Regulatory T cell modulation with selective CD28 blockade and IL-6 receptor antagonist in kidney transplant recipients: Results of CTOT-24-a prospective clinical trial.

We hypothesized that combined blockade of CD28 and interleukin-6 would favor regulatory T cells (Tregs) and prevent rejection in a novel calcineurin inhibitor-free immunosuppression regimen. In CTOT-24, a multicenter, prospective, phase I/II, pilot clinical trial, live donor kidney transplant recipients received lulizumab pegol, a novel anti-CD28 domain antibody, and tocilizumab, an anti-IL-6R antibody, for 3 months followed by belatacept and tocilizumab for 3 months. All subjects received antithymocyte globulin, steroids, and mycophenolate mofetil or everolimus. The primary endpoint was the proportion of subjects free of biopsy-proven acute rejection at 6 months posttransplantation. Of 8 treated subjects, 5 discontinued the study therapy prematurely for early acute T cell-mediated rejection, severe neutropenia, and subject preference; 3 completed the regimen without rejection and remained on belatacept, mycophenolate mofetil, and prednisone with a mean estimated glomerular filtration rate of 85.63 mL/min/1.73 m2 at 2 years posttransplantation. There were no cases of antibody-mediated rejection, death, or graft loss. Flow cytometric analyses showed no increase in circulating Tregs under the study regimen and no differences between rejectors and nonrejectors. We conclude that a regimen of combined CD28 and interleukin-6 blockade prevented rejection in only a minority and that alternative strategies are needed to promote Tregs under CD28 blockade. NCT04066114.