Clinical trials in traumatic brain injury: cellular therapy and outcome measures

Abstract

Clinical trials for traumatic brain injury (TBI) have not successfully produced a new therapeutic for neuroprotection or neurorestoration, despite multiple attempts. Stem cell–based therapies and/or cellular therapies have been developed over the past 20 years such that clinical trials are now in Phase II and III stages for neurologic diseases such as TBI and stroke. Many of the vexing issues from past clinical failures still exist today, namely, preclinical data that may not translate to clinical trial because of design and injury heterogeneity that poorly stratifies enrolled patients. Recognition of these problems has led us to advocate for outcome measures that are clinically meaningful, but do not represent a global functional “score.” Specifically, we seek to measure those early physiologically relevant outcomes (intracranial pressure, edema, and therapeutic intensity) and later structural outcomes in regions of interest that are linked to putative mechanisms of action of cell based therapies. Early approval of therapeutics that are successful by these metrics would then allow further access to treatments that could be further tested via patient registries and other surveillance for ultimate adoption. Continuing to do the same thing with each iterative trial will assure the same results.

Mesenchymal Stromal Cell Therapeutic Delivery: Translational Challenges to Clinical Application

“…Perhaps most widely known, the systemically IV-infused Remestemcel-L (Prochymal) has been developed by Osiris Therapeutics (Now Mesoblast), to primarily treat graft-vs.-host disease (GvHD) (82). Other notable efforts also include the use of Multistem, a multipotent adult progenitor cell that is somewhat similar to MSCs, to treat ischemic stroke (83) and our own use of cell therapies to treat traumatic brain injury (84). Common among these approaches is the use of cell therapies to modulate inflammation and activation of the immune system in order to decrease inflammation-related secondary injuries and restore homeostasis.…”

Efficacy of Cell-Based Therapies for Traumatic Brain Injuries

“…In addition, up-regulation of pro-inflammatory cytokines by microglia increases BBB permeability and expression of cell adhesion molecules and chemokines, further increasing immune cells infiltration and augmenting the damaging consequences of the inflammatory response [11]. Microglia play a critical role in driving neuroinflammation and may serve as a target both for monitoring and modulating the neuroinflammatory response to TBI [12,13]. This inflammatory cascade, initiated by TBI, may persist and become amplified in the brain, predisposing TBI patients to neurological decline and neurological disorders [14,15].…”

Progenitor cell therapy for acquired pediatric nervous system injury: Traumatic brain injury and acquired sensorineural hearing loss

“…14,15 Global and callosal volume loss are associated with poor neurocognitive outcomes. 16 This volume loss is thought to be the result of progressive histopathologic damage mediated by the post-TBI immune response. 17 Because of the rapidly changing developmental state of the central nervous system and variable age dependent mechanism(s) of trauma, pediatric TBI includes an extremely heterogeneous spectrum of injury.…”

“…26 For TBI, the extreme variability of the patient population and relative insensitivity of existing classification tools requires a new approach. 16 In his seminal 1948 monograph "Restoration of Function After Brain Injury," A.R. Luria described his experience treating Russian Soldiers who sustained head injuries during the second World…”