Cell therapy after ischemic stroke in the thrombectomy era?

By Francisco Moniche, MD, PhD, Stroke Unit, Neurology Department, Hospital Universitario Virgen del Rocio, Institute of Biomedicine of Seville (IBiS), Avda. Manuel Siurot s/n. CP 41013. Seville, Spain

 A 73-year-old man was found at his house with a global aphasia and right hemiparesis. Last seen normal was 5 hours ago. An emergent brain CT and angio-CT showed a M1 occlusion of left MCA and an ASPECTS score of 6. Thrombectomy was performed with complete recanalization of MCA. However, an extensive infarction was developed at 24-hours CT and he had a moderately severe disability with a modified Rankin scale (mRS) score of 4 at 3-month follow-up.

Thrombectomy has become a revolutionary treatment for stroke, with just 2.6 patients needed to treat to reduce disability for one patient (1). However, many stroke patients are not eligible for thrombectomy or thrombolysis and, moreover, some patients have a futile recanalization with around 40-50% of patients having significant disability in the long-term. Therefore, restorative approaches are urgently needed. Until now, neuroprotective or neurorestorative drugs have failed to improve neurological deficits in clinical trials. Stem cells are self-renewing cells that can differentiate into specialized cell type. There are many examples of successful clinical applications of stem cells with many patients benefiting from stem cells transplantation for treatment of leukemias, immunodeficiencies, damaged cornea or severe burns.

In stroke, efficacy of cell therapy has been demonstrated in animal models to improve neurological deficits through several mechanisms. The primary mechanism is believed to be through paracrine effects that include the release of cytokines, chemokines, and growth factors. Stem cells induce modulation of inflammation, both systemic and brain inflammation, that may ameliorate disability after stroke. Also, stimulating endogenous neurogenesis, and improving synaptogenesis and angiogenesis that occur after an ischemic lesion may help to recover neurological deficit after stroke.

The most studied cells for stroke cell therapy are autologous bone marrow mononuclear cells and allogenic mesenchymal stem cells. Transplantation of these stem cells is also the most promising therapies. Several clinical trials have demonstrated the safety of this approach. In a recent meta-analysis for ischemic stroke (2), stem cell therapy was associated with a significant improvement in NIHSS, Barthel Index, mRS, and Fugl-Meyer Assessment scores compared to control. However, most previous clinical trials are small phase I-II trials with lack of power to robustly demonstrate efficacy. We have learnt that the effect of stem cell therapy seems to be most effective when administered earlier after stroke onset, but many questions are not answered yet such as the choice of cell type, best dose or route of administration. Several phase IIb-III clinical trials with intravenous or intra-arterial routes to further evaluate efficacy and dose of cells are currently ongoing (3-4) and in just a few years we will have more clues from these larger trials.

Even in the revolutionary era of thrombectomy, stroke is still a major cause of disability. Restorative therapies are needed and cell therapy may offer new opportunities for stroke patients. Ongoing clinical trials will give light to this approach in the next years, but there is still a long way to go to enter in the cell therapy era.

References

1. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials Lancet. 2016;387:1723-31.
2. Ouyang Q, Li F, Xie Y, et al. Meta-Analysis of the Safety and Efficacy of Stem Cell Therapies for Ischemic Stroke in Preclinical and Clinical Studies. Stem Cells Dev. 2019;28:497-514.
3. Moniche F, Escudero I, Zapata-Arriaza E, et al. Intra-arterial bone marrow mononuclear cells (BM-MNCs) transplantation in acute ischemic stroke (IBIS trial): protocol of a phase II, randomized, dose-finding, controlled multicenter trial. Int J Stroke. 2015;10:1149-52.

MultiStem® Administration for Stroke Treatment and Enhanced Recovery Study (MASTERS-2). ClinicalTrials.gov Identifier: NCT03545607. https://clinicaltrials.gov/ct2/show/NCT03545607