which demonstrated impressive renal sparing benefits, a striking reduction in de novo donor specific antibodies (DSA), and improved long-term outcomes. The core hypothesis underlying this proposal is that belatacept, combined with an entry period of concomitant tacrolimus, will preserve or protect renal function in de novo heart transplant recipients and provide sustained long-term benefit. Specifically, we hypothesize that, in addition to the renoprotective benefits of a CNI-free regimen, belatacept will improve outcomes by i) impairing de-novo humoral responses and their downstream consequences, ii) mitigating alloimmune memory, and iii) reducing the burden of comorbidities. The goal of the current R34 application is to develop a clinical trial protocol that will test our hypothesis by 1) determining the efficacy of a belatacept-based CNI sparing regimen on improving renal function and cardiac allograft outcomes in heart transplant recipients, and 2) investigating the effects of belatacept on T-cell alloimmunity, humoral responses, and fibrosis.
Survival after heart transplant remains limited by cardiac allograft vasculopathy and chronic graft dysfunction which is compounded by a high burden of chronic kidney disease driven by long-term exposure to calcineurin inhibitor (CNI) based immunosuppression. The proposed clinical trial will test the hypothesis that costimulation blockade with belatacept (CTLA4-Ig), when used with an early CNI taper, can abrogate the progression of renal dysfunction and inhibit humoral alloimmune responses leading to better long-term survival. The goal of the current R34 application is to i) generate a finalized clinical trial protocol and prepare research related documents, ii) submit the required regulatory approvals, iii) actively recruit additional collaborators, and iv) prepare and submit the protocol to the institutional review board (IRB).
