title: IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation.
abstract: Graft-versus-host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16thApril 2014 and 19thDecember 2015, 20 patients received IL-2 (200,000 IU/m2thrice weekly, days 0 to +90) with SIR (5-14 ng/mL) and tacrolimus (TAC) (3-7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8%vs.16.0%,P=0.0016; 0.052 k/uLvs.0.037 k/uL,P=0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7%vs.50%,P=0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3+CD4+T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. (clinicaltrials.gov identifier: 01927120).
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA brian.betts@moffitt.org.|Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Betts
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.|Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pidala
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jongphil
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Asmita
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Taiga
authors.initials: T
authors.lastname: Nishihori
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Lia
authors.initials: L
authors.lastname: Perez
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jose Leonel
authors.initials: JL
authors.lastname: Ochoa-Bayona
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Farhad
authors.initials: F
authors.lastname: Khimani
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Walton
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bookout
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Nieder
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Divis K
authors.initials: DK
authors.lastname: Khaira
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.|Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Davila
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Alsina
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Field
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Ayala
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Frederick L
authors.initials: FL
authors.lastname: Locke
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Marcie
authors.initials: M
authors.lastname: Riches
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kharfan-Dabaja
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Hugo
authors.initials: H
authors.lastname: Fernandez
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.|Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000517:prevention & control; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D020123:Sirolimus / Q000627:therapeutic use; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D007376:Interleukin-2; D020123:Sirolimus