Cell therapies for acute and chronic traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a global health problem, for which there are no approved therapies. Advances in acute clinical care have improved post-TBI survival, yet many patients are left with chronic TBI-related disabilities (i.e. chronic TBI). Existing treatments that focus on rehabilitation and symptom management do not modify the disease and have limited effectiveness. Consequently, chronic TBI-related disabilities remain a significant unmet medical need. Cell therapies have neuroprotective and neurorestorative effects which are believed to modify the disease. In this article, we review the safety and efficacy of cell therapies in early-phase clinical studies that have shown potential to improve outcomes in acute to chronic phases of TBI.

Keywords:

• Acute
• cell therapies
• chronic
• long-term disabilities
• stem cells
• traumatic brain injury

Introduction

Traumatic brain injury (TBI) is a global health problem, affecting more than 50 million people worldwide each year, with direct and indirect costs of treating TBI globally estimated to be US$400 billion per year^1,2. Although there are no approved therapies for TBI, advances in acute clinical care have resulted in improved rates of post-TBI survival^3–5. However, many patients experience long-term disabilities, as demonstrated by unchanged return-to-work rates reported over the last 50 years^6,7. Estimates vary for the prevalence of chronic TBI-related long-term disabilities (i.e. chronic TBI), which range from 704/100,000 persons in France⁸ to 1766/100,000 persons in the United States⁹. Chronic TBI-related disabilities include pain, headache, fatigue, motor impairments, abnormal movements, balance impairments, cognitive impairments (e.g. memory, concentration, learning), impulsivity or aggression, sleep disturbance, and psychological impairments (e.g. anxiety, depression)⁸. The most frequently experienced chronic TBI-related disabilities are reported to be fatigue (69%), cognitive impairments (64%), and pain (61%)⁸. Chronic TBI-related disabilities also affect patient quality of life, with role limitations due to physical health and emotional problems being major concerns¹⁰. The burden of chronic TBI is a large unmet medical need and represents a major burden on patients, families, and caregivers worldwide.

Literature search methodology

Literature searches were conducted between 15 September 2021 and 2 March 2022 using the PubMed database to identify 10 studies described in this review. The following search terms were used: (Hematopoietic) OR (Mononuclear Cells) OR (Mesenchymal Cells) AND (Traumatic Brain Injury) AND (Study).

Traumatic brain injury: modifying the disease with cell therapies

Existing approaches for the treatment of chronic TBI, which focus on rehabilitation and symptom management, have limited effectiveness and do not modify the disease¹¹. However, cell therapies have shown potential in early-phase clinical studies to be effective treatments for acute and sub-acute phases of TBI and chronic TBI-related disabilities by modifying the disease through neuroprotective and neurorestorative effects. The majority of cell therapies for TBI involve the transplantation of multipotent adult stem cells which survive in situ in the brain for a short time. Multipotent adult stem cells exert their effects by the secretion of neurotrophic factors which promote neurogenesis, angiogenesis, and endogenous neural stem cell migration and differentiation^12,13. Multipotent adult stem cells also have anti-inflammatory and immunosuppressive effects^12,13. Cell therapies for TBI also include the transplantation of multipotent fetal neural stem cells, which integrate and differentiate into neural and glial cells in situ and survive to elaborate neural processes which express neurotransmitters and form synapses¹⁴.

Cell therapy clinical studies for traumatic brain injury

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

Cell therapies for acute and sub-acute severe TBI have been investigated in pediatric and adult patients, using a variety of cell types in several small early-phase clinical studies (Table 1). In a small retrospective, uncontrolled study, Cox et al. treated 10 pediatric patients with acute severe TBI with 6 × 10⁶ cells/kg of autologous bone marrow-derived mononuclear cells (BMMNC) by intravenous (IV) infusion within 48 h of injury¹⁵. At 6 months, favorable MRI data showed no significant loss of gray matter volume, white matter volume, or intracranial volume, and no significant increase of cerebrospinal fluid volume compared to Month 1¹⁵. In addition, 70% of patients experienced favorable outcomes (i.e. moderate disability) on a dichotomized Glasgow Outcome Scale, and mean functional and neuropsychological outcomes significantly improved at 6 months (both, p < .05)¹⁵. Cox et al. reported that there were no deaths, no episodes of cell harvest-related depression of systemic or cerebral hemodynamics, and no infusion-related toxicity¹⁵.

