Human Mesenchymal Stem Cell (hMSC) Donor Potency Selection for the “First in Cystic Fibrosis” Phase I Clinical Trial (CEASE-CF)

Abstract

Human Mesenchymal Stem Cell (hMSC) immunotherapy has been shown to provide both anti-inflammatory and anti-microbial effectiveness in a variety of diseases. The clinical potency of hMSCs is based upon an initial direct hMSC effect on the pro-inflammatory and anti-microbial pathophysiology as well as sustained potency through orchestrating the host immunity to optimize the resolution of infection and tissue damage. Cystic fibrosis (CF) patients suffer from a lung disease characterized by excessive inflammation and chronic infection as well as a variety of other systemic anomalies associated with the consequences of abnormal cystic fibrosis transmembrane conductance regulator (CFTR) function. The application of hMSC immunotherapy to the CF clinical armamentarium is important even in the era of modulators when patients with an established disease still need anti-inflammatory and anti-microbial therapies. Additionally, people with CF mutations not addressed by current modulator resources need anti-inflammation and anti-infection management. Furthermore, hMSCs possess dynamic therapeutic properties, but the potency of their products is highly variable with respect to their anti-inflammatory and anti-microbial effects. Due to the variability of hMSC products, we utilized standardized in vitro and in vivo models to select hMSC donor preparations with the greatest potential for clinical efficacy. The models that were used recapitulate many of the pathophysiologic outcomes associated with CF. We applied this strategy in pursuit of identifying the optimal donor to utilize for the “First in CF” Phase I clinical trial of hMSCs as an immunotherapy and anti-microbial therapy for people with cystic fibrosis. The hMSCs screened in this study demonstrated significant diversity in antimicrobial and anti-inflammatory function using models which mimic some aspects of CF infection and inflammation. However, the variability in activity between in vitro potency and in vivo effectiveness continues to be refined. Future studies require and in-depth pursuit of hMSC molecular signatures that ultimately predict the capacity of hMSCs to function in the clinical setting.

Human mesenchymal stromal cells inhibitMycobacterium aviumreplication in clinically relevant models of lung infection

“… 19 However, they found considerable source-dependent heterogeneity and MSCs from 2 of 12 sources displayed no detectable activity against MAC, consistent with the MSCs from our sources. This may be related to differential secretion of antimicrobial peptides 34 and the intrinsic resistance of MAC to some AMPs secreted by MSCs. 35 We also found interdonor variation in macrophage response to MSC treatments, with some demonstrating greater intracellular control of MAC than others.…”

Comparison of Cost and Potency of Human Mesenchymal Stromal Cell Conditioned Medium Derived from 2- and 3-Dimensional Cultures

“…IL-8 has been suggested as a target for anti-cancer drugs [ 63 , 64 ] and has been associated with adverse outcomes in COVID-19 patients, along with TNF-α, IL-6, IL-1β, and IL-33 [ 65 ]. In the context of cystic fibrosis clinical trials, the IL-8 delta CT post-LPS effect of MSC-CM was assessed as a potency predictor for selecting MSC lots [ 66 ]. Therefore, analyzing TNF-α, IL-6, and IL-8 seems reasonable to evaluate anti-inflammatory responses, and further studies could investigate the correlation between the in vitro inhibition of these cytokines and the in vivo anti-inflammatory effects in patients.…”

Potency Assays for Mesenchymal Stromal Cell Secretome-Based Products for Tissue Regeneration

“…Moreover, sometimes, the only factor sufficient for recovery may not be established. Additionally, given the effort required to establish individual metrics for each marker, functional attribute, or disease condition, it seems reasonable to develop assays applicable for a broad range of activities [58][59][60]. Hence, the restoration of a whole damaged stem cell niche may be worth considering for analysis in potency assays (Figure 1).…”