title: Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells.
abstract: Preclinical studies using bone marrow derived cells to treat traumatic brain injury have demonstrated efficacy in terms of blood-brain barrier preservation, neurogenesis, and functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe traumatic brain injury demonstrated safety and potentially a central nervous system 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. Adults with severe traumatic brain injury (Glasgow Coma Scale 5-8) and without signs of irreversible brain injury 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 ×106cells/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-related hemodynamic changes, infusional toxicity, and adverse events. Outcome measures included magnetic resonance imaging-based measurements of supratentorial and corpus callosal volumes as well as diffusion tensor imaging-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 postinjury. Functional and neurocognitive outcomes were measured and correlated with imaging data. Inflammatory cytokine arrays were measured in the plasma pretreatment, posttreatment, and at 1 and 6 month follow-up. There were no serious adverse events. 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 downregulated. 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 central nervous system structural preservation, consistent with previous pediatric trial data. Inflammatory biomarkers are downregulated after cell infusion. Stem Cells 2016 Video Highlight: https://youtu.be/UiCCPIe-IaQ Stem Cells 2017;35:1065-1079.
authors: Department of Pediatric Surgery, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Charles S
authors: CS
authors: Cox
authors: Department of Surgery, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Robert A
authors: RA
authors: Hetz
authors: Department of Surgery, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: George P
authors: GP
authors: Liao
authors: Department of Neurology, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Benjamin M
authors: BM
authors: Aertker
authors: Department of Pediatrics, The University of Texas McGovern Medical School, Houston, Texas, USA.|Department of Psychiatry and Behavioral Sciences, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Linda
authors: L
authors: Ewing-Cobbs
authors: Department of Pediatrics, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Jenifer
authors: J
authors: Juranek
authors: Department of Neurology, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Sean I
authors: SI
authors: Savitz
authors: Department of Pediatric Surgery, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Margaret L
authors: ML
authors: Jackson
authors: Department of Pediatrics, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Anna M
authors: AM
authors: Romanowska-Pawliczek
authors: Department of Pediatric Surgery, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Fabio
authors: F
authors: Triolo
authors: Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Pramod K
authors: PK
authors: Dash
authors: Center for Clinical Research and Evidence-Based Medicine, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Claudia
authors: C
authors: Pedroza
authors: Department of Hematology and Oncology, Nationwide Children's, Columbus, Ohio, USA.
authors: Dean A
authors: DA
authors: Lee
authors: Department of Pediatrics, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Laura
authors: L
authors: Worth
authors: Department of Emergency Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors: Imoigele P
authors: IP
authors: Aisiku
authors: Department of Neurology, The University of Texas McGovern Medical School, Houston, Texas, USA.|Department of Neurosurgery, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Huimahn A
authors: HA
authors: Choi
authors: Department of Surgery, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: John B
authors: JB
authors: Holcomb
authors: Department of Neurosurgery, The University of Texas McGovern Medical School, Houston, Texas, USA.
authors: Ryan S
authors: RS
authors: Kitagawa
mesh_terms: D000328:Adult; D001519:Behavior; D015415:Biomarkers / Q000097:blood; D001854:Bone Marrow Cells / Q000166:cytology*; D000070642:Brain Injuries, Traumatic / Q000097:blood / Q000473:pathology / Q000628:therapy*; D003337:Corpus Callosum / Q000473:pathology; D016207:Cytokines / Q000097:blood; D005260:Female; D066128:Gray Matter / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D008297:Male; D011712:Pyramidal Tracts / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators
keywords: adult human bone marrow; adult stem cells; bone marrow stromal cells; cellular therapy; clinical trials; diffusion tensor imaging; traumatic brain injury