Areez Shafqat, Nadir Kadri, Abba Zubair, Shahrukh K Hashmi
The U.S Food and Drug Administration approval of remestemcel-L for pediatric steroid-refractory acute graft-versus-host disease (GVHD) marks the culmination of 2 decades of efforts to translate mesenchymal stromal cells (MSCs). However, the path to this milestone reveals a pattern of MSCs failing in late-phase clinical trials. Multiple sources of heterogeneity may explain these results, including variability in donor and recipient biology, product manufacturing and characterization, and trial design. For example, certain subsets of acute GVHD patients, particularly those with inflammatory/immune activation, may derive the greatest clinical benefit from MSCs. Trials failing to stratify for this patient-level heterogeneity risk failure while obscuring signals of efficacy in responsive subgroups. Improving trial design considering heterogeneity requires leveraging advances in MSC manufacturing and refining clinical trial methodologies. The development of pooled and early-passage MSCs, induced pluripotent stem cell-derived (iPSC)-MSCs, biomaterial-encapsulated MSCs, and gene-edited or chimeric antigen receptor-expressing MSCs may reduce heterogeneity and improve trafficking to and survival at disease sites. Equally important, trial methodologies must explicitly address heterogeneity from MSC manufacturing and patient enrollment. Adaptive/Bayesian designs and master protocols may allow multiple biomarkers and MSC products to be tested simultaneously, with successful combinations being translated into practice, drawing from strategies that have been successful in precision medicine.