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Facilitating Resolution of Life-Threatening Acute Graft-vs-Host Disease with Human Chorionic Gonadotropin and Epidermal Growth Factor

27 Pages Posted: 26 Nov 2019

See all articles by Shernan Holtan

Shernan Holtan

University of Minnesota - Blood and Marrow Transplant Program

Andrea Hoeschen

University of Minnesota

Qing Cao

University of Minnesota

Mukta Arora

University of Minnesota - Blood and Marrow Transplant Program

Veronika Bachanova

University of Minnesota - Blood and Marrow Transplant Program

Claudio G. Brunstein

University of Minnesota - Blood and Marrow Transplant Program

Jeffrey S. Miller

University of Minnesota - Minneapolis - Blood and Marrow Transplant Program

Armin Rashidi

University of Minnesota - Blood and Marrow Transplant Program

Arne Slungaard

University of Minnesota - Blood and Marrow Transplant Program

Celalettin Ustun

Rush University

Gregory M. Vercellotti

University of Minnesota - Blood and Marrow Transplant Program

Erica D. Warlick

University of Minnesota - Blood and Marrow Transplant Program

Brian C. Betts

University of Minnesota - Blood and Marrow Transplant Program

Najla El Jurdi

University of Minnesota - Minneapolis - Blood and Marrow Transplant Program

Fiona He

University of Minnesota - Blood and Marrow Transplant Program

Chi Chen

University of Minnesota

Isha Gandhi

University of Minnesota - School of Biological Sciences

John E. Wagner

Department of Pediatrics

Bruce R. Blazar

University of Minnesota

Pamala Jacobson

University of Minnesota

Ashraf Shabaneh

University of Minnesota

Jinhua Wang

University of Minnesota

Angela Panoskaltsis-Mortari

University of Minnesota

Margaret L. MacMillan

University of Minnesota

Daniel J. Weisdorf

University of Minnesota - Minneapolis - Medical Center, Fairview

More...

Abstract

Background: 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 two potential mechanisms: immunomodulation (akin to its role in pregnancy) and supplementation of epidermal growth factor (EGF, to aid in epithelial repair).  

Methods: In phase I, 26 participants received subcutaneous injections of uhCG in addition to standard immunosuppression (13 initial therapy for Minnesota high risk aGVHD and 13 receiving 2nd line therapy).  Participants underwent serial blood testing for biomarkers of hormone response, immune modulation, and aGVHD activity on study.  

Findings:  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 2nd line cohort had a complete response at study day 28. Plasma EGF was elevated 6-fold (from 4 to 24 pg/ml, p=0.02) at 6 hours post-dose in the high risk cohort, in contrast to no peak in plasma EGF in the more severe 2nd line cohort. After 1 week of uhCG, patients demonstrated a 2-fold increase in regulatory T cell to conventional T cell ratio, suggesting immune modulation despite high dose steroids. Responding patients showed significantly lower plasma amphiregulin and higher plasma butyrate at study completion, suggesting improvement in mucosal damage over time.  

Interpretation:  hCG is a novel, safe supportive therapy, proceeding to phase II testing at 2,000 units/m2 in high-risk aGVHD.

Trial Registration: This study is registered at ClinicalTrials.gov (NCT02525029).

Funding Statement: This study was funded by the BMT Fund for the Future (SGH), a Regenerative Medicine Minnesota clinical trial award (SGH), and R01 HL11879, R01 HL56067 and R37 AI34495 (BRB). SGH is a University of Minnesota Women’s Early Research Career (WERC) award recipient and conducted this study during her time as a WERC scholar.

Declaration of Interests: The authors have no relevant financial conflicts of interest to disclose. SGH has provided consulting services for Incyte, Bristol Myers Squibb, Janssen, and CSL Behring. BRB receives remuneration as an advisor to Kadmon Pharmaceuticals, Inc, Five Prime Therapeutics Inc, Regeneron Pharmaceuticals, Magenta Therapeutics, BlueRock Therapeuetics and 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., Leukemia and Lymphoma Society, Childrens' Cancer Research Fund, and KidsFirst Fund, and is a co-founder of Tmunity.

Ethics Approval Statement: This study was approved by the University of Minnesota Institutional Review Board, and all participants signed written, informed consent.

Keywords: graft-versus-host disease, human chorionic gonadotropin, epidermal growth factor, amphiregulin, butyrate, regulatory T cells

Suggested Citation

Holtan, Shernan and Hoeschen, Andrea and Cao, Qing and Arora, Mukta and Bachanova, Veronika and Brunstein, Claudio G. and Miller, Jeffrey S. and Rashidi, Armin and Slungaard, Arne and Ustun, Celalettin and Vercellotti, Gregory M. and Warlick, Erica D. and Betts, Brian C. and El Jurdi, Najla and He, Fiona and Chen, Chi and Gandhi, Isha and Wagner, John E. and Blazar, Bruce R. and Jacobson, Pamala and Shabaneh, Ashraf and Wang, Jinhua and Panoskaltsis-Mortari, Angela and MacMillan, Margaret L. and Weisdorf, Daniel J., Facilitating Resolution of Life-Threatening Acute Graft-vs-Host Disease with Human Chorionic Gonadotropin and Epidermal Growth Factor (11/9/2019). Available at SSRN: https://ssrn.com/abstract=3487807

Shernan Holtan (Contact Author)

University of Minnesota - Blood and Marrow Transplant Program ( email )

United States

Andrea Hoeschen

University of Minnesota

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Qing Cao

University of Minnesota

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Mukta Arora

University of Minnesota - Blood and Marrow Transplant Program

United States

Veronika Bachanova

University of Minnesota - Blood and Marrow Transplant Program

United States

Claudio G. Brunstein

University of Minnesota - Blood and Marrow Transplant Program

United States

Jeffrey S. Miller

University of Minnesota - Minneapolis - Blood and Marrow Transplant Program

United States

Armin Rashidi

University of Minnesota - Blood and Marrow Transplant Program

United States

Arne Slungaard

University of Minnesota - Blood and Marrow Transplant Program

United States

Celalettin Ustun

Rush University

Chicago, IL
United States

Gregory M. Vercellotti

University of Minnesota - Blood and Marrow Transplant Program

United States

Erica D. Warlick

University of Minnesota - Blood and Marrow Transplant Program

United States

Brian C. Betts

University of Minnesota - Blood and Marrow Transplant Program

United States

Najla El Jurdi

University of Minnesota - Minneapolis - Blood and Marrow Transplant Program

United States

Fiona He

University of Minnesota - Blood and Marrow Transplant Program

United States

Chi Chen

University of Minnesota

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Isha Gandhi

University of Minnesota - School of Biological Sciences

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

John E. Wagner

Department of Pediatrics ( email )

420 Delaware St. SE
Minneapolis, MN 55455
United States

Bruce R. Blazar

University of Minnesota

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Pamala Jacobson

University of Minnesota

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Ashraf Shabaneh

University of Minnesota

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Jinhua Wang

University of Minnesota

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Angela Panoskaltsis-Mortari

University of Minnesota

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Margaret L. MacMillan

University of Minnesota

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Daniel J. Weisdorf

University of Minnesota - Minneapolis - Medical Center, Fairview

MN
United States

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