cardiovascular cell therapy: what’ s new? on clinical scenarios and clinical trials

Cardiovascular Cell Therapy: What’ s New?On Clinical Scenarios and Clinical Trials

Stefan P. Janssens, MD, PhD

Department of Cardiology

University of Leuven, Belgium

Madrid, April 24th, 2008No disclosures

30 years later: VALIANT study(14,703 post-MI pts EF<35%, clin CHF)

1 y mortality

1 y death, re-MI, CHF rehosp

Pfeffer et al . NEJM 2003

Cardiac Regeneration in 2008: the stem cell approach

Premise: myocyte deficit contributes to dysfunctional phenotype?

Caulfield et al . Circ 1976

Infarct size(% LV mass)

Shock, Death CHF

48% 28%

13%

26%

Stem Cells: from Bench to Bedside Clinical Scenarios


1. Acute Myocardial Infarction with significantly impaired LV function:

- is safety & efficacy sufficiently established to start a Phase IIIrandomized, controlled outcome trial?

or

- are additional innovative, mechanistic Phase II studies required?

5

Stem Cell Therapy in Post-MI Patients with Depressed LV Function is Safe

BOOST LEUVEN ASTAMI REPAIR-AMI

Follow-up (months) 18 12 12 12

Control/Placebo n=30 C n=34 P n=50 C n=103 P

Mortality 1 (3%) 0 0 6 (6%)

Reinfarction 0 1 0 6 (6%)

Revascularisation 4(13%) 2(6%) 11(22%) 37(36%)

BMC group n=30 n=33 n=50 n=101

Mortality 0 2(6%)# 0 2(2%)

Reinfarction 1(3%) 1(3%) 1(2%) 0

Revascularisation 5(17%) 2(6%) 13(26%) 22(22%)

(Adapted from Arnesen et al. Lancet 2007;369,2142)# unrelated to BMC

RC Trials using Intracoronary BMC post MI

LEUVEN-AMI

MI size

-28%(P=0.03)

ND

ND

P=n.s.

ND

+ 2.8% (P=n.s.)*

* 18-months follow-up

Stem Cells: from Bench to Bedside

Clinical Scenarios

What does an increase in global LVEF of a few % points mean?

Infarct Size Reduction in Reperfused STEMI

Infarct SizeReduction (%)

Small Infarcts(<17% LV mass)

Large Infarcts(>17% LV mass)

Small Infarcts (n=29)

LargeInfarcts(n=29)

Age 58±11 61±11

BP adm 140/82 128/80*

LV-EDP 18±5 26±8 **

IRA

LAD 11 15

RCA 17 12

Cx 1 2

Time to PCI 284±180 292±173

Max Trop 60±28 115±68 **

Meds ACE-/BB/Stat/Asp

ACE-/BB/Stat/Asp

Infarct Size Determines Global and Regional Functional Recovery in Reperfused STEMI

Change in LV-EF (%)


n=29


n=29

Δ+ 3%P=0.003

P=NS

SWT(mm)


n=29


n=29

Border Infarct BorderInfarct

P=0.01

P=0.003

P=NS

P=NS

Bone Marrow Cell Transfer Post-AMI Infarct size and Coronary Flow Reserve (Doppler)

(Schachinger et al., NEJM 2006; 355:1210-21)

BMCPlac

20

-20

10

-10

0

<48.9% >48.9%

P=0.002

P=0.81

(52) (41) (40) (54)

Baseline EF (%)

Δ EF (%)

(Erbs et al., Circulation 2007)

(n=30) (n=28)

Infarct Size Determines Global Functional Recovery in Reperfused STEMI

Change in LV-EF

(%)

Large Infarcts(>20% LV mass, n=20)

Change in LV-ESVI

(mL)

CON

BMSC

Baseline Baseline1 year 1 year

P=0.06 for interaction

P=0.07 for interaction

44

48

43 45

Wall Motion Score Index and Ejection Fraction for Risk Stratification after AMI

Predictors of mortality(forward Cox PHA)

HR P

Age (per 10y) 1.65 <.0001

Kilip Class 1.44 <.0001(per 1 increase)

WMSI 1.15 <.0001(per 0.2 increase)

(Moller et al. Am Heart J 2006;151:419-25)

Powerful MRI and TDI Analysis of Biological Signals: Infarct Transmurality & Segmental Contraction

Coronary occlusion

20 min 60 min 3h >6h

LV

apexapex

midmidbasebase

Time (ms)

-20

-10

0

0 200 400 600 800 1000

Strain Septum 4 months (%)

-30

AVCAVCAVOAVO

-20

-10

0

200 400 600 800

-30

AVCAVCAVOAVOBaseline Strain Septum (%)

Improved contraction (%)

0

20

40

60

80

CONTROL BMC

(29 o

f 53)

(33 o

f 63)

(14 o

f 32)

