Treatment of chronic GvHD with mesenchymal stromal cells induces durable responses: A phase II study

Author:

Boberg Erik12,Bahr Lena1,Afram Gabriel23,Lindström Carina4,Ljungman Per34,Heldring Nina1,Petzelbauer Peter5,Garming Legert Karin6,Kadri Nadir1,Le Blanc Katarina14

Affiliation:

1. Department of Laboratory Medicine Karolinska Institutet, Stockholm, Sweden

2. Department of Hematology Karolinska University Hospital, Stockholm, Sweden

3. Department of Medicine Karolinska Institutet Huddinge, Stockholm, Sweden

4. Department of Cellular Therapy and Allogeneic Stem Cell Transplantation Karolinska University Hospital Huddinge, Stockholm, Sweden

5. Skin and Endothelial Research Division, Department of Dermatology Medical University of Vienna, Vienna, Austria

6. Department of Dental Medicine Karolinska Institutet, Stockholm, Sweden

Abstract

Abstract Steroid-refractory chronic graft-vs-host disease (cGvHD) contributes to morbidity after allogeneic hematopoietic stem cell transplantation. Here, we report on 11 patients with severe, refractory cGvHD treated with repeated infusions of allogeneic bone marrow-derived mesenchymal stromal cells (MSC) over a 6- to 12-month period. Six patients responded to MSC treatment following National Institutes of Health response criteria, accompanied by improvement in GvHD-related symptoms and quality of life. This response was durable, with systemic immunosuppressive therapy withdrawn from two responders, and a further two free from steroids and tapering calcineurin inhibitors. All responders displayed a distinct immune phenotype characterized by higher levels of naïve T cells and B cells before treatment compared with the nonresponders, and a significantly higher fraction of CD31+ naïve CD4+ T cells. MSC treatment was associated with significant increases in naïve T cells, B cells, and Tregs 7 days after each infusion. Skin biopsies showed resolution of epidermal pathology. CXCL9 and CXCL10 showed differential responses in responder and nonresponder patients. Our data support the use of MSC infusions as treatment for steroid-refractory cGvHD with durable responses. We propose CXCL9 and CXCL10 as early biomarkers for responsiveness to MSC treatment. Our results highlight the importance of the MSC recipient immune phenotype in promoting treatment response. This trial was registered at www.ClinicalTrials.gov as #NCT01522716.

Funder

Karolinska Institutet

Tobias Foundation

Swedish Society of Medicine

Cancerföreningen i Stockholm

Stockholms Läns Landsting

VINNOVA

Swedish Research Council

Cancerfonden

Svenska Läkaresällskapet

Vetenskapsrådet

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,General Medicine

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