Acute graft-versus-host disease (aGVHD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation that fails to improve with intense immunosuppression in some patients. We hypothesized that urinary-derived human chorionic gonadotropin (uhCG) could help facilitate resolution of life-threatening aGVHD when added as supportive care via 2 potential mechanisms: immunomodulation (akin to its role in pregnancy) and supplementation of epidermal growth factor (EGF; to aid in epithelial repair). In a phase 1 study, 26 participants received subcutaneous injections of uhCG in addition to standard immunosuppression (13 receiving initial therapy for high-risk aGVHD [according to the Minnesota criteria] and 13 receiving second-line therapy). Participants underwent serial blood testing for biomarkers of hormone response, immune modulation, and aGVHD activity on study. uhCG was well tolerated, with no dose-limiting toxicities. Sixty-two percent of patients in the high-risk cohort and 54% of patients in the second-line cohort had a complete response at study day 28. Plasma EGF was elevated sixfold (from 4 to 24 pg/mL; P 5 .02) at 6 hours postdose in the high-risk cohort, in contrast to no peak in plasma EGF in the more severe second-line cohort. After 1 week of uhCG, patients reported a twofold increase in the regulatory T cell to conventional T-cell ratio, suggesting immune modulation despite high-dose steroids. Responding patients reported signiﬁcantly lower plasma amphiregulin and higher plasma butyrate levels at study completion, suggesting improvement in mucosal damage over time. uhCG is a novel, safe, supportive therapy, proceeding to phase 2 testing at 2000 units/m2 in high-risk aGVHD. This study was registered at www.clinicaltrials.gov as #NCT02525029.
Bibliographical noteFunding Information:
Conflict-of-interest disclosure: S.G.H. has provided consulting services for Incyte, Bristol-Myers Squibb, Janssen, and CSL Behring. B.R.B. receives remuneration as an advisor to Kadmon Pharmaceuticals, Inc., Five Prime Therapeutics Inc., Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeutics; consulting services for Bristol-Myers Squibb, Incyte, Equillium, Regimmune, Dr. Reddy, GT Bio-pharma, and Incyte Corp; research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences, Inc., AbbVie Inc., the Leukemia and Lymphoma Society, Children’s Cancer Research Fund, and Kids First Fund; and is a cofounder of Tmunity. The remaining authors declare no competing financial interests.
The authors thank Michael Ehrhardt in the Cytokine Reference Laboratory at the University of Minnesota for completing the cytokine and growth factor analyses and Julie Curtsinger in the Translational Cell Therapy Laboratory for supervising the flow cytometry studies. This study was funded by the BMT Fund for the Future (S.G.H.), a Regenerative Medicine Minnesota clinical trial award (S.G.H.), and National Institutes of Health, National Heart, Lung, and Blood Institute grants R01 HL11879 and R01 HL56067 and National Institute of Allergy and Infectious Diseases grant R37 AI34495 (B.R.B.). S.G.H. is a University of Minnesota Women's Early Research Career award recipient and conducted this study during her time as a Women's Early Research Career scholar.
This study was funded by the BMT Fund for the Future (S.G.H.), a Regenerative Medicine Minnesota clinical trial award (S.G.H.), and National Institutes of Health, National Heart, Lung, and Blood Institute grants R01 HL11879 and R01 HL56067 and National Institute of Allergy and Infectious Diseases grant R37 AI34495 (B.R.B.). S.G.H. is a University of Minnesota Women’s Early Research Career award recipient and conducted this study during her time as a Women’s Early Research Career scholar.
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