Travis Byrd, Ph.D
The Ohio State University Wexner Medical Center
Columbus, OH - USA
Since the initial exploration of mesenchymal stromal cells (MSCs) for therapeutic use by Dr. Arnold Caplan’s group in 1995, hundreds of clinical trials have been registered to evaluate their potential applications. These trials span a wide range of diseases, including inflammatory, autoimmune, neurological, pulmonary, hepatic, and hematological disorders, as well as graft-versus-host disease (GvHD). GvHD is a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT), wherein the transplanted donor immune cells (the “graft”) attack the recipient’s (the “host”) tissues. Given the immunomodulatory properties of MSCs, they have emerged as a promising therapeutic option for managing GvHD.
This topic was a focal point at the first ISCT North American Town Hall of 2025, held on March 12th. The event featured a presentation by Dr. Silviu Itescu, CEO of Mesoblast, highlighting the company’s breakthrough product, Ryoncil® (remestemcel-L), the first FDA-approved MSC therapy. Ryoncil® received FDA approval in December 2024 for the treatment of steroid-refractory acute GvHD (SR-aGvHD) in pediatric patients aged two months and older. The approval was based on a successful multicenter, single-arm study in which participants received intravenous infusions of Ryoncil® twice weekly for four consecutive weeks.
For professionals working in the IND/GMP space, Dr. Itescu provided valuable insights into the extensive clinical development process of Ryoncil®, which spanned over a decade. Notably, he discussed how advancements in manufacturing significantly reduced product potency variability between production lots. Prior to these improvements, only two-thirds of Ryoncil® batches met the FDA-approved potency release criteria. Following optimization of the manufacturing process, 100% of the product lots met the required potency standards. This underscores the critical role of continuous process refinement in ensuring the quality and consistency of cell-based therapeutics.
Dr. Itescu also elaborated on the immunomodulatory mechanism of action (MOA) of Ryoncil®. He presented data demonstrating that, by day 180 post-treatment, there was a 64% reduction in circulating CD3+CD4+CD25+HLA-DR+ activated T cells compared to baseline levels. Additionally, tumor necrosis factor receptor 1 (TNFR1) levels decreased by 79%, while Suppressor of Tumorigenesis 2 (ST2), a biomarker associated with gut inflammation, was reduced by 75%.
The FDA approval of Ryoncil® marks a significant milestone for the MSC field, potentially paving the way for broader acceptance of MSC-based therapies. However, despite this progress, there remain critical challenges and questions that must be addressed. One major concern is the variability in MSC products across different manufacturing processes or even across different manufacturers, given that MSCs are highly sensitive to culture conditions and expansion protocols. This raises the issue of standardization and reproducibility, which regulators and industry leaders must continue to refine.
As a therapeutic advances through clinical trials, the establishment of robust potency assays and a well-defined MOA are key milestones on the path to FDA approval. Dr. Itescu’s presentation provided valuable insights into these aspects, offering a rare glimpse into the regulatory and scientific challenges that accompany MSC-based product development. Ultimately, while Ryoncil® represents an exciting advancement, it is only the beginning. The approval signals a renewed interest in MSC research and underscores the need for continued innovation in manufacturing, regulatory oversight, and clinical validation. With renewed excitement in the field, the coming years may bring further breakthroughs in regenerative medicine and immune modulation.