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

Abstract

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well tolerated, and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single-arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies for aGVHD treated with MSC product (remestemcel-L) dosed at 2 £ 10 6 cells/kg twice weekly for 4 weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared with the prespecified control OR value of 45% (70.4% versus 45%, P = .0003). The statistically significant OR (70.4%) was sustained through day 100, including an increase in complete response from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days, and survival was significantly greater in day 28 responders compared with nonresponders through day 100 (86.8% versus 47.1% for responders and nonresponders, respectively, P = .0001) and through day 180 (78.9% versus 43.8%, P = .003). Remestemcel-L was well tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability, and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.

Overview of Immune Response During SARS-CoV-2 Infection: Lessons From the Past

“…Early treatment with rIFN resulted in a dampening of cytokine and chemokine release that lowered the migration of neutrophils and other cells in lung ( 91 ). An allogenic mesenchymal stem cell-based (Remestemcel-L) therapy developed by Mesoblast, which has been previously used for inflammatory conditions and graft vs. host disease in children and adults, is now being assessed for COVID-19 ( 192 – 194 ). In this therapy, bone marrow-derived MSCs from the donor are grown in vitro and are then transfused to the recipient patients.…”

Mesenchymal stromal cell therapies: immunomodulatory properties and clinical progress

“…In addition, an overall survival rate at 6 months for the MSCtreated group was shown to be 69%, a considerable improvement compared with the historical survival rates of 10-30% in patients with steroid refractory grade III and IV GvHD. With these results [159][160][161][162][163], Biologics License Application (BLA) for Remestemcel-L (Ryoncil™) for the treatment of children with steroid-refractory acute GvHD has been lately accepted for the priority review by the US FDA, which has set a Prescription Drug User Fee Act (PDUFA) action date of September 30, 2020, and if approved, Remestemcel-L will be commercially available in the USA.…”

Promising role for mesenchymal stromal cells in coronavirus infectious disease-19 (COVID-19)-related severe acute respiratory syndrome?

“…A phase-3 trial comparing MSCs or placebo in subjects with corticosteroid refractory acute G v HD showed no benefit [ 54 , 55 ]. A single arm trial of ex vivo expanded MSCs for corticosteroid refractory acute G v HD in children had a 70% overall response rate compared with a pre-specified target of 45% [ 56 ]. These trials were neither blinded nor placebo-controlled.…”

“…Giving MSCs to humans seems safe [ 8 , 9 , 54 , 56 , 61 , 72 ]. A meta-analysis with data of >1000 subjects reported only transient fever [ 74 ].…”