Ultra Low-Dose IL-2 for GVHD Prophylaxis after Allogeneic Hematopoietic Stem Cell Transplantation Mediates Expansion of Regulatory T Cells without Diminishing Antiviral and Antileukemic Activity

Kennedy-Nasser, Alana A.; Ku, Stephanie; Castillo-Caro, Paul; Hazrat, Yasmin; Wu, Meng; Líu, Hao; Melenhorst, J. Joseph; Barrett, A. John; Ito, Sawa; Foster, Aaron E.; Savoldo, Barbara; Yvon, Eric; Carrum, George; Ramos, Carlos A.; Krance, Robert A.; Leung, Kathryn; Heslop, Helen E.; Brenner, Malcolm K.; Bollard, Catherine M.

doi:10.1158/1078-0432.ccr-13-3205

Cited by 183 publications

(163 citation statements)

References 38 publications

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“…13 These data indicated that even though IL-2 could prevent cGVHD, relapse is still an important problem that should be addressed. Consistent with previously published data, 14,15 we found that NK and Treg cells had profoundly expanded in patients receiving IL-2 treatment. In addition, the data showed that the incidence of cGVHD was decreased after IL-2 treatment.…”

Section: Discussionsupporting

confidence: 92%

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

Zhao

Wang

et al. 2016

OncoImmunology

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Leukemia relapse and chronic graft-versus-host disease (cGVHD) are still major obstacles of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The numbers and activity of natural killer (NK) and Tregulatory cells can be increased post-transplantation by exposure to interleukin-2 (IL-2). We tested whether administering low-dose IL-2 would decrease leukemia relapse while reducing cGVHD after allotransplantation. This controlled, open-label randomized trial included 90 recipients of allotransplants. Subjects were randomized in a 1:1 ratio to either receive or not receive low-dose IL-2 during the early post-transplantation period. Patients in the IL-2 arm received a subcutaneous injection of low-dose IL-2 (1£10 6 U/d) on day 60 after allo-HSCT. IL-2 was administered daily for 14 d followed by a 14-d hiatus. The primary endpoint was the cumulative incidence of leukemia relapse (CIR). Three-year CIRs for the IL-2 arm and control arm were 23% (range 16-30%) and 11% (range 6-15%; p D 0.20), respectively. Minimal residual disease-positive (MRDC) tests were more common in the IL-2 arm compared to the control arm (36% [range 29-44%] vs. 15% [range 10-20%], p D 0.03). The cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) was lower in the IL-2 arm compared to the control arm (33% [range 26-39%] vs. 57% [range 49-64%), p D 0.02). Therefore, the 3-y GVHD-free and GVHD progression-free survival (GPFS) rates were significantly higher in the IL-2 arm compared to the control arm (47% [range 39-55%] vs. 31% [range 25-38%], p D 0.048). Blood Tregs, NK cells, and NK-cell cytotoxicity were increased in subjects in the IL-2 arm between 3 mo and 6 mo post-transplantation. Administration of low-dose IL-2 during the immediate post-transplantation period was associated with a higher GPFS but did not decrease the CIR.

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Section: Discussionsupporting

confidence: 92%

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

Zhao

Wang

et al. 2016

OncoImmunology

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“…But excessive exposure to IL-2 due to very low CsA concentrations may compromise Treg expansion. This assumption is also supported by some studies establishing that only ultralow doses of IL-2 are necessary to a better expansion of Treg (35)(36)(37).…”

Section: Application To New Patientsmentioning

confidence: 69%

Model-Based Determination of Effective Blood Concentrations of Cyclosporine for Neutrophil Response in the Treatment of Severe Aplastic Anemia in Children

Philippe

Hénin

Bertrand

et al. 2015

AAPS J

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Abstract. Optimal immunosuppressive therapy in acquired severe aplastic anemia (SAA) remains to be refined, especially cyclosporine (CsA) use. Current recommendations state that CsA trough blood concentrations (TBC) should be maintained between 200 and 400 ng/mL despite the lack of supporting data. This study aimed at quantifying relationships between CsA exposure and neutrophil response and determining an effective range for CsA TBC. Twenty-three SAA patients treated with CsA were retrospectively analyzed. Nonlinear mixed effect modeling approaches were used to develop a pharmacokinetic-pharmacodynamic model. The pharmacokinetic model described the relationships between CsA doses and TBC. The pharmacodynamic model allowed to estimate boundaries for optimal CsA effects, neutrophils being used as biomarker of response. A time-to-event model linked effective concentration to time-to-therapeutic success. CsA TBC were adequately described by a twocompartment model with first-order absorption, a lag time, and a linear elimination. The efficient range of CsA TBC was estimated between 87 and 120 ng/mL. Model-based simulations and external validation in three additional patients confirmed these results. This original modeling approach was successful in describing the relationship between CsA TBC and neutrophil response in SAA patients. Although further evaluation of the model is necessary, this work suggests that an optimal CsA TBC target of 100 ng/mL would be associated with a better neutrophil response in children with SAA.

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“…New indication of IL-2 for immune tolerance was proposed from the field of HSCT and thereafter extending to the field of autoimmunity within just a few years, suggesting the study of clinical GVHD could be an important platform to develop new cellular therapy for No grade II-IV aGVHD [34] GVHD prophylaxis 1 × 10 6 IU/m 2 /day, daily administration for 14 days followed by a 14-day hiatus, from day 60…”

Section: Resultsmentioning

confidence: 99%

“…Huston group first tested the effect of prophylactic IL-2 for pediatric patients after HSCT [34]. IL-2 (1-2 × 10 5 IU/ m 2 /day) was daily administrated from days 30 to 120, which resulted in Treg increase in the first month after the initiation of IL-2.…”

Section: Prophylactic Intervention In Treg Homeostasis By Low-dose Il-2mentioning

confidence: 99%

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

Matsuoka

2017

Int J Hematol

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CD4 + CD25 + Foxp3 + Treg is a functionally distinct subset of mature T cells with broad suppressive activity and has been shown to play an important role in the establishment of immune tolerance after HSCT. Altered cytokine environment in post-HSCT lymphopenia with a relative functional deficiency of IL-2 could hamper the reconstitution of Treg, leading to refractory GVHD. Based on the theory of low-dose IL-2 in which Treg can be selectively stimulated through the high-affinity IL-2 receptor, clinical studies have been conducted and demonstrated that low-dose IL-2 administration can restore Treg homeostasis and promote the expansion of this subset on the polymorphic processes of Treg reconstitution after HSCT. The new therapeutic indication of IL-2 for immune tolerance has launched in the field of HSCT and is spreading to the other fields including the treatment for autoimmune diseases. To further extend the indication of low-dose IL-2 to more patients with various immunological problems, the optimization of the timing and dosing of IL-2 intervention and the concomitant immune suppressive therapy according to each patient-based assessment are to be desired in the near future. Further prospective studies may facilitate the development of novel therapeutic algorithms for the effective and safe induction of immune tolerance after HSCT.

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Ultra Low-Dose IL-2 for GVHD Prophylaxis after Allogeneic Hematopoietic Stem Cell Transplantation Mediates Expansion of Regulatory T Cells without Diminishing Antiviral and Antileukemic Activity

Cited by 183 publications

References 38 publications

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

Model-Based Determination of Effective Blood Concentrations of Cyclosporine for Neutrophil Response in the Treatment of Severe Aplastic Anemia in Children

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

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