Governance of stem cell therapy Consequences of innovation

Department of Cardiac Surgery Governance of stem cell therapy Consequences of innovation Prof. Dr. med. Gustav Steinhoff Exchange of cardiomyocytes...
Author: Grant Cameron
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Department of Cardiac Surgery

Governance of stem cell therapy Consequences of innovation Prof. Dr. med. Gustav Steinhoff

Exchange of cardiomyocytes Bergmann, O. et al. : Turnover after the fallout: Evidence for cardiomyocyte renewal in humans. Science 2009; 324: 98–102



Method: Integration of carbon-14, generated by nuclear bomb tests indicates age of cardiomyocytes



Results: 1% turning over annually (age dependent) Fewer than 50% of cardiomyocytes are exchanged at the age of 75



Conclusion: “… it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.”

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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What are the effects of CABG surgery? Knapp, M et. al.: Myocardial contractility improvement after coronary artery by-pass grafting in a 1-year observation: The role of myocardial viability assessment, Card. J., 2007, 246–251

LVEF

Wall motion score index 5%

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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Cardiac Stem Cell Therapy

direct application

mobilization

mod. Dimmeler et al. JCI 2005

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

Cell delivery

2001: First clinical stem cell application in heart disease (Strauer, Steinhoff) Stem / Progenitor Cell

Cardiology

Surgery

1.Mobilization (G-GSF) 2.Systemic iv injection 3.Intracoronary injection 4.Endocardial injection NOGA

Local implantation im Patch TE Heart valve TE

Homing Extravasation

Integration Migration

Action

Action

Strauer, Düsseldorf Intravascular application MNC BM 3/2001

Problems observed

Steinhoff, Rostock Intramyocardial application CD133 BMSC 6/2001

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

Clinical indication – acute/chronic ischemia, post infarction

Combined Revascularization (Stent, CABG) • Acute myocardial infarction (immediately - days) • Early after myocardial infarction (< 2 weeks) • Chronic ischemia: Myocardial transition / remodeling phase (2 weeks – several months) Stand alone • Completed remodeling / scar postischemic cardiomyopathy (>6 months) • Refractory angina • Chagas disease Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

Stem cell “homing” and vascular activity Role of endothelial NOS, SDF-1 alpha and local inflammation

*

Intravascular application

Intravital fluorescence microscopy in murine cremaster muscle Kaminski A et al. (Lab Investigation 2008) Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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Aspects of ventricular remodeling after infarction

Myocardial infarction in a mouse heart

Control

Hibernation

Connexin 43+ gap junctions Slezak et al. 2009

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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CD133+ cell product from human bone marrow In vitro differentiation of endothelial cells from CD133-positive origin Ong LL et al, Tissue engineering Part C, 2010

P < 0.005

P < 0.005

160 CFU-EC (%)

140 120 100 80 60 40 20 0

Biological Interaction Network

0h

24h

48h

72h

Effect of hypoxia on the differentiation of CD133 1.5% [vol/vol] oxygen and 5% [vol/vol] carbon dioxide

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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Hypothesis

Intramyocardial CD133+ stem cell treatment leads to better recovery of hibernating myocardium in addition to CABG surgery.

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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CD133+ stem cell preparation and transplantation

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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CD133+ stem cell preparation and transplantation 150–200ml

Clinical setting: CD133+ Isolation with CliniMACS-unit Miltenyi Biotec

Direct injection into myocardium

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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Target area for intramyocardial transepicardial injection viability / stress induced ischemia / reduced wall thickening LAD

Lateral LV

Posterior interventricular

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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Analysis of stem cell related effects during CABG A Clinical case reports 

(CD133+, n= …)

B Clinical trials 

Rostock Phase I

(CABG + CD133+, n=15)



Rostock Phase II

(CABG + CD133+, n=20)

Meta Analysis 

(CABG + stem cells, n=94)

Phase III Trial PERFECT

C Clinical real world 

Rostock REGISTRY (CABG + CD133+, n=99)

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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A

Case report stand alone CD133+ therapy

74 y.o. ♂ Stand-alone stem cell therapy 2 months after stented LAD-infarction

pre op

EF 32% Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

1 year

EF 47% 16

Rostock phase I/II study

B

Phase I Trial / 18 months (n=15)

early follow-up Phase II Trial / 6months (n=20 vs. control) 25

50

47±6*

50±8*

48±6*

39±9

40 30

difference in LVEF (%)

