Research

Stroke

Stem cell infusion is a promising novel therapy and is becoming recognized as a valid treatment option in both acute and chronic stroke due to human clinical studies demonstrating its safety and effectiveness. Stem cells from various tissue types have been investigated to treat stroke patients including bone marrow, adipose, and umbilical derived stem cells. The use of bone marrow derived stem cells has been the major focus within this area of research. However, due to the invasiveness of the procedure to harvest bone marrow stem cells there is growing interest in other cell types.

Based on the early human clinical trials there appears to be a strong argument for the safe and effective use of stem cell therapy in the treatment of stroke. While we wait for phase II/III trials the current data is encouraging and supports use of stem cell therapy in the clinical setting.
Below we review selected recently published clinical trials that demonstrate the safety and efficacy of intravenous application of stem cell therapy in stroke. We also include systematic reviews/meta-analysis of stem cell therapy in stroke for additional evidence.

Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke.

In 2019 Levy et al conducted a phase I/II trial to evaluate the safety and efficacy of intravenous bone marrow derived stem cell cells in patients who experienced a stroke six or more months prior and who had substantial function deficits. The primary and secondary endpoints of this study were to demonstrate safety over 1 year and examine behavior change using routine assessments, respectively. For phase 1, patients were divided into three groups, five patients in each. Each group received a single infusion of stem cells at different doses (0.5, 1.0 and 1.5 million cells/kg of body weight). Once safety was confirmed in these groups, phase 2 was initiated and included twenty-one patients who received 1.5 million cells/kg of body weight. Adverse effects were few during the 12 month follow up period and neurological assessment end points showed significant improvement. 15 serious adverse events were reported and none were possibly or probably related to treatment. Two mild adverse events which included urinary tract infection and irritation at injection site were possibly related to treatment. Further examination including serial exams, electrocardiograms, laboratory tests and CT scans showed treatment to be safe. Neurological assessment endpoints including the National Institutes of Health Stroke Scale (NIHSS) and Barthel Index (BI) showed significant improvement. 35.5% of patients achieved excellent functional outcomes at 12 months. Levy et al concluded “intravenous transfusion of allogeneic ischemia-tolerant mesenchymal stem cell in patients with chronic stroke and substantial functional deficits was safe and suggested behavioral gains.”

Intravenous Bone Marrow Mononuclear Cells for Acute Ischemic Stroke: Safety, Feasibility, and Effect Size from a Phase I Clinical Trial.

In 2019 Vahidy et al conducted a phase I clinical trial to determine the safety and feasibility of intravenous bone marrow stem cells in twenty-five patients who experienced an acute ischemic stroke. Each patient underwent bone marrow harvest and received a single intravenous infusion of a target dose of 10 million cells/kg of body weight within 24-72 hours of stroke. The primary endpoints of this study were treatment related adverse events and proportion of patients successfully completing study. All patients successfully completed the study with only 24 reported serious adverse events. None of the serious adverse events were deemed to be related to treatment. Of the 227 reported adverse events, only 31 were deemed to be related to the study of which 28 were mild (Grade 1). Secondary endpoints of this study were clinical changes using routine neurological assessments (modified Rankin score (mRS), National Institutes of Health Stroke Scale (NIHSS) and Barthel Index (BI)) and radiographic changes using MRI and CT. At 3 months, the treatment group showed significant difference in median mRS compared to historical control group. No significant change was observed in NIHSS at any time. MRI derived diffuse tensor imaging (DTI) and fractional anisotropy (FA), a measure of structural integrity and coherence of axon fibers was used to quantify microstructural changes in the brain following treatment. FA was increased at 6 and 24 months compared to baseline demonstrating an increase in corticospinal tract fiber volume and myelin sheet thickness and is suggestive of microstructural repair. Vahidy et al concluded that bone marrow harvest and infusion of bone marrow derived stem cells is “safe and feasible in patients with acute ischemic stroke.”

Meta-Analysis of the Safety and Efficacy of Stem Cell Therapies for Ischemic Stroke in Preclinical and Clinical Studies.

In 2019 Ouyang et al performed a meta-analysis to evaluate the safety and efficacy of stem cell therapy for ischemic stroke in eleven human clinical studies. Adverse reactions including mild headache and fever were reported in most studies and resolved shortly after treatment. These studies primarily used routine neurological assessment tools including Barthel index (BI) values, modified Rankin scale (mRS) scores, National Institutes of Health Stroke Scale (NIHSS) scores, and Fugl-Meyer assessment (FMA) scores to measure outcomes. Data from these assessments suggest that stem cell therapy was associated with significant better outcomes than control groups. Furthermore, their data also suggest that stem cell therapy is most effective when provided as soon as possible after stroke and administered intravenously. Ouyang et al concluded that “Stem cell transplantation can significantly improve neurological deficits and quality of life in patients with ischemic stroke, without severe adverse reactions.”

