Tildrakizumab as Prophylaxis for Graft-versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation
Investigators at the Medical College of Wisconsin, collaborating with microbiome researchers at Memorial Sloan Kettering Cancer Center, have found the addition of the IL-23p19–blocking antibody tildrakizumab to standard tacrolimus/methotrexate prophylaxis is feasible and associated with a low incidence of acute GVHD after myeloablative, HLA-matched peripheral blood stem cell transplantation. In this phase 1-2 study reported in Blood Advances, tildrakizumab was safely delivered on an extended multi-dose schedule, showed predictable pharmacokinetics without neutralizing antibodies, and was associated with microbiome patterns showing little domination by organisms linked to GVHD-related mortality. Overall, IL-23 blockade can be layered onto conventional prophylaxis to reduce acute GVHD signals, but on this schedule, did not meaningfully prevent chronic GVHD.
Acute GVHD is driven by inflammatory cytokine networks that promote donor T cell priming and differentiation toward pathogenic Th1 and Th17 programs, with IL-23 positioned upstream as a stabilizer of Th17 lineage commitment and a contributor to gastrointestinal pathology. Based on strong preclinical evidence that IL-23/IL-23R blockade reduces GVHD lethality, the investigators designed a phase 1-2 trial to test whether selective IL-23p19 inhibition is safe and can improve GVHD-related outcomes in humans. Fifty adult patients undergoing first myeloablative busulfan-based allogeneic HSCT with 8/8 matched related or unrelated peripheral blood grafts received tildrakizumab 100 mg subcutaneously on days -1, +28, +112, +196, and +280, in addition to tacrolimus and methotrexate. The primary endpoint was GVHD-free relapse-free survival (GRFS) at 12 months, with prespecified events including grade III–IV acute GVHD, systemic therapy for chronic GVHD, relapse, or death; correlative analyses included cytokine profiling, population pharmacokinetics, anti-drug antibody testing, and comparative stool microbiome profiling versus a prior tocilizumab prophylaxis cohort.
All 50 treated patients engrafted (median neutrophil recovery 15 days; median platelet engraftment 17 days), and acute GVHD rates were low: grade II–IV acute GVHD was 14% by day 100 and 18% by day 180, while grade III–IV acute GVHD was 4% at both time points. Chronic GVHD remained frequent, with systemic-therapy–requiring chronic GVHD rising from 18% at 6 months to 52.7% at 12 months, and this drove the poor GRFS signal: one-year GRFS was 19.3% (90% CI 11.8–31.4; p=0.55 vs the 20% null), with chronic GVHD the dominant triggering event. One-year outcomes included overall survival 80% (95% CI 70–92), disease-free survival 78% (95% CI 67–90), relapse incidence 14% (events 38–118 days post-transplant), and transplant-related mortality 8% at 12 months. Pharmacokinetics were consistent with prior non-transplant populations (Tmax 6–7 days; half-life ~28 days) and no anti-tildrakizumab antibodies were detected across 169 samples. Microbiome profiling (214 stool samples from 47 tildrakizumab-treated patients compared with 82 samples from 19 tocilizumab-treated patients) showed low domination overall and notably no Enterococcus domination in either cohort. These findings support IL-23p19 blockade as a clinically deployable strategy to suppress acute GVHD biology and potentially blunt high-risk dysbiosis, while also clarifying that chronic GVHD likely requires different targets, timing, or dosing intensity to achieve durable GVHD-free survival.
Reference:
Runaas L, Fank S, Palen K, et al. Tildrakizumab as Prophylaxis for Graft-versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation. Blood. Published online February 3, 2026.