Monitoring Therapeutic Efficacy of Mesenchymal Stromal Cell Infusions By Serial Measurements of Acute Graft-Versus-Host Disease Biomarkers

High ST2 and Reg3α levels correlate with the occurrence and severity of acute graft-versus-host disease (aGVHD). Pilot studies have demonstrated the efficacy of bone marrow-derived mesenchymal stromal cell (BMSC) in aGVHD, however the optimal doses and frequencies of BMSC infusions remains undetermined. Here we report serial GVHD biomarker kinetics after BMSC infusions correlating with clinical changes. A 14 year-old boy with acute lymphoblastic leukemia developed gastrointestinal aGVHD after donor lymphocyte infusion for disease relapse. He was enrolled to a protocol (NCT02379442) evaluating upfront treatment of BMSC for new-onset aGVHD. He received eight BMSC at 2 × 106/kg doses twice a week for four weeks. Plasma were collected at baseline, immediately preceding the first infusion, before each BMSC infusion, and at days 30 and 56 following the first infusion. Samples were analyzed for ST2 and Reg3α levels using an automatic microfluidic channel system. Regulatory T-cells (Tregs) and T-cell memory subsets in peripheral blood were also evaluated using flow cytometry. ST2 peaked at 79 ng/mL on d0 of infusion and decreased with subsequent administrations of BMSCs falling to 40.7 ng/mL associated with an improvement in aGVHD. ST2 levels then rose before the 4th infusion corresponding with increase in stool output. After the 5th infusion there was a marked improvement in symptoms associated with a sharp decline of ST2 levels. Reg3α showed a similar pattern to ST2 but lagged behind ST2 changes by several days. Naïve and central memory T-cell subsets rose by d28 after first infusion (5.7 to 10.1% and 5.2 to 9.7% respectively) but no changes were observed in Tregs frequencies. ST2 dynamically correlated with clinical symptoms of aGVHD and response to BMSC infusion. Results suggest that serial biomarker measurement may guide the individual scheduling of BMSC infusion for aGVHD. ST2 appeared to be more useful than Reg3α in this respect.