Mesenchymal Stem Cell Transplantation in Multiple Sclerosis
Transcript of Mesenchymal Stem Cell Transplantation in Multiple Sclerosis
Mesenchymal Stem Cell Transplantation in Multiple
Sclerosis
Mark S. Freedman MSc MD FAAN FRCPCProfessor of Medicine (Neurology)University of OttawaCANADA
The Issues
Cell source – (eg. BM, adipose tissue, placenta)Autologous vs. commercial allogeneicMS vs. non-diseased controls Production technicals (e.g. FBS vs. PL)
Dosage Route of Administration (IV vs. IT) Frequency of administration
Source of MSC: Self vs. Non-Self
AutologousUnlikely to be rejectedRequires source of tissue (BMT, adipose)Must likely be replenished with subsequent
repeat tissue harvestHeterogeneity among donorsMay possess different properties compared
with non-diseased humansMight be affected by prior or ongoing Tx
Source of MSC: Self vs. Non-Self
AllogeneicMinimally immunogenic
No MHC II (minimal MHC 1) expression Do not induce MLR-like proliferation or IFN-
production by allogeneic T cells Are not targeted, lysed or induce production of
IFN- or TNF- by allogeneic cytotoxic T cellsAre not rejected upon xenogeneic
transplantation in miceAre not rejected in human studies
No Difference in Differentiating Potential Between MS & Normals
Mallam E et al. Mul Scler 2010;16:909–918
Allo-MSCT in MS
MSC derived from umbilical cord & grown with 5% FBS
Single rapidly progressive case of PPMS quadraplegic after 8 mths
Pre-conditioning CTX 600mg daily x 3 1 x 107 cells IT & 2 x 107 cells IV Prednisone 10mg daily post-transplant
Liang J et al. Mult Scler 2009;15: 644–646
Allo-MSCT in MS Day 3: sensory impairment significantly
improved Day 9: muscle strength increased - she
could sit with assistance Day 52: objective improvement of
neurological signs – now mobile but staggering
EDSS score decreased at least 2 points from baseline 8.5
Day 56: MRI showed a significant reduction in the T2 lesion load, especially in the cervical cord
Liang J et al. Mult Scler 2009;15: 644–646
MSCT in MS Phase I/II study 15 pts (7M:8F) – mean EDSS 6.7 Disease duration > 5 years (mean 10.7) No response to DMD 2 attacks or 1 EDSS pt worsening in the
previous year MSC made with FBS, pre-frozen &
thawed & washed before administration Dose 2/3 of ~6-10 x 107 cells IT & 1/3 IV
Karussis et al, Arch Neurol 2010;67:1187-94
Clinical Follow-Up of MS Patients Following MSCT (6 months)
Karussis et al, Arch Neurol 2010;67:1187-94
MSCT in MS
Phase I 10 pts (7F:3M) mean age 33 ± 5.90 EDSS 3.5 – 6 A mean volume 5.5 ml containing 8.73 x
106 cells IT (1 pt given 2nd infusions 4 mths after 1st – not clear why)
Mohyeddin Bonab M, et al. Iran J Immunol 2007;4:50-57
MSCT in MS
Headache: 9 pts had slight headache relieved in 2 by 3 doses of analgesics
Aseptic meningitis: 1 F 4 hrs after injection: 1M after a 2nd injection (4 mthslater) - both with N CSF but received A/B for 14 days
6 pts had new attacks 1-7 (1 with 2) all Txwith IVMP
Mohyeddin Bonab M, et al. Iran J Immunol 2007;4:50-57
MSCT in MS
Phase I Progression despite “standard” Tx EDSS 4.0-7.5 MSC cultures with FBS & cryopreserved Thawed cells washed & injected directly
IT 5mL @ C1-2 & 5 mL L2-3
Yamout B et al. J Neuroimmunol 2010;227:185-9
MSCT in MS Adverse Events:
Pt 1 - transient encephalopathy with seizures a few days after cell injection, requiring hospitalization & IV VPA
Pt 3 - transient cervical & low back pain for few days without fever or meningeal signs
MRI: At 3 mths new/enlarging lesions in 5/7 & Gd+
lesions in 3/7 patients At 1 year only 4 patients with data - 1 with a
single Gd+lesion
Yamout B et al. J Neuroimmunol 2010;227:185-9
MSCT in SPMS Phase IIa POC study in SPMS EDSS 5.5-6.5 with visual pathway lesions Mean dose 1.6 x 106/Kg IV MSC made with FBS, pre-frozen &
