Combined OX40L and mTOR blockade controls effector T cell activation while preserving T reconstitution after transplant.

A critical question facing the field of transplantation is how to control effector T cell (T) activation while preserving regulatory T cell (T) function. Standard calcineurin inhibitor-based strategies can partially control T, but breakthrough activation still occurs, and these agents are antagonistic to T function. Conversely, mechanistic target of rapamycin (mTOR) inhibition with sirolimus is more T-compatible but is inadequate to fully control T activation. In contrast, blockade of OX40L signaling has the capacity to partially control T activation despite maintaining T function. We used the nonhuman primate graft-versus-host disease (GVHD) model to probe the efficacy of combinatorial immunomodulation with sirolimus and the OX40L-blocking antibody KY1005. Our results demonstrate significant biologic activity of KY1005 alone (prolonging median GVHD-free survival from 8 to 19.5 days), as well as marked, synergistic control of GVHD with KY1005 + sirolimus (median survival time, >100 days; < 0.01 compared to all other regimens), which was associated with potent control of both T/T1 (T helper cell 1/cytotoxic T cell 1) and T/T17 activation. Combined administration also maintained T reconstitution [resulting in an enhanced T/T ratio (40% over baseline) in the KY1005/sirolimus cohort compared to a 2.9-fold decrease in the unprophylaxed GVHD cohort]. This unique immunologic signature resulted in transplant recipients that were able to control GVHD for the length of analysis and to down-regulate donor/recipient alloreactivity despite maintaining anti-third-party responses. These data indicate that combined OX40L blockade and sirolimus represents a promising strategy to induce immune balance after transplant and is an important candidate regimen for clinical translation.