Graft-versus-host disease and treatment with mesenchymal stromal cells

Graft-versus-host disease of both the acute (aGvHD) and chronic (cGvHD) variety remains a major cause of mortality and morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). During the last 15 years, mesenchymal stromal cells (MSC) have been explored as a promising new treatment for aGvHD, but there are many questions to be answered in this young field.

The aim of this thesis is to expand our understanding of MSC treatment and GvHD with a specific focus on safety, factors affecting the outcome of MSC therapy and the possibility of treating also cGvHD with MSC.

In paper I we performed a long-term follow up study of the first patients treated with MSC, and reported on their outcome. We demonstrated a high frequency of infections and recommend the use of prophylactic drugs and close surveillance of patients during and following MSC treatment. Regarding factors affecting the outcome, we reported an association between low passage MSC and better clinical outcome, indicating that MSC lose some of their potency with extensive culturing. In paper II, we analysed autopsy reports and tissue samples from patients treated with MSC and could demonstrate that MSC do not appear to engraft in the patients. The risk of malignant transformation of donated MSC should therefore be very low.

In paper III we demonstrated a correlation between vitamin D deficiency prior to HSCT and an increased incidence of cGvHD, indicating vitamin D deficiency as a possible risk factor for cGvHD.

Paper IV reports on a clinical trial of MSC therapy in refractory cGvHD. Eleven patients were included; of whom nine received up to six repeated infusions of MSC and could be evaluated for response. Of these nine, six patients responded to MSC therapy with durable improvement in cGvHD symptoms and could significantly reduce systemic immunosuppression.

To summarize, this thesis provides new data regarding the safety of MSC therapy and suggests that the use of MSC is relatively safe, provided that necessary precautions are taken regarding infectious complications. With this information at hand, we could move forward to expanding the use of MSC in conditions with less dire expectations than refractory aGvHD, such as cGvHD. The clinical study of MSC therapy in cGvHD is one of the largest reported worldwide and suggests that repeated infusions of MSC could be a valuable treatment option for these patients.

List of scientific papers

I. von Bahr L, Sundberg B, Lönnies L, Sander B, Karbach H, Hägglund H, Ljungman P, Gustafsson B, Karlsson H, Le Blanc K, Ringdén O. Long- term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy. Biol Blood Marrow Transplant. 2012 Apr;18(4):557–64.
https://doi.org/10.1016/j.bbmt.2011.07.023

II. von Bahr L, Batsis I, Moll G, Hägg M, Szakos A, Sundberg B, Uzunel M, Ringden O, Le Blanc K. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells. 2012 Jul;30(7):1575–8.
https://doi.org/10.1002/stem.1118

III. von Bahr L, Blennow O, Alm J, Björklund A, Malmberg K-J, Mougiakakos D, Le Blanc A, Oefner PJ, Labopin M, Ljungman P, Le Blanc K. Increased incidence of chronic GvHD and CMV disease in patients with vitamin D deficiency before allogeneic stem cell transplantation. Bone Marrow Transplant. 2015 Sep;50(9):1217–23.
https://doi.org/10.1038/bmt.2015.123

IV. von Bahr L, Heldring N, Afram G, Modin C, Garming-Legert K, Ljungman P, Davies LC, Le Blanc K. Treatment of Chronic GvHD with Mesenchymal Stromal Cells Induces Durable Responses; a Phase II Study. [Manuscript]