Phase 1/2 trials of donor regulatory T cells for the treatment of steroid-refractory chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) remains a major hurdle to the success of hematopoietic stem cell transplantation, directly affecting patient morbidity and mortality. Impaired regulatory T-cell (Treg) recovery in patients with cGVHD has led to clinical studies aiming to increase peripheral Treg numbers. We conducted phase 1 dose-escalation clinical trials testing the feasibility and safety of using freshly isolated donor-derived Treg infusions in steroid-refractory/dependent cGVHD. The phase 1 was extended to a preliminary phase 2 trial, resulting in a total of 33 treated patients. We report that Treg purification from donor leukapheresis using CliniMACS were feasible and that Treg infusions were safe. Importantly, Treg infusions resulted in improved symptoms, particularly at higher Treg doses. Global responses were observed in 71% of patients, and 52% of patients had at least a 2-point improvement in the cGVHD severity scale. Furthermore, improvement in cGVHD symptoms resulted in reductions in corticosteroids, ruxolitinib, and mycophenolate in 58%, 83%, and 33% of patients, respectively, whereas calcineurin inhibitors were discontinued in 75% of patients. Exploratory analyses revealed the detection of infused Treg clonotypes up to 12 months after infusion and suggest increased Treg numbers in circulation. We observed increases in serum levels of interleukin-7 and interferon gamma and decreases in soluble CD13 and suppression of tumorigenicity 2 over time, which were not statistically significant after adjustment for multiple comparisons. Although these studies were not powered to assess efficacy, they suggest potential therapeutic benefits of donor-derived Treg in cGVHD treatment and highlight the need for larger phase 2 clinical trials. The trials were registered at www.clinicaltrials.gov as #NCT02385019 and #NCT03683498.