Identification of Novel Targetable Kinases in SR-a GvHD

Investigation of Novel Targetable Kinases in Steroid-refractory Acute Graft-versus-host Disease

In this study, the investigators aim to identify novel targetable kinases in SR-a GvHD patient samples and investigate their role in different immune cell subtypes.

Study Overview

• Status: Completed
• Conditions: Graft Versus Host Disease

Detailed Description

Corticosteroids are the first-line treatment of a GvHD, however many patients do not respond to corticosteroids. Patients with steroid-refractory a GvHD (SR-a GVHD) have a low 1-year survival rate. In this study, the investigators aim to identify and validate novel targetable kinases in SR-a GvHD patient peripheral blood mononuclear cells (PBMCs) by using a kinase-specific proteomic approach, and thereafter to investigate the role of the identified kinases in different immune cell subtypes by analyzing biopsies taken from SR- a GvHD patients.

• Study Type: Observational
• Enrollment (Actual): 24

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adult patients with acute GvHD, steroid-refractory or steroid-responsive

Description

Inclusion Criteria:

• allo-transplanted
• confirmed diagnosis of a GvHD
• age ≥ 18 years
• peripheral blood samples and biopsies available
• written informed consent
• ability to understand the nature of the study and the study-related procedures and to comply with them

Exclusion Criteria:

• age < 18 years
• lack of informed consent
• patients that cannot be classified in one of the 2 groups (steroid-refractory, steroid-responsive)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Steroid-refractory a GvHD; Analysis of peripheral blood and intestinal biopsies of patients suffering from steroid-refractory a GvHD
Steroid-responsive a GvHD; Analysis of peripheral blood and intestinal biopsies of patients suffering from steroid-responsive a GvHD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of differentially regulated kinases	Bead-based Kinase Assay enrichment (Knet beads) of PBMC lysates	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of protein expression	Analysis of PBMC lysates by western blot	3 years
Analysis of immune cell subtype	Immunohistochemistry of intestinal biopsies	3 years

Collaborators and Investigators

• Sponsor: University of Freiburg
• Investigators: Principal Investigator: Robert Zeiser, Prof. Dr., University Medical Center Freiburg

Publications and helpful links

General Publications

• Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, Spoerl S, Ditschkowski M, Ecsedi M, Sockel K, Ayuk F, Ajib S, de Fontbrune FS, Na IK, Penter L, Holtick U, Wolf D, Schuler E, Meyer E, Apostolova P, Bertz H, Marks R, Lubbert M, Wasch R, Scheid C, Stolzel F, Ordemann R, Bug G, Kobbe G, Negrin R, Brune M, Spyridonidis A, Schmitt-Graff A, van der Velden W, Huls G, Mielke S, Grigoleit GU, Kuball J, Flynn R, Ihorst G, Du J, Blazar BR, Arnold R, Kroger N, Passweg J, Halter J, Socie G, Beelen D, Peschel C, Neubauer A, Finke J, Duyster J, von Bubnoff N. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015 Oct;29(10):2062-8. doi: 10.1038/leu.2015.212. Epub 2015 Jul 31.
• Hulsdunker J, Ottmuller KJ, Neeff HP, Koyama M, Gao Z, Thomas OS, Follo M, Al-Ahmad A, Prinz G, Duquesne S, Dierbach H, Kirschnek S, Lammermann T, Blaser MJ, Fife BT, Blazar BR, Beilhack A, Hill GR, Hacker G, Zeiser R. Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset. Blood. 2018 Apr 19;131(16):1858-1869. doi: 10.1182/blood-2017-10-812891. Epub 2018 Feb 20.
• Zeiser R, Blazar BR. Acute Graft-versus-Host Disease - Biologic Process, Prevention, and Therapy. N Engl J Med. 2017 Nov 30;377(22):2167-2179. doi: 10.1056/NEJMra1609337. No abstract available.
• Schwab L, Goroncy L, Palaniyandi S, Gautam S, Triantafyllopoulou A, Mocsai A, Reichardt W, Karlsson FJ, Radhakrishnan SV, Hanke K, Schmitt-Graeff A, Freudenberg M, von Loewenich FD, Wolf P, Leonhardt F, Baxan N, Pfeifer D, Schmah O, Schonle A, Martin SF, Mertelsmann R, Duyster J, Finke J, Prinz M, Henneke P, Hacker H, Hildebrandt GC, Hacker G, Zeiser R. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat Med. 2014 Jun;20(6):648-54. doi: 10.1038/nm.3517. Epub 2014 May 18.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2017
• Primary Completion (ACTUAL): December 31, 2019
• Study Completion (ACTUAL): December 31, 2019

Study Registration Dates

• First Submitted: April 8, 2020
• First Submitted That Met QC Criteria: April 8, 2020
• First Posted (ACTUAL): April 13, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 13, 2020
• Last Update Submitted That Met QC Criteria: April 8, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Myeloid cells; Steroid-refractory GvHD; Allogeneic hematopoietic cell transplantation (allo-HCT)
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: KIN-SR-GvHD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No