Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future

Abstract

Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization.

Keywords: abatacept; alloantibodies; belatacept; costimulation; immunosuppression; kidney transplantation.

Figure 1

Relative contributions of immunosuppression drugs in the current Emory University belatacept protocol. The protocol consists of basiliximab induction and an early low-dose bridge of tacrolimus to minimize early rejections that is weaned off starting at 9 months post-transplant, leaving patients on calcineurin inhibitor-free prednisone, MMF and monthly belatacept maintenance therapy long-term. MMF, mycophenolate mofetil.

Figure 2

Current obstacles to the widespread clinical adoption of belatacept, and potential avenues to surmount these obstacles and expand belatacept clinical use. AMR, antibody-mediated rejection; CNI, calcineurin inhibitor; DSA, donor-specific antibody.