*Purpose: Belatacept is a costimulatory blocker that is used as de novo maintenance immunosuppression in kidney transplantation to avoid toxic effects of calcineurin inhibitors and improve long term outcomes. However, in patients maintained on belatacept, mycophenolate (MPA), and corticosteroids, acute rejection has been noted to be more frequent and severe than in calcineurin inhibitors. In view of experimental studies showing synergy between costimulatory blockade and mTOR inhibitors (mTORi), we developed a belatacept regimen incorporating everolimus.

*Methods: We prospectively enrolled 67 kidney transplant recipients (43 deceased; 24 living donors) at our center to receive denovo belatacept from August 2012 to October 2018. PBMCs were collected prior to transplantation and at the time of cause and protocol biopsies. All patients received thymoglobulin for induction (3mg/kg divided into 2 doses) with belatacept 10mg/kg administered on POD 1, 4, 14, 28, 56, and 84. Monthly maintenance dose of 5mg/kg was given starting week 16. Patients were started initially on MPA but were converted to everolimus after 1 month, and all patients were maintained on prednisone. Protocol biopsies were performed at 6 months.

*Results: In the first 12 months post-transplant, 16.4% of patients developed acute rejection: 2 patients were noted to have ACR 1a (at 4 weeks, 6 weeks), 1 with ACR 2a (at 6 months), 6 with ACR 2b (at 6 weeks (n=2), 2 months, 3 months, 6 months, 9 months), 1 with AMR (at 4 months), and 1 with simultaneous ACR 1a and AMR (at 9 months). All 11 rejections occurred in those who were on MPA and not on mTORi (3 switched back from mTORi to MPA due to intolerance; 8 had not switched to mTORi due to clinical contraindications). In addition, 12 patients were found to have borderline rejection on protocol biopsies (5 on mTORi, 7 on MPA). 33 patients did not have any inflammation on biopsies. 57 patients remained on belatacept, and 10 patients were converted to tacrolimus (1 patient was switched to tacrolimus due to poor intravenous access and not due to rejection).

*Conclusions: This trial of combining belatacept with mTORi shows that it is possible to significantly reduce the rate of acute rejection in belatacept-based regimens. All acute rejection occurred in patients who could not be converted to mTORi or needed to be converted back to MPA due to intolerance to mTORi. The synergy between mTORi and belatacept may be related to mTORi’s inhibitory effect on memory CD8+CD28-CD38+ cells that are refractory to costimulatory blockade (Castro C et al, ATC abstract 2018). Pretransplant immunotyping of circulating T cells to identify those with low percentage of CD8+CD28- cells may select patients who will be at lowest risk of rejection on belatacept-MPA based regimen (Shoji J et al, ATC abstract 2018).

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