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The future of clinical trials of mesenchymal stromal cells in acute graft-versus-host-disease
Shafqat, Areez Kadri, Nadir Zubair, Abba Hashmi, Shahrukh K
Shafqat, Areez
Kadri, Nadir
Zubair, Abba
Hashmi, Shahrukh K
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English
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Abstract
The FDA approval of remestemcel-L for pediatric steroid-refractory acute graft-versus-host disease (GVHD) marks the culmination of two 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 characterisation, 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 CAR-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 enrolment. 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.
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A. Shafqat, N. Kadri, A. Zubair, S.K. Hashmi, "The future of clinical trials of mesenchymal stromal cells in acute graft-versus-host-disease," Cytotherapy, pp. 102886-, 2026, https://doi.org/10.1016/j.jcyt.2026.102886.
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Cytotherapy
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32 Biomedical and Clinical Sciences, 3201 Cardiovascular Medicine and Haematology, 3204 Immunology
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Elsevier