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.

In a follow-on retrospective cohort study, Liao et al. treated 10 pediatric patients with acute severe TBI with 6 × 10⁶ cells/kg of autologous BMMNCs by IV infusion within 48 h of injury¹⁶. Cell-treated patients were compared to 19 age- and severity-matched control patients¹⁶. Compared with control patients, cell-treated patients required significantly lower treatment intensity for the management of intracranial pressure (Pediatric Intensity Level of Therapy scale, p < .05) and associated organ injury (Pediatric Logistic Organ Dysfunction score, p < .05) during the first week of treatment¹⁶. In addition, the mean duration of neurointensive care was significantly shorter in cell-treated compared to control patients (8.2 vs. 15.6 days, p < .05)¹⁶. Liao et al. reported that 1 patient in the cell-treated group developed hydrocephalus, which required multiple ventriculostomies and the establishment of a ventriculoperitoneal shunt, and 1 patient in the control group died¹⁶.

Cox et al. also investigated the use of autologous bone marrow-derived mononuclear cells in adult patients with acute severe TBI¹⁷. In a Phase 1/2a open-label, non-randomized, dose-escalation study (NCT0157540), 25 adult patients were enrolled in the following format: five control patients, five patients each treated with 6 × 10⁶/9 × 10⁶/12 × 10⁶ cells/kg, and five control patients¹⁷. Cell-treated patients received BMMNCs by IV infusion within 48 h of injury¹⁷. At 6 months, MRI showed significantly greater preservation of supratentorial (p = .03) and cerebral white matter volumes (p = .005) in pooled cell-treated compared to control patients¹⁷. Diffusion Tensor Imaging showed that the Mean Diffusivity of the corpus callosum significantly improved (p = .008), and the Mean Diffusivity and Fractional Anisotropy of the corticospinal tract significantly improved (both, p = .01) in pooled cell-treated compared to control patients at 6 months¹⁷. In addition, when cell-treated and control patients were combined, Fractional Anisotropy values for the corpus callosum improved and correlated significantly with the improvement of functional and neurocognitive outcomes (both, p < .05) at 6 months¹⁷. Moreover, expression of plasma pro-inflammatory cytokines trended lower in cell-treated compared to control patients at 6 months¹⁷. The most favorable cell-treatment dose effects were seen in the 6 × 10⁶ and 9 × 10⁶ cells/kg doses, which may be used in future investigations¹⁷. Cox et al. reported that there were no deaths or serious adverse events, however, patients who received the 12 × 10⁶ cells/kg dose experienced mild pulmonary toxicity which was not clinically significant¹⁷.

Following earlier clinical studies, the development of autologous BMMNCs (CEVA101) was granted Regenerative Medicine Advanced Therapy (RMAT) designation for the treatment of TBI by the U.S. Food and Drug Administration (FDA)^21,22. CEVA101 is currently in Phase 2 clinical development for the treatment of acute severe TBI in pediatric and adult patients, although no results have been published to date²¹.

In a small retrospective, uncontrolled study of 1 pediatric and 6 adult patients with sub-acute severe TBI, Zhang et al. used a combined procedure in which autologous bone marrow-derived mesenchymal stromal cells (BMMSC) were administered firstly to the site of injury during a cranial correction or replacement surgery, and secondly by IV infusion¹⁸. The study reported that Barthel Index (BI) scores significantly improved from a mean of 30 points (i.e. very dependent) at baseline to a mean of 80 points (i.e. able to live independently) at 6 months post-treatment (p ≤ 0.05)¹⁸. However, limitations of this study include lack of demographic details, the wide age range of patients (6–55 years), variability of cell dose in both the first (6.6 × 10⁷–1.7 × 10⁹ cells) and second treatments (1.5 × 10⁸–8.8 × 10¹⁰ cells), and variability of the interval between treatments (4–12 days)¹⁸. Zhang et al. reported that there were no deaths, and no episodes of cell-infusion-related toxicity up to 6 months post-treatment¹⁸. However, a single patient experienced 2 episodes of seizures during the first 2 months post-treatment¹⁸.

