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 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. (clinicaltrials.gov identifier: 01927120).

Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives

“…Less grade II-IV aGVHD (if IL-2 discontinued early) [36] HCV vasculitis 1-3 × 10 6 IU/m 2 /day from days 1 to 5 every 21 days, 4 courses 90% Clinical response [40] Systemic lupus erythematosus 1 × 10 6 IU/m 2 /day every other day for 14 days, 3-6 courses 95% Clinical response [43] Alopecia areata 1-3 × 10 6 IU/m 2 /day from days 1 to 5 every 21 days, 4 courses 80% Clinical response [42] Type1-diabetus 0.3-3 × 10 6 IU/m 2 /day, daily administration for 5 days Selective Treg increase [41] 1 3…”

“…Incidence of chronic GVHD was significantly lower than control, while the cumulative incidence with the positive minimum residual disease (MRD) test was significantly higher in IL-2 cohort compared with the control cohort. Betts et al conducted the very early IL-2 administration trial [36]. 20 patients received IL-2 (2 × 105 IU/m 2 / day), thrice weekly, from days 0 to + 90.…”

Future prospects for CD8+ regulatory T cells in immune tolerance

“…3,[103][104][105][106][107] Encouraging results were obtained in HSCT patients treated with low dose IL-2, expanding a functional CD4 + Foxp3 + Treg subset associated with a lower incidence of GVHD while maintaining a low viral infection incidence 158,159 (NCT00539695). However, soluble circulating IL2-R can mediate sequestration of IL-2 and limit its effect 160 [191][192][193] However, one study shows that the transfer of Tregs after hematopoietic stem cell transplantation can lead to overall immunosuppression and thus an increase in viral infections in the patient. 194 This is why a more specific therapy is being sought and the use of antigen-specific CAR Tregs is on the rise.…”

Therapeutic use of regulatory T cells for graft‐versus‐host disease

“…Another study tested the prophylactic utility of IL‐2 in combination with rapamycin and tacrolimus. Although the addition of IL‐2 increased the fraction of Treg cells at day 30, by day 90, Treg cells decreased and there was no reduction in acute or chronic GvHD (Betts et al , ). Therefore, the prophylactic regimen of IL‐2 should be further explored in future studies.…”