Facilitating resolution of life-threatening acute GVHD with human chorionic gonadotropin and epidermal growth factor

Abstract

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 = .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.

Conflict of interest statement

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 Biopharma, 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.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Response to uhCG therapy. The bar graphs indicate proportions of patients in the first-line therapy cohort (A) and the second-line therapy cohort (B) who had a CR, PR, MR, or NR or who died before day 56 from initiating treatment on study.

Figure 2.

Changes in laboratory parameters. (A) Serum hCG (measured in international units per liter), estradiol (E2; in picograms per milliliter), and testosterone (T; in nanograms per deciliter) were all significantly higher than baseline after 1 week on study. Progesterone (P; in nanograms per milliliter) did not change from baseline. (B) Serum albumin was significantly higher at days 28 and 56 in Arm 2 only. Data are presented as mean ± standard error of the mean (SEM). *P < .05 compared with baseline.

Figure 3.

Changes in serum EGF and T cell subsets. (A) Plasma EGF rose significantly at 6 hours post-uhCG dose in first-line patients (blue) but not in second-line patients (orange). (B) The Treg to Tcon ratio was higher at day 7 compared with baseline. Representative Treg scatterplots from a patient at baseline (C) and day 7 (D) show an elevated proportion of CD4+ CD25+ FoxP3+ CD127– Tregs. Data are presented as mean ± SEM. *P < .05 compared with baseline.

Figure 4.

GVHD biomarkers measured over time. Neither ST2 (A) nor REG3a (B) significantly changed over time compared with baseline in patients with a day 28 CR or PR to therapy. (C) However, AREG was significantly lower at day 56 compared with baseline in day 28 responders. Data are presented as mean ± SEM. *P < .05 compared with baseline.

Figure 5.

Plasma SCFA measured over time. (A, middle graph) Only butyrate increased in responders. (B) Plasma SCFA did not significantly increase or decrease over time in patients with no response. Data are presented as mean ± SEM (μmol/L).