Biology Reference
In-Depth Information
No information was provided as to how the caudal border was identified or
defined prior to grafting.
The preclinical evidence provided the grounds for a phase I open-label
nonrandomized study. The Israel-based single center study investigated eight
AIS grade A patients recruited between July 2000 and February 2002 from
Israel, Poland, the Netherlands, and the United States. Patients received
injections of 4 million peripheral blood-derived CD14 cells into four sites at
the caudal myelopathy border. Details regarding the identification of the cell
injection site were not provided. Three out of eight patients converted to
AIS B (motor complete, sensory incomplete) already at 1 month post injury.
After 12months, these three patients reachedAISCgrade (somemotor function
below the neurological level). As severe adverse events, two cases of pulmonary
embolism and one case of osteomyelitis were described. The described conver-
sion rate to less severe AIS grades (37.5%) went beyond naturally occurring AIS
conversion rates in AIS A patients, which range between 20% and 30%
(
Fawcett, Curt, Steeves, et al., 2007; Spiess, Muller, Rupp, et al., 2009
).
Based on the promising conversion rate, a multicenter (five sites in the
United States, one site in Israel) randomized controlled phase II study
followed, which failed to show a significant difference between macrophage
grafted and nonoperated patients (
Lammertse, Jones, Charlifue, et al., 2012
).
Compared to the phase I trial (
Knoller, Auerbach, Fulga, et al., 2005
), the
experimental design was modified in several aspects. Patients received 1.5
Mio cells into six sites-in the phase I study 4 million into four sites. In
almost half of the operation procedures, cell injection at the caudal lesion
border was controlled with intraoperative spinal ultrasound. After enroll-
ment of 12 patients, the cell concentration for transplantation was increased,
since analysis of the intended cell concentration within syringes was only
66% of the previously estimated concentration. From 1816 prescreened
patients, only 26 patients received dermis-stimulated macrophage grafts
within 14 days post injury. Seventeen patients with standard of care treat-
ment served as controls. All patients recruited from October 2003 to March
2006 suffered a cervical/thoracic SCI (AIS A). The clinical trial was prema-
turely halted for financial reasons. Only 10 patients reaching the 6-month
follow-up visit were used for primary outcome analysis, which surprisingly
showed a conversion rate in control patients of 58.8% versus 26.9% in mac-
rophage grafted patients. This result was not statistically significant but
suggested a trend favoring the control group. As severe adverse events of
spinal instability and bacterial meningitis were reported.
