Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM)

Abstract

The inability to generate mesenchymal stromal cells (MSCs) of consistent potency likely is responsible for inconsistent clinical outcomes of patients with aGvHD receiving MSC products. We developed a novel MSC manufacturing protocol characterized by high in vitro potency and near-identity of individual doses, referred to as “MSC-Frankfurt am Main (MSC-FFM)”. Herein, we report outcomes of the 69 patients who have received MSC-FFM. These were 51 children and 18 adults with refractory aGvHD grade II (4%), III (36%) or IV (59%). Patients were refractory either to frontline therapy (steroids) (29%) or to steroids and 1–5 additional lines of immunosuppressants (71%) were given infusions in four weekly intervals. The day 28 overall response rate was 83%; at the last follow-up, 61% and 25% of patients were in complete or partial remission. The median follow-up was 8.1 months. Six-month estimate for cumulative incidence of non-relapse mortality was 27% (range, 16–38); leukemia relapse mortality was 2% (range, 0–5). This was associated with a superior six-month overall survival (OS) probability rate of 71% (range, 61–83), compared to the outcome of patients not treated with MSC-FFM. This novel product was effective in children and adults, suggesting that MSC-FFM represents a promising therapy for steroid refractory aGvHD.

Clinical Use of Mesenchymal Stromal Cells in the Treatment of Acute Graft-versus-Host Disease

“…The majority of clinical trials confirmed the safety of MSCs in steroid-refractory aGvHD in the pediatric as well as adult patient population with variable success rates [5, 22-27]. However, children showed a trend towards better CR compared with adults [25, 28].…”

“…This novel manufacturing protocol is characterized by high potency and near-identity of individual doses, termed MSC-Frankfurt am Main (MSC-FFM) [24]. Recently, Bader et al [5] reported outcomes of 69 adult and pediatric patients who received a total of 212 doses of MSC-FFM for therapy-refractory aGvHD in a routine clinical setting in 23 allogeneic transplant centers from 6 countries. The patients were either steroid-refractory (29%) or refractory to steroids plus 1–5 additional immunosuppressive agents (71%).…”

“…These molecules contribute to the in vitro and in vivo immunomodulatory effects of MSCs, which are beneficial for a number of immune-pathological conditions, such as GvHD and type 1 diabetes [5, 14]. The mechanisms for therapeutic potential still remain largely unclear.…”

“…Certain factors, including skin involvement and lower aGvHD grade, yielded a higher response rate to MSC application [25]. Possibly, inconsistent results of clinical studies are attributable to different or inconsistent pharmacological quality of MSCs resulting from the lack of a standardized methodology for MSC generation, dosing, and interdonor heterogeneity [5, 24]. Kuçi et al [24] developed a novel approach for MSC generation from pooled bone marrow mononuclear cells of 8 allogeneic, third-party donors to overcome donor-to-donor variability.…”

“…Steroid-refractoriness is defined as a lack of response or progression after 3–7 days of systemic corticosteroid therapy. The long-term prognosis of steroid-refractory GvHD is poor, with an OS rate less than 30% at 1 year, attrition being due either to GvHD directly, or to sequelae of the aggressive immunosuppression to control GvHD, such as latent virus reactivation, sepsis, or relapse [2, 4, 5]. To date, there is no standard approach practiced as second-line therapy.…”