Sustained Immunogenic and Clinical Effects of Low-Dose Interleukin-2 Therapy with an Intermittent Maintenance Method for Refractory Chronic Graft-Versus-Host Disease: Results of Phase1/2a LDIL2-01 Study

Abstract

Introduction and Objectives Regulatory T cells (Treg) play a central role in the maintenance of immune tolerance. We previously reported that the altered Treg homeostasis in the prolonged lymphopenia after HSCT is one of the major pathogenesis of impaired Treg recovery leading to the onset of chronic GVHD and low-dose IL-2 can restore normal Treg homeostasis by a PD-1-dependent mechanism, resulting in the improvement of clinical GVHD symptoms. In these years, the tolerogenic effects of IL-2 have been tested for various autoimmune diseases by clinical trials. However, the schedules of IL-2 dosing in each trial are different and the optimal strategy to expand Treg is still unclear. Our murine study has shown that daily administration of IL-2 seems to be optimal for the initial expansion of Treg but less frequent dosing within the threshold could be preferable for the following maintenance of expanded Treg. Methods Based on the findings, we conducted a phase1/2a clinical trial of low-dose IL-2 for steroid-refractory chronic GVHD with a distinctive dosing schedule consisting of an initial induction phase (IL-2 dosing everyday for the first 4 weeks) and a subsequent maintenance phase (IL-2 dosing 3 times a week for the following 8 weeks). Patients who obtained clinical benefit by the 3 months could proceed to the extended therapy up to total 12 months. The appropriate single dose of IL-2 was examined by a three-step dose escalation design. Results A total of 12 patients were enrolled. None had progression of chronic GVHD or recurrent hematologic malignancy. Dose-limiting toxicity did not occur even at the maximum dose. All patients were evaluable for response, and 7 had clinically significant responses involving multiple sites. Response was observed most often in the joints (67%). One patient with oral GVHD and another patient with gastrointestinal GVHD achieved complete response. One patient with severe lung GVHD markedly improved pulmonary functional test (%FEV1; from 24.8% to 64.8 %) and activity of daily life (from bedridden to return to work). Treg were preferentially increased in all patients, with a peak median value almost 10 times the baseline value (P Conclusion These results indicate that the sustained efficacy of IL-2 against chronic GVHD does not necessarily require that Treg is maintained at a high level by continuing daily IL-2 administration over the long term. Our data provide important information for reconsidering IL-2 dosing methods from the viewpoint of long-term safety and possible combination with other treatments.