In a larger retrospective cohort-controlled study conducted by Tian et al., 97 adult patients with sub-acute severe TBI were treated with autologous BMMSCs by sub-arachnoidal puncture and compared to 69 untreated control patients¹⁹. Of cell-treated patients, 24 were in a persistent vegetative state and 73 had disturbed motor function at baseline¹⁹. After 2 weeks, 38 (39%) cell-treated patients experienced significant improvement of TBI symptoms compared to 14 (20%) control patients (p = .007), with 11 (46%) cell-treated patients showing improvement of persistent vegetative state compared to 3 (14%) control patients (p = .024), and 27 (37%) cell-treated patients showing improvement of disturbed motor function compared to 9 (19%) control patients (p = .025)¹⁹. In addition, the study found that improvement of symptoms in cell-treated patients was significantly associated with younger age at the time of injury (p < .05), and shorter elapsed time between injury and cell treatment (p < .05)¹⁹. However, the authors did not report baseline demographics, TBI severity, and cell dose details¹⁹. Tian et al. reported that there were no deaths or serious adverse events in the study¹⁹. However, five cell-treated patients experienced transient fever and two cell-treated patients experienced headache on Day 2 post-treatment¹⁹.

In a retrospective cohort-controlled study conducted by Seledtsov et al., 38 adult patients with sub-acute severe TBI were treated with 2 × 10⁸ of allogeneic fetal nerve and hematopoietic stem cells in a 10:1 ratio by sub-arachnoidal puncture and compared to 38 matched control patients who received standard neurointensive care²⁰. In the study, 25 patients were treated with cells once, 12 patients were treated with cells twice, and a single patient was treated with cells three times²⁰. Cell-treated patients experienced a lower death rate (two patients, 5%) compared to control patients (17 patients, 45%)²⁰. In addition, a greater number of cell-treated than control patients experienced favorable improvement on Glasgow Coma Scale (GCS), specifically 33 cell-treated patients (87%) compared to 15 control patients (39%) who experienced “good’ or “satisfactory” outcomes on GCS at 1-week post-treatment²⁰. Excluding the deaths previously mentioned, Seledtsov et al. reported that there were no serious adverse events associated with cell treatment in the study²⁰.

Cell therapy clinical studies for chronic traumatic brain injury

Cell therapies for chronic TBI have been investigated: (1) in open-label, non-randomized, uncontrolled clinical studies in pediatric and adult patients using autologous bone marrow-derived mononuclear cells; and (2) in controlled, randomized, blinded clinical studies in pediatric and adult patients using umbilical cord mesenchymal stem cells and allogeneic bone marrow derived-mesenchymal stromal cells (Table 2).

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.

In a small open-label, non-randomized, uncontrolled pilot study, Sharma et al. treated 14 pediatric and adult patients with chronic TBI with 1 × 10⁶ cells/kg autologous BMMNCs by intrathecal infusion²³. At 6 months, three patients experienced an improvement in Functional Improvement Measure (FIM), while six patients experienced improvement and seven patients had no change in Disability Rating Scale (DRS)²³. In addition, seven patients who were eligible for the SF-8 Health Survey experienced an improvement in both the mean physical component summary and mean mental component summary at 6 months²³. Sharma et al. reported that there were no deaths, but a single patient was lost to follow-up in the study. A single patient experienced a seizure within 3 months of cell treatment; however, this patient had abnormal EEG and a history of seizures at study enrollment²³.

In a larger open-label, non-randomized, uncontrolled, follow-up study, Sharma et al. treated 50 pediatric and adult patients with chronic TBI with a mean of 1.28 × 10⁸ autologous BMMNCs by intrathecal infusion²⁴. Fifteen patients underwent a second dose of cells at 6 months after initial treatment²⁴. Based on a grading system, 40 patients experienced improvement of at least 30% of TBI symptoms, and 30 patients experienced statistically significant improvement of FIM after a mean follow-up of 22 months (range: 3–71 months)²⁴. Further analyses showed that greater improvement in FIM score was associated with patients who were aged <18 years at the time of cell treatment, were 5 years or less post-injury at the time of cell treatment, and had mild GCS at the time of injury; whereas second cell dosing had no effect on FIM score²⁴. Sharma et al. reported that there were no deaths or withdrawals from the study. A single patient experienced headache and vomiting during their hospital stay, and two patients experienced seizures within 3 months of cell treatment. Both patients who experienced seizures had abnormal EEG, and one had a history of seizures at study enrollment²⁴.

