Two-year safety and clinical outcomes in chronic ischemic stroke patients after implantation of modified bone marrow–derived mesenchymal stem cells (SB623): a phase 1/2a study

Abstract

OBJECTIVEThe aim of this study was to evaluate the safety and clinical outcomes associated with stereotactic surgical implantation of modified bone marrow–derived mesenchymal stem cells (SB623) in patients with stable chronic ischemic stroke.METHODSThis was a 2-year, open-label, single-arm, phase 1/2a study; the selected patients had chronic motor deficits between 6 and 60 months after nonhemorrhagic stroke. SB623 cells were administered to the target sites surrounding the subcortical stroke region using MRI stereotactic image guidance.RESULTSA total of 18 patients were treated with SB623 cells. All experienced at least 1 treatment-emergent adverse event (TEAE). No patients withdrew due to adverse events, and there were no dose-limiting toxicities or deaths. The most frequent TEAE was headache related to the surgical procedure (88.9%). Seven patients experienced 9 serious adverse events, which resolved without sequelae. In 16 patients who completed 24 months of treatment, statistically significant improvements from baseline (mean) at 24 months were reported for the European Stroke Scale (ESS) score, 5.7 (95% CI 1.4–10.1, p < 0.05); National Institutes of Health Stroke Scale (NIHSS) score, −2.1 (95% CI −3.3 to −1.0, p < 0.01), Fugl-Meyer (F-M) total score, 19.4 (95% CI 9.9–29.0, p < 0.01); and F-M motor scale score, 10.4 (95% CI 4.0–16.7, p < 0.01). Measures of efficacy reached plateau by 12 months with no decline thereafter. There were no statistically significant changes in the modified Rankin Scale score. The size of transient lesions detected by T2-weighted FLAIR imaging in the ipsilateral cortex at weeks 1–2 postimplantation significantly correlated with improvement in ESS (0.619, p < 0.05) and NIHSS (−0.735, p < 0.01) scores at 24 months.CONCLUSIONSIn this completed 2-year phase 1/2a study, implantation of SB623 cells in patients with stable chronic stroke was safe and was accompanied by improvements in clinical outcomes.Clinical trial registration no.: NCT01287936 (clinicaltrials.gov)

Concise Review: Stem Cell Therapy for Stroke Patients: Are We There Yet?

“…Moreover, vis-a-vis comparisons between these trials will be difficult because of different donor cells and varied clinical transplant protocols ( Table 1). Phenotypic markers for MSCs include SH-2 and SH-4 [45]; specific flow cytometric antibodies (CD3, CD14, CD16, CD19, CD20, CD34, CD45, CD56, Lin 1, CD133-2) [46]; or limited to CD34 and CD45 [47]; or magnetic cell isolation procedures focused on CD34+ cells [48]; MAPCs are defined as c-Kit+, CD9+, CD13+, CD31+, CD44−, MHC-I-, CD45−, Thy1- [49,53], while SB623 are Notched-induced MSCs [15,50,51,54,55]. Additionally, the therapeutic windows spanned from acute to chronic stroke stages, as well as routes of administration varied across trials [45][46][47][48][49][50][51].…”

“…In the © 2019 The Author. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed Press STEM CELLS TRANSLATIONAL MEDICINE same token, the intracerebral dose of 200,000 cells is efficacious in the stroke rat, which is equivalent to approximately 56 million cells in the stroke patient, but again the clinical doses (2.5 and 5 million cells) used were at least 10-fold below this dose, which may explain the lack of efficacy [50,51]. The cell dose found effective in the stroke rat was correctly gated in the MAPC trial (400 to 1,200 million cells) [49] but still did not reach efficacy [57].…”

Cell therapy for ischemic stroke: Are differences in preclinical and clinical study design responsible for the translational loss of efficacy?

“…Vu et al 16 reported better mNSS performance after intracortical MSC delivery as compared to intra-arterial and intravenous delivery, whereas Lee et al 14 found no significant effect of cell delivery route on outcome. 48 The sham-controlled, recently started PISCES 3 trial (NCT03629275) is utilizing intracranial transplantation as well, but with different cell product, cell dose, and primary outcome measures; its results are keenly anticipated. However, the utility of intracortical delivery is limited clinically due to its invasiveness.…”

“…The recent phase 2b study (NCT02448641) of SB623 (transiently transfected MSCs overexpressing Notch-1) showed safety, but failed to show efficacy in chronic stroke patients, in contrast to the preliminary signs of efficacy from the preceding animal study 47 and phase 1/2b clinical trial. 48 The sham-controlled, recently started PISCES 3 trial (NCT03629275) is utilizing intracranial transplantation as well, but with different cell product, cell dose, and primary outcome measures; its results are keenly anticipated. The preclinical analysis also revealed superior effects of intraventricular over intracortical cell delivery.…”

Mesenchymal stem cells in chemotherapy‐induced peripheral neuropathy: A new challenging approach that requires further investigations

“…Furthermore, in a clinical study on patients with Alzheimer's disease, the stereotactic administration of human umbilical cord blood–MSCs into the hippocampus and precuneus was shown to be achievable and well tolerated (Kim et al, ). Recently, the clinical trials using stem cell therapy in patients with chronic stroke were safe and were also accompanied by improvements in clinical outcomes (Rikhtegar et al, ; Steinberg et al, ; Wechsler, Bates, Stroemer, Andrews‐Zwilling, & Aizman, ). Nevertheless, despite the promising results of MSC transplantation in humans that confirmed its safety, yet it only caused a partial improvement in functional outcomes with some evidence in slowing down the disease progression.…”