Summary
P., OA, pain
DISEASE PROGRESSION, DISEASE
Even with 15 completed RCTs, the sample size of 610 treated patients (with MSCs and control treatments) is relatively small to reach definitive conclusions on optimal dosing, baseline patient endotype and phenotype, delivery strategies, MSC sourcing, manufacturing, and overall treatment efficacy. Nonetheless, the findings of meta-analyses and our own analyses revealed positive effects on pain, function and symptoms at final follow-up endpoints in MSC-treated patients relative to baseline (12/15). In 11/15 RCTs, there were improvements in these metrics relative to the control group (HA, PRP, or surgical intervention) at 6 months or longer, depending on the dose of MSC, MSC basal fitness, the baseline clinical phenotype of the patient and the choice of the control comparator. MSCs have also demonstrated chondroprotective or regenerative effects on cartilage in 18/21 clinical studies, including 11/15 RCTs. MSCs have multimodal mechanisms of action, including chondroprotective effects, effects on cartilage repair and ECM anabolism, and pro-angiogenic, antifibrotic, anti-inflammatory and immunomodulatory effects, but there is a dearth of clinical data to confirm these mechanisms in OA. Defining baseline patient disease endotype along with clinical phenotyping will help identify and stratify patients who are receptive to receiving MSC therapies. Patient endotyping will require combinatorial tools, including different types of omics data, levels of systemic and local inflammatory markers, and immune cell subpopulations, which will need to be correlated with patient clinical outcomes and structural changes to validate them as sensitive and reliable biomarkers of patient endotypes. The episodic nature of OA further confounds the categorization of patients by clinical phenotype and/or disease endotyping but should be factored in to better understand the highly heterogeneous, personalized and temporally variable nature of disease progression. The selection of basally fit MSC products involves selecting MSCs from a host of donors that display CQAs that are relevant in the context of OA, including immunomodulatory properties, angiogenic properties and tissue remodeling properties. CQAs are modifiable by culture expansion and cryopreservation, and hence, care needs to be taken to optimize these parameters to maintain the CQAs of MSC products for clinical use. Ultimately, basally fit MSC products may be genetically engineered or nongenetically primed to be “fit-for-OA" with enhanced immunomodulatory and/or pro-angiogenic and/or cartilage-reparative properties to override reliance on donor heterogeneity and culture parameters. A combination of basally fit MSCs that are applied to a subset of knee OA patients who are receptive to receiving MSC treatments (based on disease endotyping and clinical phenotyping) will result in successful outcomes. Statistical modeling will need to be used to collect data from different trials to show the correlation between patient basal status, MSC basal fitness status and ultimately responder/nonresponder status. To enable this, larger sample sizes (for example, a 1020 patient Phase III trial to investigate the safety and efficacy of INVOSSA™, a gene-engineered cell therapy product for OA [These authors contributed equally: Griffin Copp, Kevin P. Robb.