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

• Published in: Science translational medicine 2017-09, Vol.9 (408)
• Main Authors: Tkachev, Victor, Furlan, Scott N, Watkins, Benjamin, Hunt, Daniel J, Zheng, Hengqi Betty, Panoskaltsis-Mortari, Angela, Betz, Kayla, Brown, Melanie, Schell, John B, Zeleski, Katie, Yu, Alison, Kirby, Ian, Cooley, Sarah, Miller, Jeffrey S, Blazar, Bruce R, Casson, Duncan, Bland-Ward, Phil, Kean, Leslie S
• Format: Article
• Language: English
• Subjects: CD11c Antigen - metabolism; CD3 Complex - metabolism; Cell Proliferation - drug effects; Cytokines - metabolism; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Drug Synergism; Graft vs Host Disease - drug therapy; Graft vs Host Disease - immunology; Hematopoietic Stem Cell Transplantation; Humans; Immunity - drug effects; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Myeloid Cells - drug effects; Myeloid Cells - metabolism; OX40 Ligand - antagonists & inhibitors; OX40 Ligand - metabolism; Signal Transduction - drug effects; Sirolimus - pharmacology; Sirolimus - therapeutic use; Survival Analysis; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Transcription, Genetic - drug effects; Transplantation, Homologous; Up-Regulation - drug effects
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aan3085

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 /T 1 (T helper cell 1/cytotoxic T cell 1) and T /T 17 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.