Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells

Abstract

Background Numerous pre-clinical studies using bone marrow derived cells for the treatment of traumatic brain injury and stroke have demonstrated efficacy in terms of blood-brain barrier preservation, neurogenesis, and other functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe TBI demonstrated safety and potentially a CNS structural preservation treatment effect. This study sought to confirm the safety, logistic feasibility, and potential treatment effect size of structural preservation/inflammatory biomarker mitigation in adults to guide Phase 2 clinical trial design. Methods Adults (aged 18-55) with severe traumatic brain injury (GCS 5-8) and without signs of serious other injury or irreversible brain injury (see Table 1) were evaluated for entry into the trial. A dose escalation format was performed in 25 patients: 5 controls, followed 5 patients in each dosing cohort (6,9,12 ×106 cells/kg body weight), then 5 more controls. Bone marrow harvest, cell processing to isolate the mononuclear fraction, and re-infusion occurred within 48 hours after injury. Patients were monitored for harvest/infusion related hemodynamic changes, infusional toxicity, and adverse events. Outcome measures included MRI based measurements of supratentorial and corpus callosal volumes as well as DTI based measurements of fractional anisotropy and mean diffusivity of the corpus callosum and the corticospinal tract at the level of the brainstem at 1 month and 6 months post-injury. Functional and neurocognitive outcomes were measured and correlated with imaging data. Inflammatory cytokine arrays were measured in the plasma pre-treatment, post-treatment, and at 1 and 6 month follow-up. Results There were no serious adverse events related to harvest/infusion. There was a mild pulmonary toxicity of the highest dose that was not clinically significant. Despite the treatment group having greater injury severity, there was structural preservation of critical regions of interest that correlated with functional outcomes. Key inflammatory cytokines were down-regulated after BMMNC infusion. Conclusions Treatment of severe, adult traumatic brain injury using an intravenously delivered autologous bone marrow mononuclear cell infusion is safe and logistically feasible. There appears to be a treatment signal as evidenced by CNS structural preservation, consistent with previous pediatric trial data. Inflammatory biomarkers are down-regulated after cell infusion. A Phase 2, prospective, randomized trial excluding the highest dose is warranted and can be powered based upon structural outcome variables.

Procoagulant in vitro effects of clinical cellular therapeutics in a severely injured trauma population

“…Doses of heparin required to restore R time increased as TF load of the CCT increased. This study is clinically relevant because CCTs are being introduced as novel therapy for TBI and acute respiratory distress syndrome . We show that CCTs accelerate clot formation in vitro in a cohort of trauma patients.…”

“…The sample was mixed twice using a pipette before starting the assay. The final molarity of CaCl 2 was 0.01 M. The final concentration of CCTs was 10 5 cells/mL, which is similar to clinical trials administering CCTs which use a concentration of 1 to 10 × 10 6 cells/kg . Control assays had an identical volume of PBS vehicle added to each sample.…”

“…For example, therapy for sequela of traumatic brain injury (TBI) or hemorrhagic shock remains largely supportive . Clinical cellular therapeutics (CCTs) like human mesenchymal stem cells (MSCs) and mononuclear cells (MNCs) may treat these deadly and morbid conditions . However, CCTs express tissue factor (TF) which is a potent activator of the coagulation cascade.…”

Preclinical progenitor cell therapy in traumatic brain injury: a meta-analysis

“…To date, two clinical trials have been published here in the Unites States showing promising results for improved outcomes with progenitor cell therapy for TBI (65, 77), and five more clinical trials are in the process of recruiting on ClinicalTrials.gov. The results published in this meta-analysis should help prove that these trials are worthy of further pursuit, and further funding.…”

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

“…Twenty-five patients receiving intravenous delivery of BM-MNCs in a dose escalation design (6, 9, 12 × 10 6 cells/ kg body weight) presented no severe adverse effects. 83 Moreover, BM-MNC treatment correlated with a downregulation of inflammatory cytokines IL-1β and IFN-γ, paralleling preclinical evidence in animal models of TBI. 83 These findings support the safety and logistical feasibility of BM-MNC transplantation for TBI.…”