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Innovation in Stem Cell
Therapy
Vincent J. Pompili, MD, FACC, FSCAI
Professor and Chief of Cardiovascular
Medicine
The University of Nebraska
DISCLOSURE
Vincent J. Pompili, MD, FACC, FSCAI
Advisory Board Member
Boston Scientific
Cordis Cardinal Health
Board of Directors/Shareholder
Arteriocyte, Inc.
Proposed Mechanisms of Benefit
New blood
vessels
Endothelial
stem cells
Direct
differentation
Resident
endothelial
progenitor
cells
Cardioprotection
Paracrine
effects
Angiogenic
stimulus
Transplanted cells
Immunomodulation
Homeostatic stimuli
Cardiogenic
stimulus
Direct
differentation
Mesenchymal stem cells
Resident
cardiac stem
cells
Healthy myocardium
Behfar, Nature CV Reviews 2014
©2015 MFMER |
3443510-11
Clinical Trials of Cell Therapy for Heart Failure (BMMNCs)
Cell Type
Endpoint
Patients
(N)
Delivery Route
BMMNC
BMMNC
BMMNC
BMMNC
LVEF
LVEF
LVEF
LVEF
28
234
30
24
Intracoronary
Intracoronary
Intracoronary
Intracoronary
LVEF
LVESV
All-cause Mortality
LVEF
Safety+SAE
Time to SAE
Time to SAE
LVEF
Mortality+Morbidity
109
92
3000
104
60
108
240
35
676
Endomyocardial
Endomyocardial
Intracoronary
Epicardial
Retrograde
Endomyocardial
Endocardial
Intracoronary
Intracoronary
LVEF
148
Intracoronary/Endo
dial
PERFECT
BMMNC
BMMNC vs placebo
BMMNC vs placebo
BMMNC vs placebo
BMMNC vs medical therapy
Cultured bone marrow
Cultured bone marrow-cardiopoetic
Repeated BMMNC
Single vs repeated (2x) BMC infusions
Intracoronary BMMNC + GCSF vs
endomyocardial BMMNC + GCSF vs GCSF
vs placebo
BM CD133+ vs placebo
142
Epicardial
PreSERVE-AMI
BM CD34+ vs placebo
160
Intracoronary
Patel et al
BM CD34+ vs placebo
LVEF
Safety+MACE+MI
Perfusion
LVEF
50
Epicardial
Study
Nonischemic HF
Suzrez et al
Ribeiro et al
TOPCARE-DCM
Martino et al
Ischemic HF
Pokushalov et al
FOCUS-HF
BAMI
Patila et al
REVIVE-1
ixCELL DCM
CHART-1
DANCELL-CHF
REPEAT
REGEN-IHD
Clinical Studies of CD34+ Cell Therapy
Study
Indication
Geography
PAD (CLI)
CD34 Cell Therapy
Exposure (N)
17
Phase 1/2 Clinical Study to Assess the Safety and Efficacy of
Autologous CD34+ Cells[1, 2]
Phase 2 Clinical Study to Assess the Safety and Efficacy of AutoCD34+ Cells (Protocol TRIASO0706)[3]
US Phase 1 Study to Assess the Safety and Efficacy of Autologous
CD34+ Cells in Subjects with PAD and severe IC
US Phase 1/2a Study to Assess the Safety and Efficacy of
Autologous CD34+ Cells in Subjects with Moderate or High-Risk
CLI[4]
PreSERVE-AMI: NBS10 (Also Known as AMR-001) Versus Placebo
Post ST Segment Elevation Myocardial Infarction (NCT 01495364)
Intramyocardial Transplantation of Autologous CD34+ Stem
Cells for Intractable Angina: A Phase I/IIa Double-Blind, Randomized
Controlled Trial [5]
Intramyocardial, Autologous CD34+ Cell Therapy for Refractory
Angina [6]
Effects of Intracoronary Stem Cell Transplantation in Patients With
Dilated Cardiomyopathy [7]
Effects of Intracoronary CD34+ Stem Cell Transplantation in
Nonischemic Dilated
Cardiomyopathy Patients 5-Year Follow-Up [8]
Effects of Transendocardial CD34+ Cell Transplantation in Patients
With Ischemic Cardiomyopathy [9]
Comparison of Transendocardial and Intracoronary CD34+ Cell
Transplantation in Patients With Nonischemic Dilated
