Kabat Maciej, Bobkov Ivan, Kumar Suneel, Grumet Martin
W. M. Keck Center for Collaborative Neuroscience, Rutgers Stem Cell Research Center, Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, New Jersey.
Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey.
Stem Cells Transl Med. 2020 Jan;9(1):17-27. doi: 10.1002/sctm.19-0202. Epub 2019 Dec 5.
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. Dose-response 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.
自2008年以来,使用间充质干细胞(MSC)的临床试验数量有所增加,但在过去几年中这一趋势有所放缓,并在2018年急剧下降。此前的报告已按疾病、阶段、细胞来源、原产国和试验启动日期对MSC临床试验进行了分析,所有这些信息都可直接从ClinicalTrials.gov下载。我们将分析范围扩大到截至2018年报告的914项更大规模的MSC试验。为了寻找可能影响新试验设计的潜在因素,我们从ClinicalTrials.gov的各个记录中提取了给药途径和剂量的数据,因为这些信息无法直接从数据库中下载。静脉注射(IV)是最常见、侵入性最小且最可重复的方法,占所有试验的43%。静脉给药的中位剂量为1亿个MSC/患者/剂量。对所有报告了阳性结果的静脉注射试验进行分析表明,在16项试验中的14项中,最小有效剂量(MED)范围为7亿至19亿个MSC/患者/剂量,另外两项试验使用的剂量则高得多,至少为9亿个细胞。仅在四项试验中报告了显示不同疗效的剂量反应数据,这表明MED范围更窄,为10亿至15亿个MSC/患者,较低和较高的静脉剂量效果较差。结果表明,在进行大型临床试验之前,在早期试验中确定MED可能至关重要。