(25 o

f 83)

(6 o

f 13)

(9 o

f 18)

(9 o

f 25)

(10 o

f 87)

Improved Regional Contraction in Dysfunctional Segments indicates BMC Functional Repair

Lancet 2006; 367:113-121

-20

-15

-10

-5

0Baseline 5 d 2 mo 4 mo 1 yr

(n=232)Infarcted segments

*** ***

ES Strain(%)

BMSC

Control

0-25

%

26-5

0%

51-7

5%76

-100

%

0-25

%

26-5

0%51

-75%

76-1

00%

P<0.05 for interaction

*

*

Schachinger, V. et al. Eur Heart J 2006 27:2775-2783

Kaplan-Meier event-free survival analysis

Cardiac Regeneration in 2008: Clinical Scenarios

VALIANT study(14,703 post-MI pts EF<35%, clin CHF)

1 y mortality

1 y death, re-MI, CHF rehosp

Pfeffer et al . NEJM 2003

13%

26%

Power calculations for Outcome study:

Significant Reduction incombined Clinical EP(death, recurrent MI, CHF hospitalizations)requires ± 1,200 pts

Bone Marrow Cell Therapy Anno 2008:Limitations for Cinical Benefit

• Modest improvement in cardiac function in 4 RCTs of BMC transfer is attributable to:

– limited homing, engraftment, and survival of BMCs

lack of cardiac muscle regeneration

IC injection18F-FDG labeled BMSC:1.3 - 2.6% homing infarct region (Hofmann et al. Circ 2005)

limited progenitor cell functionality in sick patients



2. Acute myocardial infarction with significantly impaired LV function:

- Focus on cell enhancement strategies- Labeling and in vivo tracking of different progenitor cell populations

1. luciferase bioluminescence2. Genetic or histochemical marker (GFP, Endorem, DiI, ..)3. PET/CT: compare timing of delivery and route of administration

1. Acute Myocardial Infarction with significantly impaired LV function:

- clinical outcome trial (phase III, confirmed safety & efficacy) versus- innovative, mechanistic studies (phase II)

Stem Cells: from Bench to Bedside Cell Enhancement Strategies

Priming of Progenitor Cells

Priming of Target Tissue

Impaired PC phenotype & non-responders:

~ CV Risk factors ~ progenitor cell

modification

Hostile target milieu: ~ oxidant stress ~ microvascular obstruction ~ transmigration - residency

BMC and EPC cell transfer3 hours after I/R

I/R injury

L2G85 FVB

WT FVB

Hypothesis

Imaging of Bone Marrow Mononuclear Cell Homing in Ischemic Myocardium

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I/R

Sham

Reperfusion Therapy frequently Associated with Microvascular Obstruction (MVO)

Cx occlusion

Successful PCI

Incidence postPCI: >60%

Persistent MVO

J. Bogaert & S. Janssens, Eur J Rad 2007

47 (9)

4 mo

46 (8)

LV-EF (%)

P=NS

3-4 d

LV-EDV (mL)

P=0.014162 (33) 175 (43)

3-4 d 4 mo

BMSC (n=17)

CON (n=19)

MVO

Global LV Function Recovery in AMI Patientswith and without Microvascular Obstruction

44

46

48

50

52

54

56

58

60

62

1 week 4 months

P = 0.63

P = 0.60

LV-EF (%)

12 months

BMSC (n=11)

CON (n=9)

No MVOP = 0.05

P = 0.36

+3.5%

+5.5%

Direct Labeling of Stem Cells Using Positron Emission Tomography Radionuclides

• T1/2 = 109 min

• Transport via GLUT

• Phosphorylated by hexokinase

(= metabolic trapping)

• Good labeling efficiency

• Poor retention

• Substrate for cardiomyocytes

2-[18F]fluorodeoxyglucose (FDG)

(Ma et al. 2005)

90 min postinjection



Liver

Heart

Bladder

Direct Labeling of Stem Cells Using Positron Emission Tomography Radionuclides

• T1/2 = 109 min

• No transport, no enzymatic reaction

• Incorporation in cell membrane

• Good labeling efficiency

• Good retention

• No substrate for cardiomyocytes

Hexadecyl-4-[18F]fluorobenzoate (HFB)

(Ma et al. 2005)

LiverHeart

Bladder

18F-HFB




18F-HFB BMCs vs Free label Injection post MI


Priming & Labeling of Progenitor cells

• statins• p38 inhibitors• PPAR• eNOS enhancers• Integrin activators• Cardiac specification….• gene transduction: Akt, eNOS,

…• PET- MRI tracers

• Mechanical activation • Cytokines / Growth

factors: – IGF-1, HGF, SDF-1, PDGF,….