thawed & washed before administration Cells were given within 4 min of thawing
over 15 min followed by 500 mL saline
Connick et al, Lancet Neurology 2012;11:150-6
Allogeneic MSCT in MS
Phase Ib study of allogeneic MSC derived from placenta (PDA-001)
RDBPC 3:1 trial of 2 (day 0 & 7) IV infusions of 2 doses (1 or 4 units - 1 unit of PDA-001 is ≈200 x 106) MSC cells without immunosuppressants
RR or SPMS Follow-up to 1 year
Lublin F. et al. 2012; ECTRIMS Poster 12-665
Allogeneic MSCT in MS Adverse events (AEs) mild-moderate in severity:
Fatigue (3/16; 23%) UTI irritation/infection (4/16; 25%) Headache (7/16; 44%)
Infusion-related events (6/16; 37.5%) 2 patients in the low-dose group; 4 patients in the
high-dose group Infusion-site swelling, hematoma, site mass, or pain 2 serious AEs, both in the high-dose group
Anaphylactoid reaction (fever, rigors, tachycardia)-grade 1 Superficial thrombophlebitis - grade 2
Lublin F. et al. 2012; ECTRIMS Poster 12-665
MESEMS:Trial Protocol: Inclusion Criteria
RRMS/SPMS/PPMS Age: 18-50 Disease duration: ≥2 and ≤ 10 years Evidence of:
Continued relapses, worsening MRI or progression after at least 1 year of attempted therapy
Evidence of current disease activity as demonstrated by either: ≥1 moderate-severe relapse in past 1-2 years Objective evidence of:
≥1 EDSS point deterioration in the 18 months prior to enrollment if the EDSS is 5.0, or
≥0.5 EDSS point deterioration in the 18 months prior to enrollment if the EDSS is ≥5.5 or quantifiable, objective measure of progression
≥1 gadolinium enhancing lesion or ≥1 new T2 lesion EDSS = 3.0 - 6.5 For PPMS - no relapse criteria, but must have enhancing MRI
lesions and +ve OCB
Freedman et al, Mult Scler J 2010;16:503-10
MESEMS:Trial Protocol: Exclusion Criteria
Purely progressive disease Any immunosuppressive therapy within
3 months of baseline Any disease modifying therapy
(interferon- or glatiramer acetate) within 30 days of baseline
no steroids within 30 days no relapse within 60 days
Freedman et al, Mult Scler J 2010;16:503-10
MESEMS:MSC Product
Autologous Standardized cell culture protocol (as per Dr. Atkins) Number of cells
≥ 1.0 - 2.5 x 106/kg recommended for viable protocol maximum 5 x 106/kg target 1.1 x 106/kg
Obtain enough for a single infusion and a safety back-up (in case of cell loss or need for follow-up infusion)
Obtain a “reserve” supply for immunology studies Route of administration
IV route justified by adequate safety data IT was considered, but given the lack of documented
advantage for this route of administration it should not be pursued by all, but continued safety data can be collected from the Israeli group
Freedman et al, Mult Scler J 2010;16:503-10
MESEMS:Study Design
One year study: Primary outcome determined at 24 weeks
Randomized cross-over design of “early vs. “delayed” treatment paradigmRandomization to receive cells vs. masked
“control” (cell culture media) at baselineAll initial “control” patients will then receive
active cells at week 24 and followed for another 24 weeks
Freedman et al, Mult Scler J 2010;16:503-10
Trial Outcomes: Primary outcome: MRI
Cumulative combined unique activity (Gd+ or new T2 lesions) of treated vs. delayed treatment after 6 months
MRI Protocol 2 baseline followed by scans at 1, 3 and 6 months
Other exploratory outcomes: OCT Immunological Neurophysiology (EP)
Escape criteria: Sustained progression or relapse within 6 months of MSCT
Freedman et al, Mult Scler J 2010;16:503-10
Conclusions
Consensus on the use of a culture protocol and trial paradigm are more likely to lead to conclusive evidence from several small studies
Groups interested in pursuing MSCT as a potential treatment should join this international study group in order to share data and decide upon future studies