Optimization of de novo belatacept-based immunosuppression administered to renal transplant recipients

Abstract

In the United States (US), more than 90% of renal transplant recipients are maintained on calcineurin inhibitor (CNI)-based immunosuppressive regimens. 1 CNIs (cyclosporine or tacrolimus) have been associated with systemic adverse effects (AEs), including dyslipidemia, diabetes, nephrotoxicity, and neurotoxicity, 2-14 and have the potential to negatively impact both patient and graft survival. 9,15 Belatacept is a soluble fusion protein composed of the human IgG1 Fc domain linked to the modified extracellular domain of

Belatacept Conversion in Kidney After Liver Transplantation

“… 22 Mitigation strategies to overcome the increased risk of rejection include late conversion from CNI to belatacept or the use of adjunctive de novo therapies. 12 , 23 Whereas many centers have opted for conversion, 11 at Emory we have primarily used a transient course of low-dose tacrolimus therapy within the first year posttransplant that has reduced rejection rates to levels comparable with those of CNI-based regimens while preserving the benefits of belatacept on renal function. 9 , 20 As such, in this series of KAL patients, we have effectively extended late conversion to belatacept for stable liver allograft recipients using adjunctive transient CNI therapy for the kidney graft to minimize risk of rejection and ultimately achieve CNI-free maintenance immunosuppression.…”

“…Belatacept was associated with higher rates of early acute cellular rejection, mirroring a similar effect observed in kidney recipients in the BENEFIT trial 24 that has now been mitigated by alternative de novo immunosuppressive strategies. 10 , 12 , 20 However, belatacept was also associated with an increased risk of death and graft loss 6 and 12 mo posttransplantation, with a majority of these attributable to sepsis and multisystem organ failure. 17 Although it is not clear whether the inferior outcomes observed with belatacept were a result of patient selection and preexisting immune compromise in the liver recipients or from direct interference with the CD28 pathway and impaired protective immunity, 18 we did not observe any significant adverse outcomes in this series of KAL recipients.…”

Benefit of Belatacept in Cord Blood-Derived Regulatory T Cell-Mediated Suppression of Alloimmune Response

“…However, despite promising results in preclinical and clinical trials and FDA approval a decade back, clinical use of belatacept still remains limited, in part due to severe acute rejection 32 . Previous studies have shown that in comparison to the calcineurin inhibitor (CNI)-based immunosuppressive regimens, although rejection risk increased with the new belatacept-based regimens; reduced side effects and diminished long-term cardiovascular risk remain as major advantages of these regimens 33 , 34 . One vital aim remains, which is to reduce rejection rates under belatacept-based therapy.…”

Belatacept dosing in Lung Transplantation: is there a Method to the Madness?

“…Belatacept is commonly used in kidney transplantation for maintenance immunosuppression as an alternative to calcineurin inhibitors (CNI) due to its more favorable metabolic profile, reduced chronic allograft nephropathy and incidence of de novo donor specific antibodies (DSAs), preservation of renal function, and improved long term patient and graft survival [1]. Belatacept was approved in 2011 by the US Food and Drug Administration (FDA) for use in combination with basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids for prevention of rejection in adult kidney transplant recipients seropositive for Epstein-Barr virus (EBV) [2].…”

“…While both of these studies showed superior renal and metabolic outcomes, they also found that belatacept was associated with higher rates of acute cellular rejection within the first year posttransplant [3,4]. Subsequently, alternative non-FDA approved belatacept-based maintenance regimens were explored including: (1) later post-transplant conversion from CNI to belatacept; (2) combination of belatacept plus a mammalian target of rapamycin inhibitor (MTORI); (3) belatacept plus transient CNI; and (4) T cell-depletive induction followed by belatacept plus MMF and early corticosteroid withdrawal [1]. All these strategies were described in a kidney transplant population.…”