Table 5.

Impact of cell therapy on inflammation—clinical studies

Reference(s)	Trial ID / Country, Phase /Allocation	Start / Last Update	Condition, Participants (Age)	Cell Therapy	Outcome	Investigation of Immune system reported or planned?	Administration of immuno-suppressant(s)
Ahn S. et al., 2018 PMID: 30133179	NCT02274428 Korea, 1 open label	October 2014 / April 2017	IVH (grade 3–4), 9 (23–34 weeks)	Allogenic UCB-MSC low-dose: 5 × 106 cells/kg or high-dose: 1 × 107 cells/kg route: intraventricular	- Intraventricular administration route appears safe in the small study population. - Levels of CSF-IL-6 significantly decline after MSC transplantation. - Baseline CSF-IL-6 is higher in infants who underwent shunt surgery than in infants without shunt placement. - Correlation between baseline levels of CSF-IL-6 and TNF-α and baseline ventricular index.	Reported: CSF cytokines	no
Kang M et al., 2015 PMID: 25977995	NCT01528436 Korea, 2 randomized; double-blind; placebo-controlled	February 2012/July 2012	CP, 34 (6 month - 20 years)	Allogenic UCB-TNC ≥ 2 × 107 cells/kg route: intravenous or intraarterial	- Greater improvement in muscle strength and gross motor performance in the UCB group at 3 and 6 months, respectively. - 18FDG PET-CT shows decreased periventricular inflammation in the UCB group. - Enhanced gross motor function correlates to increased plasma PTX3 and IL-8 levels up to 12 days after treatment in the UCB group. - Increased serum TLR4 1 day after treatment and correlation with muscle strength 3 months post treatment.	Reported: plasma cytokines, serum levels of TLR4, 18FDG PET-CT	yes, cyclosporine and solumedrol (=methyl-prednisolone)
N/A	NCT03130816 Korea, 1; 2 open label	April 2017/November 2020	CP, 90 (10 month - 20 years)	Allogenic UCB-TNC ≥2 × 107 cells/kg route: intravenous	N/A	Planned, but not clearly defined	yes
Min K et al., 2013 PMID: 23281216	NCT01193660 Korea, N/A double-blind; randomized controlled	September 2010/March 2012	CP, 96 (10 month - 10 years)	Allogenic UCB-TNC and erythropoietin combination > 3 × 107 cells/ kg 250–500 IU(kg) erythropoietin route: intravenous	- At 3 and 6 months younger children of the UCB + EPO group showed greater improvements than EPO alone and the placebo group for GMPM and BSID-II, in the 3 to 6 months interval additionally also the EPO alone group showed better outcome than the control. - Older children showed significant improvement in the BSID-II score during 0 to 3 months period. - MRI-DTI reveals significant correlation between changes of the FA values and GMPM increment.	Reported: 18FDG PET-CT, MRI-DTI	yes, cyclosporine
Huang L et al., 2018 PMID: 29637820	Ethical approval No. 2010–06 China, N/A randomized, placebo-controlled	September 2010/September 2015	CP, 56 (3–12 years)	Allogenic UCB-MSC 5 × 107 route: 4 x intravenous	- Significant improvement in GMFM-88 and CFA noted at 3, 6, 12 and 24 months when compared to the control group. - Immunologic tests performed to monitor rejection before and after cell administration (IgA, IgM, C3, C4, RF, CRP, anti-streptolysin) within normal ranges. - No cerebral structure improvement observed in routine MRI.	Reported: serum immune markers of rejection	no
Gu J et al., 2020 PMID: 32014055	ChiCTR-TRC-1800016554 China, N/A randomized, placebo-controlled	June 2018/July 2019	CP, 39 (2–12 years)	Allogenic UC-Wharton’s Jelly derived MSC 4.5–5.5 × 107 route: 4 × intravenous	- Significant improvements of GMFM, CFA and ADL at 1, 3, 6 and 12 months after treatment. - Regional increase in standard uptake value of glucose measured in 3 out of 5 patients of the treatment group.	Reported: 18FDG PET-CT	no
Sharma A et al., 2015 PMID: 25788947	NCT01978821 India, N/A open label	August 2010/October 2018	CP, 40 (17 month - 22 years)	Autologous BM-MNC 1 × 107 route: intrathecal	- Subgroup analysis shows improvement for diplegic and quadriplegic CP patients superior to that in the miscellaneous group of CP patients. - FDG PET-CT scans in 6 patients show metabolic changes correlating to clinical improvements.	Reported: 18FDG PET-CT	yes, methyl-prednisolone
Rah W et al., 2017 PMID:28109298 Park K et al., 2017 PMID: 28289643 Koh H et al., 2018 PMID:29780293	NCT02983708 Korea, 1; 2 randomized; double-blind cross-over	August 2011/September 2014	CP, 57 (2–10 years)	10 μg/kg G-CSF for 5 days + Autologous mPB-MNC either 1 or 7 month after cryopreservation > 1 × 108 cells/kg route: intravenous	- Neurodevelopmental improvement after G-CSF infusion, irrespective of the cell infusion or placebo. - The group receiving cell therapy seven months after G-CSF had higher motor-functional improvement, whereas the group receiving cells one month after G-CSF had a significant increase of FA values in MRI. - No cytokine differences observed between the intervention arms. - However, in clinical responders, plasma levels of IL-6 and G-CSF were significantly higher than in non responders one month after G-CSF treatment, and levels of BDNF and IGF-1 were significantly lower.	Reported: plasma cytokines, MRI-DTI, 18FDG PET-CT	no
Lee Y et al., 2012 PMID: 22443810	N/A Korea, N/A open label	N/A	CP, 20 (2–20 years)	Autologous UCB-TNC 5.5 × 107 cells/kg route: intravenous	- Safe and feasible. - Functional benefit in some CP patients that could be linked to MRI-DTI and SPECT evaluations.	Reported: MRI-DTI; SPECT	no
