IL-12/23p40 Neutralization in Combination with Sirolimus for Prevention of Acute Graft Vs. Host Disease

IL-12/23p40 neutralization in combination with sirolimus for prevention of acute graft vs. host disease

 

 

Based on pre-clinical murine and human mechanistic data, we hypothesized that IL-12/23p40 neutralization would inhibit pathogenic Th1 and Th17 cells, facilitate Treg differentiation, and more effectively prevent acute graft vs. host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT).  We conducted a randomized, double-blind, placebo-controlled trial comparing ustekinumab (UST)/sirolimus(SIR)/tacrolimus(TAC) vs. placebo/SIR/TAC (NCT01713400). UST was delivered (45mg, or 90mg for weight > 100kg) by subcutaneous injection on day -1 and day +20. The trial was powered to detect increase in Treg/total CD4+ in peripheral blood at day 30 post-HCT among UST-treated patients. Secondary biologic studies examined Th1, Th17, and Treg phenotype and function, and PK/PD measurements. Additional clinical endpoints included engraftment, acute GVHD incidence and associated therapy, relapse and mortality, and infectious complications. Adults age ≥ 18 with adequate organ function, HCT-CI < 3, and 8/8 (HLA-A, B, C, DRB1) matched sibling or unrelated peripheral blood stem cell (PBSC) donors were randomly assigned 1:1 (UST n=15, placebo n=15) with stratification for donor type. Data was un-blinded after completion of the final analysis. There were no significant differences in patient, disease, or transplantation baseline variables between groups; two cases in the UST group had –DQB1 mismatch vs. none in the placebo group. Median blood Treg/total CD4+ at day 30 post-HCT was not different (UST 13, range 2-22; placebo 11, range 3-20), p=0.41. Median Treg suppressive units at day 30 were comparable: UST 3.51 vs. placebo 2.08, p=0.7 (figure 1a). The cumulative incidence of grade II-IV acute GVHD was similar (figure 1b), however median time (UST 52 days vs. placebo 29 days, p=0.017) to acute GVHD onset was prolonged in UST patients, maximum overall acute GVHD grade differed, refractory acute GVHD was only observed in the placebo group, and average prednisone exposure was reduced in the UST group (figure 1c). A greater number of patients in the placebo group experienced death or malignancy relapse (figure 1d). The addition of UST to SIR/TAC was safe: In comparison to placebo/SIR/TAC, there were no significant differences in engraftment, thrombotic microangiopathy, hepatic veno-occlusive disease, total infection density or occurrence of CMV, EBV, or HHV-6 reactivation post-HCT. These data support the safety of this approach, and provide a signal of clinical efficacy that merits future study. Additional studies on Th1 and Th17, and PK/PD studies will be completed for mature presentation at the meeting, and analysis of allied patient-reported outcome data is underway.