Cell therapies for acute and chronic traumatic brain injury

Figures & data

Table 1. Cell therapy clinical studies for acute and sub-acute severe traumatic brain injury.

Study	Study type	Cell type	Route of administration	Population	Outcome
Cox et al. 2011^15	Retrospective, uncontrolled study	Autologous bone marrow-derived mononuclear cells	Intravenous infusion	Pediatric: 10 patients (mean age: 8.8 years) with acute severe TBI (mean Glasgow Coma Scale score: 6)	Efficacy: No loss of gray/white matter/intracranial volume or increase of cerebrospinal fluid volume at 6 months. 70% of patients achieve favorable outcomes on dichotomized Glasgow Outcome Scale at 6 months.
					Safety: No deaths, no episodes of harvest-related depression of hemodynamics or infusion-related toxicity.
Liao et al. 2015^16	Retrospective cohort, age/severity matched controlled study	Autologous bone marrow-derived mononuclear cells	Intravenous infusion	Pediatric: 10 treated (age range: 5–14 years, Glasgow Coma Scale score: 5–8) vs. 19 control patients with acute severe TBI	Efficacy: Significantly lower treatment intensity (Pediatric Intensity Level of Therapy/Pediatric Logistic Organ Dysfunction scores) during the first week in cell-treated vs. control patients. Significantly shorter duration of neurointensive care in cell-treated vs. control patients.
					Safety: 1 episode of hydrocephalus in the cell-treated group and 1 death in the control group.
Cox et al. 2017^17	Phase 1/2a open-label, non-randomized, dose-escalation study	Autologous bone marrow-derived mononuclear cells	Intravenous infusion	Adult: 5 control, 15 treated (3 doses), 5 control patients with acute severe TBI (mean age: 31 years, Glasgow Coma Scale score: 5–8)	Efficacy: Greater preservation of supratentorium, corpus callosum, and corticospinal tract in treated vs. control patients 6 months.
					Safety: No deaths or serious adverse events. Patients treated with the 12 × 10^6 cells/kg dose experienced mild pulmonary toxicity.
Zhang et al. 2008^18	Retrospective, uncontrolled study	Autologous bone marrow-derived mesenchymal stromal cells	First dose during cranial operation/second dose by intravenous infusion	Pediatric: 1 patient; Adult: 6 patients with sub-acute severe TBI (Barthel Index: <40 points)	Efficacy: Significant improvement of Barthel Index score at 6 months vs. baseline in all patients.
					Safety: No deaths, no episodes of cell-infusion-related toxicity. Two episodes of epilepsy in a single patient during the first 2 months.
Tian et al. 2013^19	Retrospective cohort, controlled study	Autologous bone marrow-derived mesenchymal stem cells	Sub-arachnoidal lumbar puncture	Adult: 97 treated vs. 69 control patients with sub-acute severe TBI	Efficacy: A significantly greater number of treated than control patients experienced improvement of persistent vegetative state and motor disorder at 2 weeks.
					Safety: No deaths or serious adverse events. Five cell-treated patients experienced transient fever and 2 cell-treated patients experienced headache on Day 2 post-treatment.
Seledtsov et al. 2005^20	Retrospective cohort, controlled study	Allogeneic fetal nervous and hematopoietic stem cells	Sub-arachnoidal lumbar puncture	Adult: 38 treated vs. 38 control patients with sub-acute severe TBI (mean age: 38 years, Glasgow Coma Scale score: 3–7)	Efficacy: Lower death rate and improved Glasgow Coma Scale score in treated vs. control patients.
					Safety: 2 cell-treated patients vs. 17 control patients died. No serious adverse events are associated with cell treatment.

Table 2. Cell therapy clinical studies for chronic traumatic brain injury.

