title: 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.
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.
authors.affiliation: Bone Marrow Transplant Program, Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Electronic address: ychen6@partners.org.
authors.forename: Yi-Bin
authors.initials: YB
authors.lastname: Chen
authors.affiliation: Division of Hematology, The Ohio State University James Cancer Hospital, Columbus, Ohio.
authors.forename: Yvonne A
authors.initials: YA
authors.lastname: Efebera
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, California.
authors.forename: Laura
authors.initials: L
authors.lastname: Johnston
authors.affiliation: Division of Bone Marrow Transplantation, University of California San Diego, Moores UCSD Cancer Center, La Jolla, California.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Ball
authors.affiliation: Hematology-Oncology, Beth Israel Deacons Medical Center, Boston, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Avigan
authors.affiliation: Division of Hematology/Oncology, University of Miami Hospital and Clinics, Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Lazaros J
authors.initials: LJ
authors.lastname: Lekakis
authors.affiliation: Sarah Cannon Center for Blood Cancer, Nashville, Tennessee.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Bachier
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: REGiMMUNE Corporation, Tokyo, Japan.
authors.forename: Omar
authors.initials: O
authors.lastname: Duramad
authors.affiliation: REGiMMUNE Corporation, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California.
authors.forename: Semi
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California.
authors.forename: Yu-Jin
authors.initials: YJ
authors.lastname: Jung
authors.affiliation: Medical Affairs 360, LLC, San Diego, California.
authors.forename: Dana
authors.initials: D
authors.lastname: Lee
authors.affiliation: D2D, LLC, San Francisco, California.
authors.forename: Lori
authors.initials: L
authors.lastname: Kunkel
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, California.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California. Electronic address: jbui@ucsd.edu.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Bui
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D051858:Forkhead Transcription Factors; D005699:Galactosylceramides / Q000008:administration & dosage* / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control*; D006801:Humans; D051740:Ikaros Transcription Factor; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000166:cytology; D020123:Sirolimus / Q000008:administration & dosage* / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005699:Galactosylceramides; C111431:IKZF2 protein, human; C493154:alpha-galactosylceramide; D051740:Ikaros Transcription Factor; D020123:Sirolimus
keywords: GVHD; NK-T cells; T-regulatory cells; sirolimus