A multi-centre study of belatacept and sirolimus for islet transplantation.

AIMS/HYPOTHESIS: Islet transplantation is an appropriate treatment for selected individuals with type 1 diabetes mellitus and hypoglycaemia unawareness. The gold standard of maintenance immunosuppression to prevent allograft rejection is calcineurin inhibitor-based therapy; however, side effects warrant exploration of alternative immunosuppression. The co-stimulatory blocker belatacept and the mammalian target of rapamycin inhibitor sirolimus have demonstrated clinical benefit in solid organ transplantation, but efficacy in human islet transplantation is unknown.

METHODS

We conducted a non-randomised, phase 2, multi-centre, open-label clinical study. Participants with type 1 diabetes receiving at least one islet transplant were treated with belatacept/sirolimus (bela/siro) and compared with a contemporaneous cohort treated with tacrolimus/mycophenolate mofetil (tac/MMF). The primary outcome was freedom from hypoglycaemia, with positive C-peptide and HbA1c <53 mmol/mol (7.0%) at 12 months after the first transplant. Secondary outcomes included metabolic control (Igls criteria, BETA-2 score), allosensitisation and changes in peripheral blood immune cell populations.

RESULTS

Nine participants with type 1 diabetes received bela/siro, compared with 24 receiving tac/MMF. Eight participants (89%) receiving bela/siro achieved the primary outcome compared with 12 (52%) from the tac/MMF cohort. HbA1c, HYPO score and insulin requirements were reduced in both groups, although renal function remained unchanged only in the bela/siro group. Immunosuppression resulted in sustained suppression of all monocyte, NK, T and B cell subsets, although CD4+FOXP3+ regulatory T cell proportions were higher in the bela/siro group.

CONCLUSIONS/INTERPRETATION: Baseline immunosuppression with bela/siro facilitated early islet engraftment and rates of insulin independence, with less impact on renal function, supporting the rationale for routine use in islet transplantation.

TRIAL REGISTRATION: ANZCTR.org.au ACTRN12619000268145.