Cardiomyopathy [10]
Immune Network and Response to Intramyocardial CD34+ Stem Cell
Therapy in Patients with Dilated Cardiomyopathy [11]
PAD (CLI)
11
Japan
PAD (IC)
17
US
PAD (CLI)
16
US
STEMI
78
US
Refractory Angina
18
US
Refractory Angina
112
US
Nonischemic HF
28
EU
Nonischemic HF
55
EU
Ischemic HF
33
EU
Nonischemic HF
40
EU
Nonischemic HF
37
EU
Japan
Clinical Trials of Cell Therapy for Heart Failure (non-BMMNC)
Study
Endpoint
Patients
(N)
Safety+SAE
Safety+SAE
42
36
GCSF peripheral blood derived CD34+
LVEF
60
ADSC
ADSC vs placebo
Allogeneic USCs
Safety+QoL
10
SAE+Infarct size 27
Safety+LVEF
10
Endomyocardial/IV
Endomyocardial
Endomyocardial
Allogeneic MSCs
LVEF
30
Epicardial
LVEF
60
Endomyocardial
SAE+LVEF
67
Endomyocardial
SAE
SAE
Safety+QoL
7
33
170
Endomyocardial
Intracoronary
Endocardial
Time to SAE
Safety+LVEF
Safety+SAE
1730
60
60
Endomyocardial
Endomyocardial
Endomyo/Epicard
Cell Type
Nonischemic HF
DYNAMIC
Allogeneic cardiac progenitor cells
POSEIDON-DCM MSCs vs allogeneic MSCs
Vrtovec et al
Ischemic HF
Parcero et al
PRECISE
Yan et al
Anastasiadis et
al
MSC-HF
MSCs vs placebo
MSCs (100 or 200M) vs BMCs (100 or 200M) vs
TAC-HFT
placebo
PROMETHEUS Low-vs high-dose MSCs vs placebo
SCIPIO
Cultured cardiac progenitors
MARVEL
Skeletal muscle
Both Nonischemic and Ischemic HF
DREAM-HF
Allogeneic MSCs
Perin et al
25 vs 75 vs 150M allogeneic MSCs vs Placebo
IMPACT-DCM
Cultured bone marrow
Delivery Route
Intracoronary
Endocardial
Intracoronary/Endom
dial
Patient Selection
1-year mortality
<5%
5-10%
10-20%
20-50%
Metra M, Ponikowski P, Dickstein K, McMurray JJ, Gavazzi A, Bergh CH, Fraser AG, Jaarsma T, Pitsis A, Mohacsi P, Böhm M, Anker S, Dargie H, Brutsaert D,
Komajda M; Heart Failure Association of the European Society of Cardiology. Advanced chronic heart failure: A position statement from the Study Group on Advanced
Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2007 ;9(6-7):684-94.
5-YEAR SURVIVAL
Vrtovec B, Poglajen G, Lezaic L, Sever M, Domanovic D, Cernelc P, Socan A, Schrepfer S, Torre-Amione G, Haddad F, Wu JC. Effects of
intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ Res. 2013;112(1):165-73.
RESULTS: LVEF
Vrtovec B, Poglajen G, Lezaic L, Sever M, Domanovic D, Cernelc P, Socan A, Schrepfer S, Torre-Amione G, Haddad F, Wu JC. Effects
of intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ Res.
2013;112(1):165-73.
Am J Cardiol 2013;112:217-225
Kandala Meta-analysis
LVEF
LVESV
LVEDV
Am J Cardiol 2013;112:217-225
LVEF
IM
IC
Am J Cardiol 2013;112:217-225
PLoS One 2013 Jun 19;8(6):e64669
Mortality
PLoS One 2013 Jun 19;8(6):e64669
Martin-Rendon Meta-analysis
Angina Class
Angina Frequency
PLoS One 2013 Jun 19;8(6):e64669
Martin-Rendon Meta-analysis
Quality of Life
Exercise Time
LVEF
PLoS One 2013 Jun 19;8(6):e64669
Screening
550 pts
Study Flow
Treatment Group
30x106 BMMNC
20 pts
2:1 Randomization
30 pts
LVA/ NOGA
Cell Injection/
Mock Injection
Early
Control Group
Mock BM Harvest
10 pts
Assessments
3 Month Assessment
- CCS
- SPECT
- NHYA
- Echo
- Holter
- MVO2
Crossover
8 pts
6 Month Assessment
- CCS
- SPECT
- NHYA
- Echo
-Holter
- MVO2
- NOGA
- Cor/LVA
MRI Subgroup
17 pts
Cell Analysis

