MSC mechanisms of action in knee OA
DISEASE, ACUTE GVHD
Despite the completion of 15 peer-reviewed RCTs, there is limited evidence on the clinical mechanism of action of MSCs in OA. An improved understanding of the mechanism of action would be beneficial in the following ways: (i) it would facilitate the design of improved MSC therapies with properties tailored to achieve the desired effects in OA; (ii) it would facilitate the selection of critical quality attributes (CQAs) for MSC investigational products that are relevant to the mechanism of action and could be used as potential release criteria; (iii) in patient stratification or precision medicine-based approaches, it could facilitate the selection of patients with a higher response likelihood to MSC interventions based on disease status biomarkers relevant to the therapeutic mechanism of action; and (iv) it would facilitate the selection of relevant readouts or biomarkers that inform clinical responses based on the expected clinical effects of an MSC intervention.To underscore the importance of understanding the mechanism of action, a previous biologic license application for Remestemcel-L™, an allogeneic MSC(M) product for the treatment of steroid-refractory acute GVHD, was rejected by the United States Food and Drug Administration (FDA), partially due to the inadequacy of the CQAs employed by the sponsor; the researchers did not demonstrate a clear relationship of the MSC CQAs to the clinical potency of the product [The following subsections provide an overview of current insights into MSC mechanisms of action in OA, with emphasis on immunomodulatory mechanisms. We provide an overview of in vitro and preclinical studies that provide insights into MSC-mediated immunomodulation as an important mechanism of action in OA. We further detail the clinical evidence (beyond the 15 RCTs in the previous section) where available, discussing immunomodulatory, chondroprotective, regenerative and other effects of MSCs in the treatment of knee OA.