Allogeneic Umbilical Cord Blood Infusion for Adults with Ischemic Stroke: Clinical Outcomes from a Phase 1 Safety Study.

In 2018 Laskowtiz et al conducted a phase I trial to assess the safety and feasibility of a single intravenous infusion of umbilical cord blood (UCB) in ten patients with acute ischemic stroke. “UCB cells were used in this study because of their superior immunotolerance and availability for infusion compared to bone marrow cells”. Patients received a mean dose of 15.4 million cells/kg of body weight within 3-10 days of experiencing a stroke. The primary endpoint was safety, determined by incidence of study related adverse effects, proportion of patients experiencing graft vs host disease (GVHD) and frequency of unexpected complications. A total of 113 adverse events were reported with the majority of them being graded as mild. No serious adverse events were related to treatment, no adverse events were determined to be definitely or probably related to treatment and only one was determined to be possibly related to treatment. There were no reports of GVHD during 12 month follow up period. The secondary endpoint was to assess change in neurological function and degree of disability using routine neurological assessment tools including National Institutes of Health Stroke Scale (NIHSS) scores, Barthel index (BI) values, and modified Rankin scale (mRS) scores. At 3 month follow up NIHSS, BI and mRS, all showed improvements compared to baseline. MRI performed 3 months after treatment showed normal evolution of stroke with no significant increase of damages areas, unexpected bleeding of brain or other safety concerns. Laskowitz et al concluded that intravenous infusion of “UCB in adults after acute ischemic stroke is safe, well tolerated and feasible. In addition, improvements in functional outcomes were observed in all participants 3 months post-infusion.”

Mesenchymal stem cell transplantation as an effective treatment strategy for ischemic stroke in Asia: a meta-analysis of controlled trials.

In 2018 Xue et al performed a meta-analysis of 23 controlled trials assessing the efficacy of stem cell therapy in ischemic stroke patients. Stem cells were obtained from multiple tissue types including bone marrow, umbilical cord and umbilical cord blood. Stem cells were administered through various routes with intravenous route being the most commonly used. The stem cell dose range and number of treatments were diverse among studies. Treatment safety was determined by frequency of adverse events. No serious adverse events were reported in any of the studies. The most common adverse effect of stem cell treatment was headache and fever which subsided within 24 hours and did not require treatment. Treatment efficacy was assessed using routine neurological and functional tools including National Institutes of Health Stroke Scale (NIHSS), Barthel index (BI), Fugl-Meyer Assessment (FMA) and Functional Independence Measure (FIM). There was an overall significant improvement in ischemic stroke patients after treatment as measured by changes in NIHSS, BI, FMA, FIM. Treated patients showed a statistical significant decrease in NIHSS at 1 and 3 months indicating reduced neurological impairment and a statistical significant increase of BI, FMA and FIM at 1 and 3 months indicating less disability and greater independence. Furthermore, cumulative results showed that stem cell therapy was more effective through intravenous application indicated by increased BI, FMA and FIM scores. Xue et al concluded that “our analysis verified the safety and efficacy of MSC therapy for ischemic stroke (IS). It significantly mitigated neurological defects and improved life quality of IS patients, without causing serious adverse events.”

Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial.

In 2017 Hess et al conducted a double blind randomized placebo controlled trial to identify the highest, well-tolerated and safest single intravenous dose of bone marrow derived stem cells (progenitor cells) and to evaluate its efficacy in the treatment for moderately severe acute ischemic stroke recovery. Patients either received 400 million cells, 1200 million cells or placebo between 24 hr and 48 hr after symptom onset. The primary safety endpoint of this study was dose limiting toxicity effects. This endpoint was achieved and safety was confirmed as there were no toxic events, no allergic reactions and no differences in adverse events between treatment and placebo groups. The primary efficacy endpoint was global stroke recovery using results from commonly used assessments (modified Rankin Score (mRS), National Institutes of Health Stroke Scale (NIHSS) and Barthel Index (BI)). At 3 month follow up there was no difference between treatment groups and placebo groups in global stroke recovery. Hess et al concluded that stem cell therapy with “multipotent adult progenitor cells were safe and well tolerated in patients with acute ischemic stroke.”

Intravenous Autologous Bone Marrow Mononuclear Cell Transplantation for Stroke: Phase1/2a Clinical Trial in a Homogeneous Group of Stroke Patients.