Immunophenotyping:


CFU-GM
Surface markers (CD 34+, 133+,)
Hematopoietic:

CFU-GM
Dil labeled ac-LDL incorporation
Tube Formation

Endothelial:
Tube Formation
 Ac LDL incorporation


Mesenchymal:
CFU-F
 Population doubling time


Chemotaxic properties:


migration (SDF-1, VEGF)
Hindlimb ischemia:
immunodeficient
murine model
CFU-F
Mesenchymal Colony Forming Units
(CFU-F)
29
28
27
25
22
Patient ID
18
17
15
Healthy Marrows
14
180
13
11
9
8
7
6
2
1
0
10
20
30
40
50
CFU Number per 106 BM Mononuclear Cells
60
MSC Growth Kinetics
20
7
Control
8
18
11
16
Cell Number (103)
13
14
14
12
15
17
10
18
8
22
6
25
27
4
28
2
29
control
0
12
36
Time (hours)
60
84
MVO2
Patients >60 Years
25.00
p=ns
Treatment
Control
(ml/Kg/min)
20.00
15.00
10.00
5.00
Baseline
3 months
6 months
MVO2
Patients <60 Years
25.00
Treatment
Control
(ml/Kg/min)
20.00
p=0.07
15.00
p=ns
10.00
5.00
Baseline
3 months
6 months
Organizational Structure: NHLBI
Cardiovascular Cell Therapy Research Network (CCTRN)
NHLBI
Skarlatos
PRC
PDC
Cell
Processing
QC Lab
Texas Heart
Institute
Willerson
Cell Processing
Satellites:
DeBakey VA
DSMB
Chair
Simari
Skills
Development
Core
U FL
Pepine
Cell Processing
Satellites:
Pepin Heart Institute
Steering Committee
Data Coordinating Center
UTSPH
Moyé
P&P
Biorepository, cMRI, Echo, MVO2, SPECT
Core Labs
Cleveland
Clinic
Ellis
Minneapolis
Heart Institute
Henry
Cell Processing
Cell Processing
Satellites:
University Hospitals
Satellites:
United Heart & Vascular Clinic
Metro Cardiology Consultants
U MN
Mayo Clinic
Skills
Development
Core
Vanderbilt
University
Zhao
Cell Processing
FOCUS-2 Rationale-Endpoints
 Severe ischemic LV dysfunction
(<45%) n= 86 pts
 Increased dose (100M cells)
 Multicenter-CCTRN
 Placebo controlled
 Combined Endpoints = SPECT, Echo
(LVV), MVO2 (all core assessed)
 Late Breaking Trials ACC 2012-JAMA
Primary Endpoint: LVESV
Change in Indexed LVES Volume by
Echo
Placebo
BMC
160
Baseline-6 mo:
140
No difference in
change BMC vs
Placebo
LVESV (ml)
120
100
80
60
65.0
40
57.9
65.0
57.0
20
0
Baseline
N=54
6 Mo
N=54
Baseline
N=28
6 Mo
N=28
Primary Endpoint: MVO2
Change in MVO2
Placebo
BMC
35
Baseline-6 mo:
Peak VO2 (ml/kg/min)
No difference in
change BMC vs
Placebo
30
25
20
15
14.6
15.0
15.3
14.7
10
5
0
Baseline
N=54
6 Mo
N=54
Baseline
N=28
6 Mo
N=28
LVEF
Global LVEF
Placebo
BMC
BMC
60
Baseline-6mo:
40
LVEF (%)
Sig increase in
LVEF change
BMC vs Placebo
(+1.4 vs -1.3,
p=0.03)
50
30
36.1
34.7
32.3
31.0
20
10
0
Baseline
N=54
6 Mo
N=54
Baseline
N=28
6 Mo
N=28
Correlation ΔLVEF and %CD34
Adjusted for Age and Therapy
20
20
15
15
10
10
ΔLVEF
ΔLVEF
Unadjusted
5
5
0
0
0
2
4
6%CD34
0
8
-5
-5
-10
-10
R2= 8%
P = 0.012
1
2
R2= 16%
P=0.043
3
4
Relationship of Age (prespecified)
Delta LVEF and Age
15
15
BMC
Placebo
10
10
5
5
0
0
20
40
-5
60
80
-5
40
50
-10
-10
-15
-15
-20
R2= 10%
P = 0.017
R2= 2%
P= NS
60
70
80
Strategies to Enhance Cell Therapy
1.
Increase the number of cells (autologous)

