Belatacept and Sirolimus Prolong Nonhuman Primate Islet Allograft Survival: Adverse Consequences of Concomitant Alefacept Therapy

Abstract

Calcineurin inhibitors (CNI) and steroids are known to promote insulin resistance, and their avoidance after islet transplantation is preferred from a metabolic standpoint. Belatacept, a B7-specific mediator of costimulation blockade (CoB), is clinically indicated as a CNI alternative in renal transplantation, and we have endeavored to develop a clinically translatable, belatacept-based regimen that could obviate the need for both CNIs and steroids. Based on the known synergy between CoB and mTOR inhibition, we studied rhesus monkeys undergoing MHC-mismatched islet allotransplants treated with belatacept and the mTOR inhibitor, sirolimus. To extend prior work on CoB-resistant rejection, some animals also received CD2 blockade with alefacept (LFA3-Ig). Nine rhesus macaques were rendered diabetic with streptozotocin and underwent islet allotransplantation. All received belatacept and sirolimus; six also received alefacept. Belatacept and sirolimus significantly prolonged rejection-free graft survival (median 225 days compared to 8 days in controls receiving basiliximab and sirolimus; p=0.022). The addition of alefacept provided no additional survival benefit, but was associated with Cytomegalovirus reactivation in 4/6 animals. No recipients produced donor-specific alloantibodies. The combination of belatacept and sirolimus successfully prevents islet allograft survival in rhesus monkeys, but induction with alefacept provides no survival benefit and increases the risk of viral reactivation.

Tacrolimus to Belatacept Conversion Following Hand Transplantation: A Case Report.

“…Studies in murine models have showed synergy between costimulation blockade and mTOR inhibitors (17). Studies in nonhuman primates have demonstrated that the combination of belatacept and sirolimus prolong renal and islet allografts survival (18,19), and we have demonstrated a therapeutic effect in NHP VCAs (data not shown). Clinically, Phase III trials have shown supremacy of belatacept in the conservation of renal function and other adverse events compared to CNIs (4).…”

CD8+ Effector T Cell Migration to Pancreatic Islet Grafts Is Dependent on Cognate Antigen Presentation by Donor Graft Cells

“…Strategies that target integrins on T cells, for example antibodies to LFA-1 or VLA-4, have proven effective but unsafe in the clinic because they interfere with the immune surveillance functions of memory T cells leading to the reactivation of latent infections (21, 22). Targeting molecules downstream of the TCR on the other hand could potentially be more specific, singling out only those effector or memory cells that are engaging Ag at the time.…”

Primate Models in Organ Transplantation

“…Polymerase chain reaction (PCR)-based assays for rhesus macaque homologs of CMV and EBV, rhCMV (Yue and Barry 2008) and LCV (Rao et al 2000;Rivailler et al 2004), respectively, are available for monitoring. Regular monitoring of transplanted animals can provide insight into the extent of immunosuppression, and perhaps, indicate when a regimen may excessively compromise protective immunity (Lo et al 2013;Lowe et al 2013). …”

“…Persistent interest in this pathway led to the development of belatacept, which differs from the base CTLA4-Ig protein by only two amino acids, but shows significantly higher inhibition of CD28 signaling (Larsen et al 2005). Belatacept was shown to be effective as maintenance therapy in primate models of islet and renal transplantation (Cardona et al 2006;Lo et al 2013;Lowe et al 2013), and subsequent clinical trials led to its successful translation to human use.…”

“…Weaver et al (2009) used the fusion protein alefacept (LFA3-Ig) in addition to CTLA4-Ig in a rhesus renal transplant model with significant prolongation of graft survival. However, a subsequent study by the same group, which replaced CTLA4-Ig with belatacept, showed no benefit with the addition of alefacept and an increase in viral infections in both renal and islet models (Lo et al 2013;Lowe et al 2013). Clearly, further experiments will be needed to clarify the role of CD2 blockade in the future.…”