Ustekinumab for Graft versus Host Disease Prevention (IND 144540)

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PROJECT SUMMARY Current standard immune suppression (IS) prophylaxis delivered after allogeneic hematopoietic cell transplantation (HCT) fails to effectively prevent graft vs. host disease (GVHD) after HCT. Importantly, GVHD leads to HCT-associated morbidity, death, and impaired quality of life. Recipients of unrelated donor HCT are in particular need given excess GVHD risk, and investigational strategies tailored to these patients are urgently needed. Our experimental and clinical trial data support that selective IL-12/23p40 neutralization is a rational and targeted approach to prevent GVHD: In murine systems, we demonstrate that IL-12 blockade prevents GVHD. In an initial proof of concept trial clinical trial, we demonstrated that IL-12/23p40 neutralization with the agent ustekinumab safely prolonged time to acute GVHD onset, improved grade II-IV acute GVHD-free survival, decreased Th1 and Th17 cell responses, decreased REG3a (a blood biomarker of GVHD lethality), and significantly improved overall survival and CRFS (chronic GVHD-, relapse-free survival). Building from these data, we now propose a randomized, double-blinded, placebo-controlled phase II trial to determine if ustekinumab therapy vs. placebo (both given with standard pharmacologic immune suppression prophylaxis) improves 6 month grade II-IV acute GVHD-free survival. Secondary endpoints will fully assess risk/benefit of the study intervention, chronic GVHD outcomes through 2 years post-HCT, and patient-reported symptom burden and QOL. We will also discern the biologic impact of this intervention on human immunity after HCT through comprehensive studies. In total, the proposal has major potential to advance the research field of transplantation, and enhance safe HCT utilization for treatment of hematological malignancies and disorders.