N/A	NCT02866331 Korea, 2 randomized; double-blind;	July 2016/December 2018	CP, 88 (2–10 years)	Autologous UCB-MNC and G-CSF (10 μg/kg/day) (Leucostim) route: intravenous	- No data published - Based upon feasibility and safety (https://www.ncbi.nlm.nih.gov/pubmed/22443810)	Planned: MRI-DTI, peripheral blood CD34+ cell counts, neurotrophic factors/anti-inflammatory cytokines.	no
Sun J et al., 2017 PMID: 29080265	NCT01147653 USA, 2 randomized, place-controlled	June 2010/November 2012	CP, 63 (1–6 years)	Autologous UCB-TNC 1–5 × 107 cells/kg Categories of low and high infused doses Low: <2 × 107/kg, n = 16 High: ≥2 × 107/kg, n = 16 route: intravenous	- No significant difference in change in GMFM-66 score between intervention and control group 1 year after infusion in the whole study cohort. - Infants who received higher cell doses (≥2 × 107/kg infused) demonstrate superior gains in both whole brain connectivity and motor function 1 year after infusion of cord blood cells.	Reported: MRI-DTI Planned: Correlation between clinical response and RNA expression of inflammatory cytokines in transplanted cord blood cells	yes, methyl-prednisolone
Liu X et al., 2017 PMID: 28235424	ChiCTR-TRC-12002568 China, 1; 2 randomized, rehabilitation-controlled	October 2012/October 2015	CP, 105 (4–10 years)	Autologous BM-MSC Autologous BM-MNC 1 × 106 cells/kg Control group: Bobath therapy only route: 4 × intrathecal	- BM-MSC administration improves significantly the total scores of GMFM and FMFM after 6 and 12 months when compared to the control group. - BM-MNC administration does not improve these scores in comparison to controls. - BM-MSC transplantation is feasible and safe.	Planned: T lymphocyte subsets determination	no
Luan Z et al., 2012 PMID: 22507684	N/A China, N/A randomized controlled	May 2005/May 2006	CP, 94 (<5–40 month)	NSPC from human aborted fetal forebrain tissue 8–10 × 106 route: intraventricular	- Significantly better GMFM and PDMS-FM in treated group after one year. - Rate of improvement decreased gradually within 3 months of transplantation. - No delayed complications observed.	no	no
review article✢	KCT0001429 (CRIS) Korea, 1; 2 open label	August 2006/August 2013	HI, 41 (≥ 36 weeks)	NSPC from human aborted fetal forebrain tissue 25 × 107 route: intracerebral (in the brain injury)	N/A	no	not specified
Cotten C et al., 2014 PMID: 24388332	NCT00593242 USA, N/A open label	January 2008/March 2017	HIE, 23 (12–72 h)	Autologous UCB-TNC 1–5 × 107 cells/dose route: 4 × intravenous	- UCB transfusion is safe and feasible. - Phase II studies are warranted.	no	yes, hydro-cortisone
Gabr et al., 2015 not available	N/A Egypt, N/A randomized, rehabilitation-controlled	June 2008/June 2009	CP, 94 (1–7 years)	Autologous BM-MSC 2 × 106 route: intrathecal	- The MSC injections show short-term safety. - PEDI and Gross motor-function score show no significant improvement.	no	not specified
Mancías-Guerra C et al., 2014 PMID: 24642016	NCT01019733 Mexico, 1 open label	July 2009/January 2011	CP with HI etiology, 18 (1–8 years)	G-CSF (10 μg per kg/day) for 4 consecutive days+ Autologous BM-TNC 13 × 108 route: intravenous and intrathecal	- G-CSF-mobilized autologous BM-TNCs intrathecal and intravenous administration in children with CP is safe. - Possible increase in neurological function.	no	yes, hydrocortisone
Chen G et al., 2013 PMID: 23351389	ChiCTR-TRC-12002056 China, N/A open label, non-randomized, controlled	July 2010/August 2015	CP, 60 (1–21 years)	NSPC-like cells derived from autologous BM-MSC 1–2 × 107 route: intrathecal	- NSC-like cells are safe. - GMFM scores in the transplantation group significantly higher 3 and 6 months post-treatment compared with the baseline scores. - No significant increase in GMFM in the control group. - No significant increases in the language quotients at months 1, 3, and 6 post-treatment when compared with the baseline quotients in both groups.	no	not specified
Romanov Y et al., 2015 PMID: 25791070	Roszdravnadzor, Permission #2009/387 Russia, N/A open label	January 2011/December 2013	CP, 80 (1–12 years)	Allogenic UCB-TNC 2.5 × 108 route: 1–6 × intravenous	- In 3–36 months follow-up, no adverse effects observed. - More UCB-infusions correlate positively with neurological status and cognitive functions.	no	prophylactic anti-allergic drug, Clemastine
N/A	NCT01639404 Korea, N/A open label	July 2012/August 2013	CP, 17 (6 month - 20 years)	Allogenic UCB-TNC route: intravenous or intraarterial	N/A	no	yes, non-myeloablative immuno-suppressant
N/A	NCT01988584 USA, 2 randomized, placebo-controlled	November 2013/May 2020	CP, 20 (2–10 years)	Autologous BM-MNC or autologous UCB-TNC route: intravenous	N/A	no	not specified
Tsuji M et al., 2020 PMID: 32165664	NCT02256618 Japan, N/A open label	August 2014/October 2019	HIE, 6 (12–72 h)	Autologous UCB-TNC 1.4–10.9 × 108 cells in total route: 3 × intravenous	UCB transfusion is safe and feasible.	no	yes, hydro-cortisone
	NCT03078621 Jordan, 1; 2 open label	September 2016/March 2020	CP, 50 (2–12 years)	Autologous BM-derived stem cells and MSC route: intravenous and intrathecal	N/A	no	not specified
Wang X et al., 2013 PMID: 24100132	ChiCTR-TRC-10000928 China, N/A open label	N/A	CP, 52 (6 month - 15 years)	Autologous BM-MSC 2 × 107 route (2 protocols): - Patients ≥5 years or with head circumference ≥ 50 cm: 2 × intrathecal +1 × intraparenchymal - Patients <5 years or with head circumference < 50: 4 × intrathecal	- Procedure is safe and feasible. - The GMFM-66 percentile used as a control index indicates a significant improvement at 1, 6 and 18 months after transplantation. - The intraparenchymal group did not profit more from transplantation.	no	not specified