In 2015 Taguchi et al conducted a small non-randomized, clinical trial to assess the feasibility and safety of intravenous bone marrow derived mononuclear cells (BM-MNCs), a diverse population of cells that include stem cells, in treating twelve patients who experienced a severe embolic stroke. Severity of stroke was determined by baseline NIHSS score, a common assessment tool to measure degree of neurological impairment. Patients were divided into low dose and high dose groups, six in each, and received an average of 250 million cells or 340 million cells, respectively. Primary safety outcome was worsening of NIHSS score and secondary safety outcome was death at the time of discharge. Serious adverse events were observed in two patients over 6 month follow up; one had aspiration pneumonia and sepsis which was deemed not related to cell therapy and the other had recurrent stroke which was deemed unclear if it was associated with cell therapy. This was the only patient who had a decreased NIHSS score. No patients experienced death at discharge. The primary efficacy outcome of this study was change in the NIHSS score 30 days after treatment and secondary efficacy outcome was changes in NIHSS score, modified Rankin Scale (mRS) score and Barthel Index (BI) score over 120 days after treatment. At 30 day follow up mean NIHSS score showed a statistically significant improvement by 4.8 +/- 4.6. Discussion of results for secondary efficacy outcome were limited in the study and only graphically represented. Blood flow to the stroke-affected area was also assessed 24 hour before, and 1 and 6 months after stem cell treatment using SPECT imaging. Results indicate trends toward improved blood flow as measured by three parameters; regional cerebral blood flow (rCBF), and regional metabolic rate of oxygen consumption (rCMRO2) and oxygen extraction fraction (OEF). To assess effect of cell dose, the difference in neurological recovery between low and high dose treatment groups was analyzed. There was no statistically significant difference between groups, however the high dose group consistently showed a trend towards better neurological recovery. Taguchi et al concluded that “our study demonstrates that intravenous administration of autologous bone marrow mononuclear cells to patients with severe embolic stroke was feasible and safe. Positive results and trends favoring neurological recovery and improvement in cerebral blood flow and metabolism in post-stroke patients receiving therapy underscore the potential of this approach.”

SOURCES OF SELECTED STUDIES:

• Levy, M. L., Crawford, J. R., Dib, N., Verkh, L., Tankovich, N., & Cramer, S. C. (2019). Phase I/II Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke. Stroke, 50(10), 2835–2841. https://doi.org/10.1161/STROKEAHA.119.026318
• Vahidy, F. S., Haque, M. E., Rahbar, M. H., Zhu, H., Rowan, P., Aisiku, I. P., … Savitz, S. I. (2019). Intravenous Bone Marrow Mononuclear Cells for Acute Ischemic Stroke: Safety, Feasibility, and Effect Size from a Phase I Clinical Trial. STEM CELLS. https://doi.org/10.1002/stem.3080
• Ouyang, Q., Li, F., Xie, Y., Han, J., Zhang, Z., Feng, Z., … Jiang, X. (2019). Meta-Analysis of the Safety and Efficacy of Stem Cell Therapies for Ischemic Stroke in Preclinical and Clinical Studies. Stem Cells and Development, 28(8), 497–514. https://doi.org/10.1089/scd.2018.0218
• Laskowitz, D. T., Bennett, E. R., Durham, R. J., Volpi, J. J., Wiese, J. R., Frankel, M., … Kurtzberg, J. (2018). Allogeneic Umbilical Cord Blood Infusion for Adults with Ischemic Stroke: Clinical Outcomes from a Phase 1 Safety Study. Stem Cells Translational Medicine, 7(7), 521–529. https://doi.org/10.1002/sctm.18-0008
• Xue, P., Wang, M., & Yan, G. (2018). Mesenchymal stem cell transplantation as an effective treatment strategy for ischemic stroke in Asia: a meta-analysis of controlled trials. Therapeutics and Clinical Risk Management, 14, 909–928. https://doi.org/10.2147/TCRM.S161326
• Hess, D. C., Wechsler, L. R., Clark, W. M., Savitz, S. I., Ford, G. A., Chiu, D., … Mays, R. W. (2017). Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Neurology, 16(5), 360–368. https://doi.org/10.1016/S1474-4422(17)30046-7
• Taguchi, A., Sakai, C., Soma, T., Kasahara, Y., Stern, D. M., Kajimoto, K., … Nagatsuka, K. (2015). Intravenous Autologous Bone Marrow Mononuclear Cell Transplantation for Stroke: Phase1/2a Clinical Trial in a Homogeneous Group of Stroke Patients. Stem Cells and Development, 24(19), 2207–2218. https://doi.org/10.1089/scd.2015.0160