Effect of Human Mesenchymal Stem Cells (Remestemcel-L) on Clinical Response and Survival Confirmed in a Large Cohort of Pediatric Patients with Severe High-Risk Steroid-Refractory Acute Graft Versus Host Disease

Abstract

compared to mice receiving wild type (WT) splenocytes 1. Here, we investigate the impact of miR-155 expression in T cell migration and elucidate the T cell population responsible for miR-155 mediated modulation of aGVHD. Materials and Methods: Lethally irradiated BALB/c or B6D2F1 recipients were infused with T cell depleted WT bone marrow (BM) cells and GFP expressing miR-155 KO or GFP-B6 WT T cells. Recipients were sacrificed, organs harvested and donor T cell infiltration evaluated via confocal microscopy. Transplants with only CD4+ donor T cells were also performed. Transwell migration assays towards CCR5 ligands macrophage inflammatory protein-1a (MIP-1a) (100ng/uL) and RANTES (100ng/uL) were performed utilizing allo-activated WT or miR-155-KO T cells. Results: There was a dramatic decrease in T cell infiltration of peripheral organs (Peyer's patches, liver, lung and skin) in recipients of miR-155-KO T cells as compared to WT T cells as evidenced by confocal microscopy of GFP labeled donor cells, on days 7, 14 and 21 post transplant. We reasoned that these effects could be due to the modulation of CCR5 and other chemokine receptors by miR-155. To demonstrate the functional significance of decreased CCR5 expression in miR-155 KO donor T cells, we performed in vitro transwell migration assays to CCR5 ligands RANTES and MIP-1a. To our knowledge, we are the first to show that allo-activated miR-155 KO T cells show significantly reduced migration (p<0.005) towards CCR5 ligands, as demonstrated by the average migration index of 1.08 when compared to the average migration index of WT T cells of 4.52. We performed a B6 into F1 transplant using only CD4+ donor T cells. Median survival of recipients of T cell depleted BM+ WT CD4+ T cells (n¼13) was 42 days as compared to 100% survival of all recipient mice of miR-155 KO CD4+ T cells (n¼12) on day 100, (p<0.0001). Recipients of miR-155 KO CD4+ T cells also exhibited significant lower aGVHD clinical (p<0.01) and pathological scores (p<0.01) than WT recipients. Conclusions: Our data suggest that miR-155 may exert its modulating effects in aGVHD by affecting T cell migration. Our results also indicate that the CD4+ T cell subset plays an important role in miR-155 regulation of aGVHD. Experiments are underway to determine the role of miR-155 in regulatory T cells and CD8+ T cell subsets in the modulation of aGVHD as well as evaluating the role of miR-155 in modulating T cell migration through other chemokine receptors CXCR4, S1P1 and ATP receptor P2X7R.

A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease

“…Few patients received additional IST therapy for aGVHD during this study, further evidence of remestemcel-L effectiveness in aGVHD symptom control. Results of this study confirm the overall response, safety, and survival demonstrated in a pediatric expanded-access program study that assessed remestemcel-L in children who failed to respond to steroids and additional immunosuppressive agents for the treatment of aGVHD [26,35]. In conclusion, MSB-GVHD001 and the MSB-GVHD002 follow-up study taken together with positive findings of other remestemcel-L studies in aGVHD [26,36,40] confirm the safety profile and demonstrate the efficacy and durability of remestemcel-L treatment for SR-aGVHD in the pediatric population.…”

“…There is a large unmet need for effective treatment. In previous studies, remestemcel-L treatment showed promising results for the treatment for SR-aGVHD in pediatric patients [26,35,36]. We report here the positive results of a prospective, multicenter, phase 3, pediatric study using remestemcel-L as first-line therapy for SR-aGVHD with long-term follow up through 180 days (MSB-GVHD002).…”

“…Allogeneic tolerance, inhibition at immune checkpoints, and paracrine signaling are MSC mechanisms particularly relevant to aGVHD [20,21]. Results from initial clinical studies of MSCs have indicated favorable clinical response rates with an acceptable safety profile when used to treat steroid-refractory GVHD (SR-aGVHD) [22][23][24][25][26]. In addition, GVHD therapy with MSCs is associated with reductions in relevant inflammatory biomarkers, including IL-2Ra, tumor necrosis factor receptor 1, IL-8, and hepatocyte growth factor, providing further evidence of the biological basis of the clinical benefit of this therapy in aGVHD [25].…”

“…In a multicenter expanded-access protocol using remestemcel-L (Protocol 275, NCT00759018), 241 pediatric patients with SR-aGVHD, the majority of whom were resistant to multiple immunosuppressive therapy (IST) as aGVHD treatment at the time of study enrollment, were treated with remestemcel-L (ex vivo culture-expanded allogeneic adult human MSC) as salvage therapy for SR-aGVHD [26]. Day 28 OR was 65% (95% confidence interval, 58.9% to 70.9%) and responder survival at day 100 in patients with a day 28 OR was significantly greater compared with nonresponders (82% versus 39%, log rank P< .001).…”

Comparative Bioactivity Analysis for Off-the-Shelf and Culture–Rescued Umbilical Cord-Derived Mesenchymal Stem/Stromal Cells in a Xeno- and Serum-Free Culture System

“…Due to their potency in immune cell regulation, MSCs have been intensively tested for graft-versus-host disease and autoimmune diseases. Prochymal (later named Remestemcel-L) is the first commercial MSC product tested in phase 3 trials, in which allogeneic, cryopreserved bone marrow-derived MSCs were thawed and infused into patients with severe graft-versus-host disease 20 , 21 . There were concerns about the use of freshly thawed cells that might limit the therapeutic efficacy of the intervention 6 , 22 , 23 .…”