In a randomized, single-blind controlled study in which assessors did not know the allocation of patients, Wang et al. used Fugl-Meyer Assessments (FMA) to measure motor impairment (Fugl-Meyer Motor Scale [FMMS]), sensation, and balance, and FIM to assess disability and level of assistance needed to conduct activities of daily living^25,27–31. In the study, 20 pediatric or adult patients with chronic sequelae from TBI were treated with 1 × 10⁷ allogeneic umbilical cord mesenchymal stem cells by lumbar puncture four times at intervals of 5–7 days²⁵. Control patients were matched and did not receive medical treatment²⁵.

At 6 months, cell-treated patients experienced significant improvement of FMAs from baseline, specifically mean Fugl-Meyer total score (5.6 points, p < .05), FMMS (mean upper extremity: 2.6 points/mean lower extremity: 1.2 points, both p < .05), mean sensation subscore (0.8-point, p < .05), and mean balance subscore (1.1 points, p < .05)²⁵. Control patients did not experience a significant change of mean FMAs from baseline, therefore improvement was significantly greater in cell-treated compared to control patients at 6 months (p < .05)²⁵. Cell-treated patients also experienced significant improvement from baseline of mean FIM total score (4.2 points, p < .05), mean self-care subscore (1.9 points, p < .05), mean mobility subscore (0.8-point, p < .05), mean locomotion subscore (0.7-point, p < .05), and mean communication subscore (0.5-point, p < .05) at 6 months²⁵. Improvement from baseline of mean FIM total score, mean self-care subscore, mean mobility subscore, and mean locomotion subscore were significantly greater in cell-treated than control patients (p < .05), who did not experience a significant mean change of FIM scores from baseline at 6 months²⁵.

Wang et al. reported that there were no deaths or withdrawals due to adverse events, however, 4 cell-treated patients experienced low intracranial pressure within 48 h of lumbar puncture, which resolved with IV saline infusion and the adoption of a supine position²⁵. Head and spinal MRIs were normal in cell-treated patients at 6 months²⁵.

More recently, Kawabori et al. published 6-month interim data from the 1-year, randomized, double-blind, controlled, Phase 2 STEMTRA study (NCT02416492)²⁶. STEMTRA is a multicenter trial, designed to evaluate the safety and efficacy of stereotactic intracranial implantation of allogeneic modified bone marrow-derived mesenchymal stromal (SB623) cells in adult patients with chronic motor deficits secondary to TBI²⁶. In the study, 61 adult patients were treated in a 1:1:1:1 ratio with 2.5 × 10,⁶ 5.0 × 10,⁶ 10 × 10⁶ SB623 cells or sham control²⁶. Forty-six patients were treated with SB623 cells and 15 patients underwent sham surgery²⁶. The STEMTRA trial used the Fugl-Meyer Motor Scale (FMMS) as the primary efficacy endpoint as this is widely accepted as a measure of motor impairment, focused on motor recovery of an affected limb^27–29.

At 6 months, the primary efficacy endpoint of significant improvement from baseline of the FMMS score by pooled cell-treated compared to control patients was achieved (SB623 least square [LS] mean: 8.3 [SE: 1.4] points vs. control: 2.3 [2.5] points; LS mean difference: 6.0 points, p = .040)²⁶. In addition, a significantly greater number of pooled cell-treated than control patients achieved the potential minimal clinically important difference for FMMS score of ≥10 points change from baseline (39.1 vs. 6.7%, p = .039) at 6 months²⁶.