✢ http://www.neo-med.org/journal/view.php?number=777, publication in Korean language

Abbreviations

N/A = not available

For pathologies

CP = cerebral palsy; HIE = hypoxic ischemic encephalopathy; IVH = intraventricular hemorrhage

For cells

UC = umbilical cord; UCB = umbilical cord blood; BM = bone marrow; TNC = total nucleated cells; MNC = mononuclear cells; MSC = mesenchymal stem cells; NSC = neural stem cells; NPC = neural progenitor cells; mPB-MNC = mobilized peripheral blood mononuclear cells

Notes

• all injected cells are of human origin

• Cell counts for administration are displayed per administration

For functional assessments.

¹⁸FDG PET-CT = 2-deoxy-2-[fluorine-18]fluoro- D-glucose integrated with computed tomography; MRI-DTI = magnetic resonance imaging (MRI)-diffusion tensor imaging; SPECT = single-photon emission computed tomography; FA = fractional anisotropy.

CFA = comprehensive functional assessment; PEDI = Pediatric evaluating self care, mobility and social function; GMPM = Gross Motor Performance Measure; FMFM = fine motor function measurement; BSID-II = Bayley Scale of Infant Development-II; PDMS-FM = Peabody Developmental Motor scale-Fine Motor; ADL = activities of daily living.

For other measures.

CSF = cerebrospinal fluid; IL = interleukin; PTX3 = pentraxin 3; TLR4 = Toll-like receptor 4; G-CSF = granulocyte colony-stimulating factor.