Trends in mesenchymal stem cell clinical trials 2004-2018: Is efficacy optimal in a narrow dose range?

Abstract

The number of clinical trials using mesenchymal stem cells (MSCs) has increased since 2008, but this trend slowed in the past several years and dropped precipitously in 2018. Previous reports have analyzed MSC clinical trials by disease, phase, cell source, country of origin, and trial initiation date, all of which can be downloaded directly from ClinicalTrials.gov. We have extended analyses to a larger group of 914 MSC trials reported through 2018. To search for potential factors that may influence the design of new trials, we extracted data on routes of administration and dosing from individual ClinicalTrials.gov records as this information cannot be downloaded directly from the database. Intravenous (IV) injection is the most common, least invasive and most reproducible method, accounting for 43% of all trials. The median dose for IV delivery is 100 million MSCs/patient/dose. Analysis of all trials using IV injection that reported positive outcomes indicated minimal effective doses (MEDs) ranging from 70 to 190 million MSCs/patient/dose in 14/16 trials with the other two trials administering much higher doses of at least 900 million cells. Doseresponse data showing differential efficacy for improved outcomes were reported in only four trials, which indicated a narrower MED range of 100-150 million MSCs/ patient with lower and higher IV doses being less effective. The results suggest that it may be critical to determine MEDs in early trials before proceeding with large clinical trials.

Pressure Stimuli Improve the Proliferation of Wharton’s Jelly-Derived Mesenchymal Stem Cells under Hypoxic Culture Conditions

“…The number of stem cells currently used in clinical trials ranges from 10 7 to 10 9 cells [ 7 ]. Therefore, producing sufficient numbers of MSCs is very important in MSC therapy [ 8 , 9 ].…”

Mesenchymal Stem Cells: A Potential Therapeutic Strategy for Neurodegenerative Diseases

“…Although numerous in vitro and in vivo experiments in animal models have confirmed the therapeutic potential of MSCs [55], the clinical results have not been encouraging. To date, there are more than 500 ongoing MSC-based clinical trials, and more than ten products have been approved for listing globally [56], indicating that their safety and effectiveness are being recognized. Studies have shown that no serious adverse reactions have been observed in animal and human clinical trials of MSCs (bone marrow, fat, umbilical cord, or placenta) from either autologous or allogeneic sources.…”

Laparoscopy for the Treatment of Congenital Hernia: Use of Surgical Meshes and Mesenchymal Stem Cells in a Clinically Relevant Animal Model

“…However, many of them have not yielded the desired results (Trounson and McDonald, 2015) and their number has dropped over the years. This decline may be due to the fact that these preclinical and clinical trials are too heterogeneous: MSCs from different sources, different cell preparation protocols, and different cell passage numbers have been used over time (Kabat et al, 2020). Under these circumstances, the application of stem cell therapy to the surgical implantation of meshes for hernia treatment remains challenging.…”