Stem Cells – Canadian Perspective

John LaffeyCritical Illness and Injury Research Centre, Keenan

Research Centre, St Michael’s Hospital.

Departments of Anesthesia, Physiology and Interdepartmental Division of Critical Care Medicine,

University of Toronto.

Conflict of Interest

• Tissue Regeneration Therapeutics, Toronto, Canada

• Orbsen Therapeutics Ltd, Galway, Ireland

• CommenceBio, California, USA

• Council member, Ontario Institute of Regenerative

Medicine

Stem Cells – A Canadian discovery

Griffiths M et al. Lancet 2005;366:245

Differentiation

Proliferation

Stem cell

Mature

cells

What are STEM CELLS?

Resident Lung Stem Cells

Embryonic Stem Cells

Induced Pluripotent Stem Cells

Endothelial Progenitor Cells

Mesenchymal Stromal Cells

www.stemcells.nih.gov/info/

Bone Marrow Stem/Stromal Cells

Advantages of MSCs

Stem Cell Therapies –

focusing on lung Repair?

?

Anaesthetize

Intubate

IV MSC

TherapyAnaesthetize

High Stretch

Ventilation

Assessment of

Recovery from

ARDS

48hrs

Compliance

ed 50%

Recover and

extubate

MSCs enhance injury resolution

following VILI

Curley et al, Thorax 2012

Hayes, Masterson et al, Anesthesiology 2014

Gupta, Krasnodembskaya et al, Thorax 2012

Time (Hours)0 12 24 36 48

Su

rviv

al

0.0

0.2

0.6

0.7

0.8

0.9

1.0

hMSCs (10-20 million/kg)

Vehicle/Fibroblast

Devaney et al, Thorax 2015

Devaney et al, Thorax 2015

• Ease of accessibility

• Absence of risk for the

donor

• Absence of pain for

donor

• Consistency in terms of

age at collection

Umbilical cord MSCs

Sham E.Coli + Vehicle E.Coli + UC-MSC

How do MSCs work?

Curley et al, Anesthesiology 2013

Krasnodembskaya et al, Stem Cells 2010

Devaney et al, Thorax 2015

MSCs enhance Macrophage Phagocytosis of

Bacteria

UNTREATED MSC TREATEDBACTERIA INFECTION

Laffey & Matthay AJRCCM 2017

MSCs – Key mechanisms of Action

hMSCs for ARDS…where

are we now?

©2015 by American Society of Hematology

Blood 2015;126:2220

• Understanding mechanisms of action

• Scaling MSC production for Clinical Trials

• Cryopreservation versus Fresh Cells

• Batch to batch variability

• Potency assays

• Optimal cell source

• Cost of large scale Clinical Trials for cell therapies

• Need for flexible approaches

• Turning critical care doctors into transplant physicians…

Stem Cells for ARDS – Challenges

Laffey and Matthay, AJRCCM 2017

• Canadian…..contributions to health research and medicine. Two stand out as landmarks: the discovery of insulin in the 1920s and the discovery of stem cells in the 1960s.

• Canada founded the entire field of stem-cell science…….discovering neural stem cells, skin stem cells and cancer stem cells.

• Canada does this for a dime….The “all in” investment in stem-cell research in Canada …..is about $75-million [2012 Figures].

• Funding still seriously lags behind California, which, with roughly the same population as Canada, has committed $3-billion over 10 years for stem-cell research.

Cell therapy trials in Ontario 2015-16

Brain and/or nerves Phase II using MSCs for Multiple

Sclerosis: Toronto*

Phase III using diabetes drug to

stimulate brain repair for malignant

brain tumours: Toronto*

Digestive systemPhase III using MSCs to induce

remission of Crohn’s disease:

London and Toronto

HeartPhase II using genetically modified

stem cells following heart attack:

Ottawa and Toronto*

Phase II using MSCs for advanced

heart failure with left ventricular

assist device: Toronto*

SpinePhase I/II using neural stem

cells for spinal cord trauma:

Toronto*

BloodPhase I using immune cells for

blood cancer relapse after

bone marrow transplantation:

Toronto*

JointsPhase I-II using stem cells mid-

to late-stage knee osteoarthritis;

Toronto*

2015-16

9 trials

11 partners

3 Ontario

cities

655+ patients

Billions of

stem cells

* OIRM researchers leading trial

Critical carePhase I using MSCs for septic

shock: Ottawa*

Hematopoietic stem cell transplantation

First Animal

studies

1954

First Human

studies

1957

First Proof

of efficacy

(in AML)

1977 1982/6

Proof of

efficacy

in CML

Ongoing Discoveries

e.g. MSCs for GVHD

2001-16

Human Allogenic

BM Transplant

1971

• Stem cells offer considerable potential for Critical Illnesses

– Pre-clinical studies highly encouraging

– MSCs now in early phase Clinical Studies for ARDS

• Clinical Translational pathway likely to be lengthy and there

will be setbacks...

• Twin-track strategy of pre-clinical research and early phase

clinical translational studies in progress

• Canada’s role in realizing clinical potential of stem cells

– World leading Preclinical/Discovery science

– CISS-1 Study a major step forward in Sepsis

Stem Cells – A Canadian Perspective

Laffey and Matthay, AJRCCM 2017

Acknowledgements

Gerard Curley

Mirjana Jerkic

Stephane Gagnon

Claire Masterson

Allen Volchuk

Grace Hogan

Lindsey Ormsher

Linda Garces

Haibo Zhang

Wolfgang Kuebler

Sergio Grinstein

Timothy O’Brien