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

• Type of Material: Article
• Authors: Victor Tkachev, Seattle Children's Research Institute; Scott N. Furlan, Seattle Children's Research Institute; Benjamin Watkins, Emory University; Daniel J. Hunt, Seattle Children's Research Institute; Hengqi Betty Zheng, Seattle Children's Research Institute; Angela Panoskaltsis-Mortari, University of Minnesota; Kayla Betz, Seattle Children's Research Institute; Melanie Brown, Seattle Children's Research Institute; John B. Schell, Seattle Children's Research Institute; Katie Zeleski, Seattle Children's Research Institute; Alison Yu, Seattle Children's Research Institute; Ian Kirby, Kymab Ltd; Sarah Cooley, University of Minnesota; Jeffrey S. Miller, University of Minnesota; Bruce R. Blazar, University of Minnesota; Duncan Casson, Kymab Ltd; Phil Bland-Ward, Kymab Ltd; Leslie Kean, Emory University
• Language: English
• Date: 2017-09-20
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 The Authors.
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aan3085
• Title of Journal or Parent Work: Science Translational Medicine
• ISSN: 1946-6234
• Volume: 9
• Issue: 408
• Start Page: eaan3085
• End Page: eaan3085
• Grant/Funding Information: Non-human primate experiments were funded by Kymab Ltd.; B.R.B. is supported by R01 HL11879, AI34495, and HL56067. LSK is supported by NHLBI 5 R01 HL095791, NIAID 5U19-AI051731.
• Keywords: LARGE GENE LISTS; IN-VIVO; Cell Biology; Research & Experimental Medicine; CALCINEURIN INHIBITOR; COSTIMULATION BLOCKADE; EXPRESSION-DATA; MYCOPHENOLATE-MOFETIL; GVHD PROPHYLAXIS; MIXED CHIMERISM; Science & Technology; Life Sciences & Biomedicine; VERSUS-HOST-DISEASE; Medicine, Research & Experimental; BONE-MARROW-TRANSPLANTATION
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Cell

Abstract

A critical question facing the field of transplantation is how to control effector T cell (Teff) activation while preserving regulatory T cell (Treg) function. Standard calcineurin inhibitor-based strategies can partially control Teffs, but breakthrough activation still occurs, and these agents are antagonistic to Tregfunction. Conversely, mechanistic target of rapamycin (mTOR) inhibition with sirolimus is more Treg-compatible but is inadequate to fully control Teffactivation. In contrast, blockade of OX40L signaling has the capacity to partially control Teffactivation despite maintaining Tregfunction. 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; P < 0.01 compared to all other regimens), which was associated with potent control of both TH/TC1 (T helper cell 1/cytotoxic T cell 1) and TH/TC17 activation. Combined administration also maintained Tregreconstitution [resulting in an enhanced Treg/Teffratio (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.