Yan Hou, MD, PhD
Substantial preclinical data support the safety and efficacy of mesenchymal stem cells (MSC) to improve outcomes during the chronic phase of stroke. Initial human studies of MSC after stroke focused on autologous cell therapies, whereby bone marrow is taken from each patient to produce his/her own MSC batch, and found MSC infusion to be safe. Compared to autologous cells, allogeneic MSC can be manufactured to enables broad clinical application, and it have been found to be safe without use of concomitant immunosuppression, because MSC are relatively immunoprivileged given their very low levels of human leukocyte antigen molecule expression. Studies of allogeneic MSC poststroke have focused on using an invasive procedure to implant cells intracerebrally. An intravenous method of introducing MSC if comparably efficacious might facilitate widespread implementation and also avoid adverse events attributable to invasive procedures.
The authors performed a phase I/II multi-center, open-labeled, dose-escalation trial that examined effects of a single intravenous infusion of allogeneic ischemia-tolerant MSC in patients with chronic ischemic stroke (>6 month from onset) and substantial functional deficits. MSC were grown from the bone marrow of a single human donor and are from the same batch used in prior preclinical and clinical studies. Thirty-six patients were enrolled (75% were males, 86% were Caucasians, at age 61.1 ± 10.8, time from stroke to infusion was 4.2 ± 4.6 years). Part 1 of the study consisted of 3 cohorts (n=5 per cohort) in a dose-escalation manner, with subjects receiving one of 3 doses based on body weight (0.5, 1, and 1.5 million cells/kg). The target dose of 1.5 million cells/kg corresponds to allometric scaling from animal studies using the intravenous route in the post-acute period. In Part 2 of the study, 21 patients received a single dose of 1.5 million cells/kg. The primary outcome was safety, and preliminary estimates of treatment efficacy were also examined. Patients were followed for one year after MSC infusion without any restriction of other medications.
A total of 15 serious adverse events were reported, including infections, vascular disorders, and pain syndromes. All serious adverse events were deemed unrelated or unlikely related to MSC injection. A total of 109 adverse events were reported, of which 2, both mild, were considered by the site investigator to be possibly related to the investigational product: one urinary tract infection and one report of intravenous site irritation. Both adverse events recovered completely. One subject had moderate intraventricular conduction delay on electrocardiogram at 1-month follow-up visit. One patient had a soft tissue density in the anterior abdominal wall seen at 6-months that was stable when reimaged at 12-months on CT scans of the chest, abdomen, and pelvis. Improvements were seen in NIHSS, Barthel Index (BI), Mini-Mental Status Exam at 12-month follow-up visits (Baseline Mini-Mental 24.2+-6.0, change of 1.3 ± 2.7 at 12 months; baseline NIHSS score 8, change of -2 (-3.5 to -0.5) 12 months; baseline Barthel Index score 65 ± 28.7, change of 10.8 ± 15.5 12 months).
The current study is the first largest trial of intravenous allogeneic MSC in patients with chronic stroke. It shows intravenous allogeneic MSC was safe and associated with improvement of NIHSS, Mini-Mental Status Exam, as well as BI in one year follow up. However, one year follow up is a short period and unable to assess most concerned side effect of stem cell therapy such as malignancy. The study was focused on safety; no control group was included. It followed 2-point improvement in NIHSS and the improvement of 1.3 in Mini-Mental Status Exam at 12 months were statistically significant but not clinically significant. Another important weakness is that the study couldn’t provide evidence or measurement showing direct effect of MSC on neuronal regeneration or brain function.