2.
Whole bone marrow (Harvest)
Selected cells (autologous)

Adipose derived cells (Cytori)
 CD34+ cells (Baxter)
 ALD-bright (Aldagen)
3.
Expand and/or enhanced cells (autologous)

Aastrom Biosciences
 C-Cure
 MSC-HF
4.
Allogeneic

MPC (Mesoblast-Teva)
 MSC (Osiris)

MAPC (Athersys)
5. Cardiac derived
 Caduceus (Capricor)
 SCIPIO
Cardiac Cell Repair Therapy
Future Directions – Which Cells for Which Disease?
Ischemic tissue
• Scar
• Necrotic tissue
IDC
Dysfunctioning muscle
Left ventricular
Peripheral
Cells
dysfunction arterial disease • MSC
• Guided MSC**
• Mesenchymal precursor cells***
Cells
• IPS
CD 34+ve**
Enriched BMC
• Resident Cardiac SC*
CD 133+ve
Mixed BMSC
• Combination MSC and C-Ki****
Angiogenic
potential
*BAMI – 3,000 pts
**RENEW – 400 pts
(Terminated 12/13)
Which cells? – CD34+
– CDCIS+
• Gene therapy
• MSC + LVAD
(MPC Trial)
Regenerative
potential
***Teva Revascor – >600 pts chronic CHF
**CHART-I 240 pts EF <35%/CHART-2? – Neutral
*ALLSTAR – 312 pts
****CONCERT – HF
+DYNAMIC Trial – (CDCIS)
42 pts
©2015 MFMER |
3568273-02
Ongoing Clinical Trials of
Stem Cell Therapy
The field of stem cell research is active, robust
international and encompasses both bench and bedside
• 39 trials – 1,675 pts (range 30-1,730)
• Ischemic and non-ischemic cardiomyopathy
• Phases 1, 2 and 3
Cell source
• Autologous
• Allogeneic
• Umbilical cord
Cell types
• 11 different cells and combinations
Delivery
•
•
•
•
•
Intracoronary
Intramyocardial
Intravenous
Transendocardial
Precursor cells
(mesoblast)
Kelkar JACC, 2015
©2016 MFMER |
3551108-15
Cardiac Cell Repair Therapy
is at a Crossroads
‟The end of the beginning or the beginning of the end”?
-Winston Churchill
Causes for cautious optimism
• Ongoing basic research on
multiple fronts and countries
but
“lost in clinical translation”
Clinical trial results
Safety
Modest
benefits
Trends in
the right
direction
• Improved clinical trial design
Concerns
• Benefits – modest
• Neutral trials
• Unrealistic expectations
Physicians
Public/media
• Overreaction to neutral trial results
• Perceptions in scientific community
over extent of stem cell research
funding
• Concerns re scientific credibility –
justified and unjustified
©2015 MFMER |
3485742-3
Cardiac Cell Repair Therapy
Conclusions
• A pivotal trial demonstrating significant benefits on LV
function (eg, EF 10%)
Will change clinical practice
• Resident cardiac stem cells and guided MSCs
are promising
• Larger trials are needed to assess relative benefits
compared to BMSC and other progenitors
• Enhancement strategies are needed to improve
current results
©2015 MFMER |
3485742-4
ISSCR Releases Updated Guidelines for Stem Cell
Research and Clinical Translation
Washington 2016
Sean J. Morrison, PhD
ISSCR President
“ Highlight the responsibility of all groups
communicating stem cell science and medicine –
scientists, clinicians, industry, science
communications and media – to present accurate,
balanced reports of progress and setbacks”
©2016 MFMER |
3557938-3