Study	Study type	Cell type	Route of administration	Population	Outcome
Sharma et al. 2015^23	Open-label, non-randomized, uncontrolled pilot study	Autologous bone marrow-derived mononuclear cells	Intrathecal infusion	Pediatric/adult: 14 patients with chronic TBI (median age: 26 years, time post-injury not reported)	Efficacy: Improvement of Functional Improvement Measure, SF-8 Health Survey, and Disability Rating Scale in some patients at 6 months.
					Safety: 1 patient experienced a seizure within 3 months of cell treatment. The patient had an abnormal EEG and a history of seizures at enrollment.
Sharma et al. 2020^24	Open-label, non-randomized, uncontrolled study	Autologous bone marrow-derived mononuclear cells	Intrathecal infusion	Pediatric/adult: 50 patients with chronic TBI (mean age: 29 years, 77% within 5 years of injury)	Efficacy: 30 patients experienced statistically significant improvement of the Functional Improvement Measure at a mean follow-up of 22 months.
					Safety: 1 patient experienced headache and vomiting shortly after cell treatment. Two patients experienced seizures after cell treatment. Both patients had abnormal EEG and 1 patient had a history of seizures at enrollment.
Wang et al. 2013^25	Controlled, randomized, single-blind study	Allogeneic umbilical cord mesenchymal stem cells	Sub-arachnoidal lumbar puncture	Pediatric/adult: 20 cell-treated (mean age: 27.5 years; mean time post-injury to treatment: 4.8 years; mean Glasgow Coma Scale score at injury: 6.6) vs. 20 control (mean age: 28.6 years; mean time post-injury to treatment: 5.9 years; mean Glasgow Coma Scale score at injury: 6.9) patients with chronic TBI	Efficacy: Cell-treated patients experienced statistically significant improvements in Fugl-Meyer Assessments and Functional Independence Measure compared to baseline and control patients at 6 months.
					Safety: 4 cell-treated patients experienced low intracranial pressure within 48 h of lumbar puncture.
Kawabori et al. 2021^26	Phase 2, controlled, randomized, double-blind, phase 2 study	Allogeneic bone marrow-derived mesenchymal stromal cells	Stereotactic intracranial implantation	Adult: 46 cell-treated (mean age: 34.0 years; mean time post-injury to treatment: 7.8 years; Extended Glasgow Outcome Scale score at enrollment: 3–6) vs. 15 control (mean age: 35.5 years; mean time post-injury to treatment: 8.3 years; Extended Glasgow Outcome Scale score at enrollment: 3–6) patients with chronic TBI	Efficacy: Cell-treated patients experienced statistically significant improvement in the Fugl-Meyer Motor Scale score compared to control patients at 6 months.
					Safety: 100% of cell-treated vs. 93.3% of control patients experienced TEAEs. Four cell-treated patients experienced 6 TESAEs vs. 2 control patients experienced 2 TESAEs.

TEAEs: treatment-emergent adverse events; TESAEs: treatment-emergent serious adverse events.

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Liao GP, Harting MT, Hetz RA, et al. Autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children. Pediatr Crit Care Med. 2015;16(3):245–255.

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Cox CS Jr., Hetz RA, Liao GP, et al. Treatment of severe adult traumatic brain injury using bone marrow mononuclear cells. Stem Cells. 2017;35(4):1065–1079.

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Zhang ZX, Guan LX, Zhang K, et al. A combined procedure to deliver autologous mesenchymal stromal cells to patients with traumatic brain injury. Cytotherapy. 2008;10(2):134–139.

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Tian C, Wang X, Wang X, et al. Autologous bone marrow mesenchymal stem cell therapy in the subacute stage of traumatic brain injury by lumbar puncture. Exp Clin Transplant. 2013;11(2):176–181.

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Seledtsov VI, Rabinovich SS, Parlyuk OV, et al. Cell transplantation therapy in re-animating severely head-injured patients. Biomed Pharmacother. 2005;59(7):415–420.

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Sharma A, Sane H, Kulkarni P, et al. Cell therapy attempted as a novel approach for chronic traumatic brain injury – a pilot study. SpringerPlus. 2015;4:26.

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Sharma AK, Sane HM, Kulkarni PP, et al. Autologous bone marrow mononuclear cell transplantation in patients with chronic traumatic brain injury – a clinical study. Cell Regen. 2020;9(1):3.

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Wang S, Cheng H, Dai G, et al. Umbilical cord mesenchymal stem cell transplantation significantly improves neurological function in patients with sequelae of traumatic brain injury. Brain Res. 2013;1532:76–84.

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Kawabori M, Weintraub AH, Imai H, et al. Cell therapy for chronic TBI: interim analysis of the randomized controlled STEMTRA trial. Neurology. 2021;96(8):e1202–e1214.

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