Abstract
INTRODUCTION:
Haploidentical allogeneic stem cell transplantation (haplo-SCT) incurs a risk of bidirectional immune reactions with either severe acute graft versus host disease (aGVHD) or graft rejection. Induction of immune tolerance with post-graft cyclophosphamide dramatically improves the outcomes of haplo-SCT. However the optimal duration and the combination of systemic immunosuppressive agents in haplo-SCT remain controversial. Ultra-low dose interleukin 2 (ULD IL-2) preferentially expands regulatory T cells (Tregs) and natural killer (NK) cells, promoting both GVHD prevention and graft versus leukemia (GVL) effects. These properties suggest that ULD IL-2 could play a useful role in haplo-SCT. Here we report the outcomes of a pilot study to determine the safety and feasibility of ULD IL-2 as GVHD prophylaxis in haploidentical allo-SCT (14-H-0180, Clinical Trials.gov ID: NCT02226861)
METHODS:
Ten subjects with high risk hematological malignancies received a myeloablative conditioning regimens of fludarabine 120mg/m2 (day -10 to day -8) and total body irradiation (TBI; 600-1200 cGy, day -10 to day -6). Thereafter the subjects received donor lymphocyte infusion (DLI) products (2x108 CD3+/kg) on day -6, followed by post-DLI cyclophosphamide 120mg/kg on days -3 and -2. CD 34+ selected, peripheral blood stem cell product was infused on day 0. Sirolimus was initiated on day -1 with goal trough level of 5-12ng/mL until day+60. ULD-IL2 (aldesleukin, 100,000 IU/m2) was given subcutaneously daily for 12 weeks starting day +1. Peripheral blood mononuclear cells (PBMC) and plasma samples were collected at days 14, 28, 60, 84, 100 post-transplant. Multi-color flow cytometry immunophenotyping assay were performed to characterize the subsets of memory T cells, Tregs, NK cells, and monocytes with various functional markers. Plasma levels of biomarkers (ST2, Reg3α, sTNFR1, ANG1, IL-6) were measured using a multiplex microfluidic channel assay.
RESULTS:
The median age at transplant was 35 years (range 20-66). Most subjects had a high risk EBMT score (median 4, range 2-7) and HCT co-morbidity index (median 4, range 2-7). All subjects achieved successful engraftment (neutrophil >500/uL; median 13 days, platelet >20k/uL; median 15 days) and rapid full donor myeloid and lymphoid chimerism by day 21. At median follow up of 6 month, the overall survival was 71%. One subject died of hepatic veno-occulusive disease (VOD) on day 32 and one subject died of relapse on day 178. All evaluable subjects tolerated ULD-IL2 without significant toxicities. Four subjects experienced either de-novo or rapid exacerbation of acute GVHD after discontinuation of ULD IL-2, resulting in the cumulative incidence of grade II-IV aGVHD of 61% and grade III-IV aGVHD of 36% (Figure A). ULD IL-2 expanded and maintained Helios+FoxP3+Tregs population (pre-transplant, 4.7%±3.1%; day 30, 36.2%±23.1%; day 84, 17.4%±10.6%) as well as CD56brightNK cells population (pre-transplant, 10.7%±13.7%; day 30, 49.7%±10.8%; day 84, 26.1%±6.8%). However on discontinuation of ULD IL-2 both populations decreased to low levels within one week. The timing of aGVHD correlated with a fall of %Tregs in PBMC and a sharp increase of ST2 level in plasma (Figure B).
CONCLUSION:
ULD IL-2 can be safely administered as GVHD prophylaxis after haplo-SCT. Rebound GVHD after discontinuation of ULD IL-2 implies that donor-derived Tregs acquired dependency to exogenous ULD IL-2. Our study is proof of principle that ULD IL-2 induces immune tolerance through Tregs expansion in haplo-SCT, inspiring further clinical and basic researches in human IL-2 biology.
No relevant conflicts of interest to declare.
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