IL-2 promotes early treg reconstitution after allogeneic hematopoietic cell transplantation

Brian C. Betts, Joseph Pidala, Jongphil Kim, Asmita Mishra, Taiga Nishihori, Lia Perez, Jose Leonel Ochoa-Bayona, Farhad Khimani, Kelly Walton, Ryan Bookout, Michael Nieder, Divis K. Khaira, Marco Davila, Melissa Alsina, Teresa Field, Ernesto Ayala, Frederick L. Locke, Marcie Riches, Mohamed Kharfan-Dabaja, Hugo FernandezClaudio Anasetti

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 16th April 2014 and 19th December 2015, 20 patients received IL-2 (200,000 IU/m2 thrice 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/uL vs. 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.

Original languageEnglish (US)
Pages (from-to)948-957
Number of pages10
JournalHaematologica
Volume102
Issue number5
DOIs
StatePublished - Apr 30 2017
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the Miles for Moffitt Milestone Award (BCB).We thank Prometheus Labs for providing aldesleukin. The Moffitt Cancer Center Flow Cytometry and Biostatistics Cores (P30-CA076292) contributed to the completion of this trial.

Publisher Copyright:
© 2017 Ferrata Storti Foundation.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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