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

Source of MSC: MS vs. Non-MS

Malzzanti B et al. JNI 2008;199:142-150

Source of MSC: MS vs. Non-MS

Malzzanti B et al. JNI 2008;199:142-150

No Difference in Differentiating Potential Between MS & Normals

Mallam E et al. Mul Scler 2010;16:909–918

Clinical Studies of MSCT in MS

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

Allo-MSCT in MS

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

MSCT in MS

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

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

Yamout B et al. J Neuroimmunol 2010;227:185-9

MSCT in MS: EDSS

Yamout B et al. J Neuroimmunol 2010;227:185-9

MSCT in MS: MSFC

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

MSCT in SPMS

Connick et al, Lancet Neurology 2012;11:150-6

MSCT in SPMS

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

Lublin F. et al. 2012; ECTRIMS Poster 12-665

Allogeneic MSCT in MS

Lublin F. et al. 2012; ECTRIMS Poster 12-665

Allogeneic MSCT in MS

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

Testing MSCT in MS

Freedman et al, Mult Scler J 2010;16:503-10

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

Ottawa, CANADA