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Increased Foxp3+Helios+ Regulatory T Cells and Decreased Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation in Patients Receiving Sirolimus and RGI-2001, an Activator of Invariant Natural Killer T Cells.

  • Author(s): Chen, Yi-Bin
  • Efebera, Yvonne A
  • Johnston, Laura
  • Ball, Edward D
  • Avigan, David
  • Lekakis, Lazaros J
  • Bachier, Carlos R
  • Martin, Paul
  • Duramad, Omar
  • Ishii, Yasuyuki
  • Han, Semi
  • Jung, Yu-Jin
  • Lee, Dana
  • Kunkel, Lori
  • Negrin, Robert S
  • Bui, Jack D
  • et al.

Published Web Location

https://pdf.sciencedirectassets.com/272926/1-s2.0-S1083879117X00049/1-s2.0-S1083879117301945/main.pdf?X-Amz-Date=20191113T192644Z&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Signature=f6bd755c0f02d8ff7b7a518dd6034327dba887e150729fc08e1aa887fd8c4c8f&X-Amz-Credential=ASIAQ3PHCVTYUWRNVROG%2F20191113%2Fus-east-1%2Fs3%2Faws4_request&type=client&tid=prr-30b17dc5-f230-46e3-8aa0-0ee98f553e2a&sid=be69368064598146036af4a90cb41b35be3egxrqa&pii=S1083879117301945&X-Amz-SignedHeaders=host&X-Amz-Security-Token=IQoJb3JpZ2luX2VjEAsaCXVzLWVhc3QtMSJHMEUCIQCuuSPhQKQ6RSGRaZYNOTimIEYjeqBET4%2FglNpHO6PtegIgUlTCm0LcsCVZNq7www7gZT9m4qFPbB1KNYqvlSDI4CMq0AIINBACGgwwNTkwMDM1NDY4NjUiDI8gKWlll5lo73IwaSqtAs%2F1OLTCZJyRjsWau7o5RdAZR9MOIfMdqQ7orZapMgfwBGxJPFXoEOgLZjBEJr4ExtbB3tArTgnoaYEu%2Fp40Nn9a5v4ANYTqoiRRqiPQy5YJa8px4MeVDm8H8b9G9kf3D3GoM2pZghSC0LBaA8vVc6X599k3nDVWuxy1ADq9q5AxusMWHGu0oi0Om0pAKFJbv7arYcMuWezI6eaIJhr9K7nrRrMyvU9qxIneWYdUlcpKFT7XEf4G4%2BaQ1NNn2caG65a6NEnwkQ1K7W37%2BxBeXUDyp7jd1YXEmhCQ3yPsE0q53fMShy%2FLJGxaWonT0Bjwv4ZH7yS%2BNIzdIJopvvf0gWWEKSilD24ewUlNMdJZuBFej0C18UIYYoHIsUmt1B40wt3ywYH1mQieg7UJWbwwwKWx7gU6zwIGjzwSytCwTu33wnXXdsGEwT4Wi5p2cSQK873DDJy1tIMdoYvJUk1mQjs5pEsBhOmLa9sLLHnRPebC6WHzIjZKTSUixuAVrM%2BA72yCgAMQiRuLnhv7u0p2HSEGwLWhiSTMxrazdFMkLZzLdiHgd%2FxX%2FNIhWWslcqF%2BkiXXaWRTvjJdg2tC1Gi8AbgsI2lSYJUmhu%2BtUXRMViilI5p2dUHNxN%2F%2FZlOoHZUUeDuqONU4BuOBYegX6m4XzqBfS45j0yBkf5ILUPCFICS1V1EZl4nRvp0nAJDvNUR%2Fm66mMHV9TH4aa7zaxJ0B2BXjb6uzmcuxpbFw717fE%2B6vLKLRRNENuv5r86X3jeUhFTxT5okziNIaUNUM2ILcOxT7%2FAv3b3Eu7uuuKvv%2BGz2GgLWbwZC4E1q5gks6Gxif6weSTk33Pg0i%2BrRARFlAuk0915qJMA%3D%3D&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&X-Amz-Expires=300&hash=9fcad6b02ee7dcd31f41830ff47813afd681b015a120ca159d9a3981391ec785
No data is associated with this publication.
Abstract

Regulatory T (Treg) cells play a central role in immune tolerance and prevention of aberrant immune responses. Several studies have suggested that the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) can be ameliorated by increasing Tregs. We have developed an approach of in vivo expansion of Tregs with RGI-2001, a novel liposomal formulation of a synthetic derivative of alpha-galactosylceramide, a naturally occurring ligand that binds to CD1 and activates and expands invariant natural killer cells. In preclinical studies, a single intravenous infusion of RGI-2001 expanded Treg and could ameliorate GVHD in a mouse model of allogeneic HCT. To explore the role of RGI-2001 in clinical HCT, we initiated a phase 2A clinical trial (n = 29), testing 2 different doses of RGI-2001 administered as a single infusion on day 0 of allogeneic HCT. RGI-2001 was well tolerated and without infusion reactions or cytokine release syndrome. A subset of patients (8 of 29, 28%) responded to RGI-2001 by inducing a markedly increased number of cells with a Treg phenotype. The Treg had a high Ki-67 index and were almost exclusively Helios+ and Foxp3+, indicating that their accumulation was due to expansion of natural Treg. Notably, the incidence of grade 2 to 4 GVHD in the 8 patients who responded to RGI-2001 was 12.5%, compared with 52.4% in the 21 patients who did not respond. No grade 3 or 4 GVHD was observed in the responder group, compared with a 9.5% incidence among nonresponders. Immunosuppression with sirolimus was also associated with a low incidence of GVHD, suggesting that RGI-2001 may have synergized with sirolimus to promote Treg expansion.

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