• NO

Priming of Target Tissue

Impaired EPC phenotype & non-responders ~ CV Risk factors ~ post MI cell modification

Hostile target milieu ~ oxidant stress ~ microvascular obstruction ~ transmigration - residency

Stem Cells: from Bench to BedsideInformative Cell Delivery Studies

• REGENT Poland (NCT 00313339) - recruitment completeR, open label, safety/efficacy: BMNC vs CD34+/CxCR4+ vs CON post AMI (EF<40%)Prim EP: LVEF and volumes (Echo and angio) ---> 2008?

• SWISS AMI (NCT 00355186)

(EF<45%, IC transfer at 5-7d vs 3-4 w, MRI analysis LVEF) ---> evaluate after 60

• MYSTAR Austria (NCT 00384982)

(4 arm 360 pts, LVEF<45%, comp 21-42 d vs 3 mo post-AMI and IC vs IM delivery vs combination)Prim EP: perfusion defect and LVEF by gated SPECT, NOGA ---> 2008 - 2009?

• AMORCYTE REPAIR US (NCT 00313339)

(Ph I, CD34+ cells post AMI, n=40)

(www.ClinicalTrials.gov)

Stem Cells: from Bench to BedsideInformative Cell Delivery Studies

• REVEAL US (NCT 00378352) Ph I/II: dose finding -> RCT Db blind, safety/efficacy: EPCs vs CON post AMIPrim EP: Infarct size (MRI), n=210

• NEURONYX US (NCT 00361855) & PROVACEL Osiris, US (NCT 00114452)

Ph I, RCT, safety escalating doses allogeneic hBM-derived SCs-MSC n=18 and 48

• MAGIC-Cell-5-Combicytokine (Korea, ± 120 pts, 1:1:2)Ph II, RCT: safety/efficacy CON vs G-CSF+MN Cell apheresis vs G-CSF+MN Cells + EPO

• CHF or Chronic refractory ischemia - Surgery:– BMNC during CABG Berlin (NCT 00462774)

60 pts, CD133+ cells in infarct border zone LVEF<35%), MRI EP: LVEF - Refractory ischemia Kobe (NCT 00221182)

10 pts, CD34 + cells IC, sestamibi SPECT scans- BMNC and CABG for CHF Helsinki (NCT 00418418)

RCT, dble blind, efficacy; Incl if CABG and EF 15-45%; prim EP: LVEF by MRI at 6 mo- TABMMI Biocardia endocardial delivery chronic infarcts Argentina (NCT 00507468)

Ph I , safety, prior AMI with LVEF<40%, n=20 pts

(www.ClinicalTrials.gov)

Sca-1+ cellsc-Kit + cells

SP cells

Endothelial Progenitor Cells

Hematopoietic SCsMesenchymal SCs

HemangioblastsSP cellsMAPC

Sca-1+ cellsMyoblastsSP cells

Mesenchymal SCsSPcells

PLURIPOTENT

Acute MI

Chronic Ischemia

Cardiac Stem Cells

Cardiac Stem Cells

• Revascularisation using CSC US Kentucky (NCT 00474461)

- Ph I: n=40; - RAA resection during CABG - Reinfusion of CSC after 4 mo if LVEF < 40%

Anversa P.et al. Circulation 2007

Acknowledgments

- X. Liu, MD, PhD- P. Pokreisz, PhD- T. Vandendriessche - M. Chua- K. Sipido, MD, PhD

- C. Dubois, MD- G. Marsboom, PhD- O. Gheysens, MD- S. Vandenwyngaert, MSc- H. Gillijns, BSc- M. Pellens, BSc

Cardiology lab and CTG SCIL- C. Verfaillie, MD, PhD- M. Boogaerts, MD, PhD- L. Mortelmans, MD, PhD

KUL & Univ Hospital

- F. Van de Werf, MD, PhD- G. Marchal, MD, PhD- J. Bogaert, MD, PhD- G. Bormans, PhD- A. Verbruggen, MD, PhD

Stanford University- S. Gambhir, MD, PhD

Harvard University- K. Bloch, MD

Conclusions

Modest effects of BM-derived progenitor cell transfer in AMI is likely attributable to limited homing and engraftment and lack of cardiomyogenesis.

Comprehensive 3D-MRI analysis suggests early infarct imaging correlates with diverging patterns of functional and structural recovery post-MI.

Progenitor cell transfer is best reserved for patients with large MI, at risk for developing maladaptive remodeling and heart failure. Potential confounding factors including MVO and cell functionality, warrant focused trials.



1. Labeling and (in vivo) tracking of different progenitor cell populations• In vivo tracking:

- luciferase bioluminescence- PET/CT

• Genetic marker (Lentiviral infection GFP, RFP,..)• Histochemical labeling (Endorem, DiI, …)

2. Factors limiting Functionality/Survival of progenitor cell populations (hypoxia and tissue ischemia) (microvascular obstruction)

cardiovascular cell therapy: what’ s new? on clinical scenarios and clinical trials

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