60

LVEF (%)

p=0.0009

30

70

20

20 15

9.7%

10 5

3.4%

0 -5 -10

10 preop

discharge

6 months

18 months

CABG & CD133+ cells

CABG

Absolute LVEF Improvement in %

Stamm et al. J Thorac Cardiov Surg, 133(3):717-25; 2007

Increase in myocardial perfusion at 6 months

30 Stem cell group Control group

25 20 15 10 5 0 25-35

25-40

25-45

>25

subgroup analysis n=35 vs. control n=20 at 6 months

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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B

Myocardial perfusion after CD133 + CABG – 3years

1,4

*

1,2 1

Preoperative value=1

0,8 0,6 0,4 0,2 0 1 year

3 years

CABG+Stem cell

Control

*p 5%) Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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C

REGISTRY / Arrhythmia in CABG + CD133+ Median change in number of ventricular ES / h

8 6 4 2 0 -2

preop

postop

f ollow-up

-4 -6 -8 -10

 Mean change in VES / all beat percentage: -0.8% Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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C

REGISTRY / Survival

Survival vs.

93% in CABG + CD133+(93 out of 99) 88% in Control Phase II patient 1 – patient 2 – patient 3 – patient 4 – patient 5 – patient 6 –

10 months (Phase II) 02 months (Registry) 74 months (Phase I) 07 months stroke (Phase I) 81 months (Phase I) 62 months (Registry)

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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Update 2010  











1988 - 2009 Animal models, mechanism and safety research 2001: worldwide first application and phase I study of intramyocardial injection of purified CD133+ bone marrow stem cells in coronary bypass patients 2001 – 2006: Safety and efficacy approval in Phase I (2001-2003) and Phase II (2003-2005) clinical trials Since 2006 Reimbursement by German health insurance companies (sDRG) 2008 Establishment of national reference center for cardiac stem cell therapy (RTC, Rostock) 2001-2009 Clinical safety and efficacy approval in longterm vigilance studies 9/2009 Start of Phase III clinical outcome study (Sponsor: Miltenyi-Biotec GmbH)

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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Intramyocardial CD133+ Bone Marrow Stem Cell Therapy,

Preclinical research

1988



Clinical research (I) (II) (III)

2001

2003

EMEA license

Standard therapy

2009

  !

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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Standardization of cardiac stem cell therapy

•Indication (ischemia/postinfarction/cardiomyopathy/Htx) •Safety (arrhythmia, tumor, calcification) •Dosage/Toxicity •Standardization of cell preparation •Efficacy (longterm, quality of life) •Biodistribution of cells (migration, survival) •Tumorogenicity •Mechanism of action (paracrine, cellular) •Comparison of different stem cell types •CLINICAL OUTCOME (PE,MACE,QoL) Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

Department of Cardiac Surgery, University of Rostock www.cardiac-surgery-rostock.com www.cardiac-stemcell-therapy.com

Cardiac Surgery A. Liebold / B. Westphal / A. Kaminski / P. Donndorf / C. Nesselmann / C. Klopsch Research Partners (RTC) N. Ma / P. Mark / W. Li / D. Furlani / R. Gäbel / W. Wang , C. Lux Intenational Partners NU Singapur, Beijing/Hefei/Nankai, China Asahara, CDB/RIKEN, Kobe, Japan RenkeLiToronto, Kanada; Capogrossi, IDI, Rome, Italy Pompilio, Milano, Italy R&D Partners: Miltenyi Biotec GmbH D-Trust GmbH, Berlin ATP GmbH, Rostock Helmholtz (GKSS/Teltow) Clinical Development Partners: A. Haverich, MH Hannover R. Hetzer/C. Stamm, DHZ Berlin

This work was supported by the Helmholtz Gemeinschaft, Mecklenburg-Vorpommern (Nachwuchsgruppe Regenerative Medizin Regulation der Stammzellmigration 0402710), BMBF BioChance PLUS (0313191), Miltenyi Biotec, Sonderforschungsbereich/Transregio 37, B5, B2 and A4; and BMBF Reference and Translation Center of Cardiac Stem Cell Therapy (2008–2011).

Translation Management G. Tiedemann / J. Große / A. Wagner / J. Gabriel / B.E. Strauer

Reference and Translation Center for Cardiac Stem Cell Therapy / Cardiac Surgery University of Rostock

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