36 Scopus citations


Human CD4+25- T cells cultured in interleukin 2 (IL-2), rapamycin, and transforming growth factor β (TGFβ) along with anti-CD3 monoclonal antibody-loaded artificial antigen-presenting cells generate FoxP3+ induced regulatory T cells (iTregs) with potent suppressive function. We performed a phase 1, single-center, dose-escalation study to determine the safety profile of iTregs in adults with high-risk malignancy treated with reduced-intensity conditioning and mobilized peripheral blood stem cells (PBSCs) from HLA-identical sibling donors. Sixteen patients were enrolled and 14 were treated (2 productions failed to meet desired doses). One patient each received 3.0 × 106/kg, 3.0 × 107/kg, and 3.0 × 108/kg iTregs with corresponding T-conventional-to-iTreg ratios of 86:1, 8:1, and 1:2. After 3 patients received 3.0 × 108/kg in the presence of cyclosporine (CSA) and mycophenolate mofetil (MMF) with no dose-limiting toxicities, subsequent patients were to receive iTregs in the presence of sirolimus/MMF that favors Foxp3 stability based on preclinical modeling. However, 2 of 2 developed grade 3 acute graft-versus-host disease (GVHD), resulting in suspension of the sirolimus/MMF. An additional 7 patients received 3.0 × 108/kg iTregs with CSA/MMF. In the 14 patients treated with iTregs and CSA/MMF, there were no severe infusional toxicities with all achieving neutrophil recovery (median, day 13). Of 10 patients who received 3.0 × 108/kg iTregs and CSA/MMF, 7 had no aGVHD, 2 had grade 2, and 1 had grade 3. Circulating Foxp3+ iTregs were detectable through day 14. In summary, iTregs in the context of CSA/MMF can be delivered safely at doses as high as 3 × 108/kg. This trial was registered at www.clinicaltrials.gov as #NCT01634217.

Original languageEnglish (US)
Pages (from-to)1425-1436
Number of pages12
JournalBlood Advances
Issue number5
StatePublished - Mar 9 2021

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants R01 HL11879 (B.R.B., K.L.H.) and R01 HL56067 (B.R.B.) from the National Heart, Lung, and Blood Institute, R37 AI34495 (B.R.B.) from the National Institute of Allergy and Infectious Diseases, R01 HL114512 (M.L.M., K.L.H., J.E.W., D.J.W.) from the National Heart, Lung, and Blood Institute, and P01 CA065493 (J.E.W., B.R.B., D.H.M.) from the National Cancer Institute; Leukemia & Lymphoma Translational Research (grant R6029) (B.R.B.); National Institutes of Health National Heart, Lung, and Blood Institute Production

Publisher Copyright:
© 2021 by The American Society of Hematology.


  • Adult
  • Graft vs Host Disease/prevention & control
  • Humans
  • Mycophenolic Acid
  • Siblings
  • T-Lymphocytes, Regulatory
  • Transplantation, Homologous

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Clinical Trial, Phase I
  • Journal Article
  • Research Support, N.I.H., Extramural


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