In the STEMTRA trial, there were no deaths or withdrawals due to adverse events, but 100% of cell-treated patients experienced at least one treatment-emergent adverse event (TEAE) compared to 93.3% of control patients (p = .25) at 6 months²⁶. The most frequently reported TEAE at 6 months was a headache in both cell-treated (50.0%) and control patients (26.7%, p = .14), with more TEAEs assessed as possibly, probably, or definitely related to the surgical procedure than cell treatment in both cell-treated and control patients, who underwent sham surgery²⁶, which was in common with previous studies that used stereotactic cell implantation^32,33. At 6 months, 4 (8.7%) cell-treated patients experienced six treatment-emergent serious adverse events (TESAEs) (delirium [two cases], impairment of sensitivity in right limbs, transient ischemic attack, seizure, worsening of poor balance), all of which except worsening of poor balance recovered without sequelae; this compared to 2 (13.3%) control patients who experienced two TESAEs (wound infection and bicycle fall which resolved without sequelae and with sequelae, respectively)²⁶.

SB623 (allogeneic modified bone marrow-derived mesenchymal stromal cells) was granted RMAT designation for the treatment of chronic TBI in adult patients by the U.S. FDA and is in further clinical development³⁴.

Discussion

Although the clinical studies described in this review are mostly small, uncontrolled, and use a variety of cell types and routes of administration, they show positive effects in the first hours and days after TBI, as evidenced by improvement of persistent vegetative state and disturbed motor function, reduced intracranial pressure and associated organ injury, coma, risk of death, and the preservation of brain structures associated with improvement of disability, activities of daily living, and function scales^15–22. In the chronic setting, years after injury, both controlled and uncontrolled clinical studies show that cell therapies improved measures of motor impairment (FMA), including upper and lower extremities, sensation, and balance, disability (DRS), quality of life (SF-8 Health Survey), and activities of daily living (FIM), including self-care, mobility, and locomotion^23–26. In addition, improvement of FIM was associated with lower patient age, shorter time post-injury, and mild Glasgow Coma Scale at the time of injury^23,24.

These findings support the proposed neuroprotective effects of short-lived transplanted multipotent adult stem cells, which reduce inflammation and have immunosuppressive effects in the acute and sub-acute phases of TBI^12,13. Moreover, the neurorestorative effects of neurogenesis, angiogenesis, and endogenous neural stem cell migration and differentiation caused by the secretion of neurotrophic factors may be responsible for improvements in impairment, function, and disability seen in the chronic setting of TBI^12,13. The greater improvement of FIM associated with younger patients with milder injury and shorter time since injury may result from greater neuroplasticity found in younger individuals.

The field of cell therapies for the treatment of TBI will be advanced by further research using controlled clinical trials that focus on optimizing cell type(s), dosing, and route(s) of administration, as well as specific patient characteristics, such as the phase of TBI, age, and time since injury. Moreover, the careful selection of disability, function, impairment, quality of life, and activities of daily living scales with the capacity to detect clinically meaningful change will also be important.

Strengths and limitations

Although the 10 studies reviewed in this article report the positive potential of cell therapies for acute to chronic TBI, it should be noted that eight studies were small, uncontrolled, and/or of a retrospective design, with only three studies having control cohorts^{15–20,23–26}. As such, statistical comparisons between baseline and later time points and between groups should be interpreted with caution. In addition, two studies lacked details, such as baseline demographics, TBI severity, and cell dose^18,19. The remaining two studies were controlled, randomized, and single- or double-blinded studies that investigated chronic TBI^25,26. In addition, these early studies raise several unresolved issues which may affect interpretation, such as variability of patient age (i.e. pediatric and adult), different cell types, such as bone marrow-derived mononuclear cells and mesenchymal stem/stromal cells of autologous and allogeneic origin, various routes of administration, and different cell doses, number of doses, and intervals between cell dosing^{15–20,23–26}.

Conclusions

The burden of TBI is a large unmet medical need, however, early clinical studies have shown the potential for cell therapies to be safe and effective treatments in acute to chronic phases of TBI, which strongly supports their further clinical development to augment existing approaches that focus on acute clinical care, rehabilitation, and symptom management.

Transparency

Declaration of funding

This article was funded by SanBio, Inc.

Declaration of financial/other relationships

MK is a consultant for SanBio, Inc. DC and BN are employees of SanBio, Inc. AHS is a consultant for SanBio, Inc. DOO declares no conflict of interest. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors contributed to the literature review, and reviewed and edited the manuscript. AHS drafted the original manuscript. All authors approve this final version of the manuscript for publication and agree to be accountable for all aspects of the work.

Acknowledgements

No assistance in the preparation of this article is declared.