Despite multiple improvements in the last decade in the field of HSCT, acute graft versus host disease (aGVHD) remains a life-threatening complication and reduces substantially efficacy of HSCT. In particular, the outcome of patients with severe steroid-resistant aGVHD is very poor. Therefore, it remains important to search for new therapeutic strategies for the treatment of aGVHD.
Feasibility of the generation and efficacy of mesenchymal stroma cells (MSCs) generated with fetal calf serum (FCS) has been suggested recently. However, FCS is a putative source of prions and virus transmission. Therefore, the feasibility of the generation of MSCs expanded with human plasma and platelet lysate (hPPL) was tested as well as the feasibility and safety of the application of hPPL-MSCs in patients with steroid-refractory aGVHD. Furthermore multiple immunological changes after infusion of MSC were characterized, in vitro. However, truly active mechanisms in human are poorly understood as well as whether infusion of MSC selectively impairs GVHD-inducing immune cells or also anti-virus and anti-leukemia reactive T-cells. Therefore, phenotypical and functional changes in immunological cell types and cytokine levels were investigated.
In an open-label, non-randomized prospective phase I/II study MSCs were extracted from the bone marrow of healthy volunteers, expanded with hPPL, and stored. Patients with steroid-refractory aGVHD grade II to IV were treated with hPPL-MSC. 50 patients were included and received up to four infusions. Response rate, transplantation-related deaths, and other adverse events were assessed for up to 12 months after the last infusion of the cells. In addition, a comprehensive phenotypical and functional analysis was performed with PBMCs and serum isolated from all patients before, during, and after infusion of MSC.
Between January 2009 and July 2012, 50 patients were included, 2 patients dropped out, 5 patients are so far incompletely documented. Thus 43 patients were so far available for analysis, 6 children and 37 adults. Median age was 51,5 years (1.3–65.9). Organs involved in aGVHD were the skin (56%), the gastro-intestinal tract (86%) and the liver (33%). Overall grade was II for 11 (26%), III for 28 (65%), and IV for 3 (7%) patients. Mean number of infusion were 3 (1–4). No severe side effects were observed. Median follow-up was 4.06 months (range 0.43–12). Complete overall response was observed in 24 patients (56%) after a median of 53 days (range 3–116 days). The overall survival was significantly better in responders when compared to non-responders (p <0.001). Most patients who relapsed with GVHD of the gut were again sensitive to steroids, except one patient who then responded well to a second cycle of MSCs. Immunological monitoring suggests that anti-viral and anti-leukemia reactive T-cells are well preserved in all patients who responded to MSC treatment. In addition, we identified biomarkers which associate even 2 weeks after MSC infusion with a complete resolution of GVHD, which occurred usually after months.
Generation and infusion of hPPL-MSCs in steroid-resistant aGVHD grade II- IV is feasible, safe and appears to be effective. In addition, also patients who initially responded to hPPL-MSCs but develop later a relapse of aGVHD during tapering or cessation of immunosuppressive drugs become again sensitive to the treatment with steroids. Infusion of MSC did not impair anti-virus and anti-leukemia reactive T-cells. Identified biomarkers predict very early a usually late clinical resolution of GVHD, thus might be useful to early guide clinical decisions.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.