c-kit stem cell therapy of ischemic cardiomyopathy/media/clinical/pdf-files/... · 11/8/2011 ·...

Roberto Bolli, M.D.

Los Angeles, CA

c-Kit Stem Cell Therapy of Ischemic Cardiomyopathy

Institute of Molecular Cardiology

University of Louisville

American Heart Association Scientific Sessions American Heart Association Scientific Sessions

Presenter Disclosure

information

FINANCIAL DISCLOSURE: None

UNLABELED/UNAPPROVED USES DISCLOSURE: None

c-Kit Stem Cell Therapy of Ischemic Cardiomyopathy

Roberto Bolli, M.D.

SCIPIO (Study of Cardiac Stem Cells

Infusion in Patients with Ischemic

CardiOmyopathy)

• Phase I, open-label, randomized trial

• Single center

• 20 treated and 13 control patients

• http://clinicaltrials.gov/ct2/show/NCT00474461

Publius Cornelius Scipio Africanus

(235–183 BC)

SCIPIO (Study of Cardiac Stem Cells

Infusion in Patients with Ischemic

CardiOmyopathy)

Piero Anversa Annarosa Leri Jan Kajstura Domenico D’Amario

John Loughran Atul Chugh Brandon Elmore Sohail Ikram Marcus Stoddard Steve Wagner Garth Beache


Brigham and Women’s Hospital

Primary Objective

1. To assess the feasibility and safety of infusing autologous

c-kitpos CSCs in patients with ischemic heart failure.

Secondary Objective

2. To obtain preliminary evidence for or against the efficacy

of CSCs in augmenting LV function, improving functional

status, and promoting myocardial regeneration.

The overall goal is to translate the discovery of CSCs

into clinically useful therapies.

SCIPIO: Objectives

SCIPIO: Time Line

A result of many years of preclinical work:

Trial opened to

enrollment in

February 2009

First CSC infusion

July 17, 2009

FDA contacted

in October

2004

2004 2012

IND application

submitted on

January 2006

2006

FDA

approval on

August 8,

2008

2008 2010

First patient

enrolled on

March 13,

2009

Last Patient

Enrolled

May 17,

2011

November 14, 2011

LVEF ≤ 40%

A history of Q-wave MI with a residual scar (as evidenced by ECG, cardiac MRI, low-dose dobutamine stress echo, and/or rest perfusion images on a sestamibi SPECT study)

Patient scheduled for CABG within 2 weeks of the initial screening.

SCIPIO

Inclusion Criteria

Enrollment CABG & Tissue

Harvesting

< 2 Weeks

SCIPIO: Protocol

At the time of CABG, the right atrial appendage is resected and

prepared for CSC isolation

CSC isolation and expansion

Enrollment CABG & Tissue

Harvesting

< 2 Weeks

SCIPIO: Protocol

4 ± 1 Months

•Cardiac MRI

•2-D & 3-D Echo • ECG, Physical Exam

• BMP, LFTs, CBC, and BNP

• Minnesota Heart Questionnaire and NYHA class

assessment

Follow-Up

2 Years

CSC

Infusion

SCIPIO: Protocol

CSC

Rx

• ECG x 3

• BMP, LFTs

•CBC

•Cardiac enzymes x

3

• Physical exam

•2-D & 3-D Echo • 24-h Holter monitor

• ECG

• BMP & LFTs

•CBC, & cardiac enzymes

• Physical Exam

•2-D & 3-D Echo • 24-h Holter monitor

• ECG

• BMP & LFTs

• CBC, & cardiac enzymes

• Physical Exam

Follow-up 24h Week 1 Week 2 Week 4 Month 4

• ECG

• BMP, LFTs

•CBC

•Cardiac enzymes

• Physical exam

•2-D & 3-D Echo

•Cardiac MRI • ECG, Physical Exam


• Minnesota Heart Questionnaire and NYHA class

assessment

CSC

Rx

Follow-up Month 8 Year 1 Year 2

• 2-D & 3-D Echo

•Cardiac MRI

• ECG, Physical Exam


• Minnesota Heart Questionnaire and NYHA class assessment

• ECG

• BMP, LFTs

•CBC

• 2-D & 3-D Echo

•Cardiac MRI • ECG, Physical Exam


• Minnesota Heart Questionnaire and NYHA class assessment

SCIPIO: Protocol

SCIPIO

Phenotype of CSCs

SCIPIO: Phenotype of CSCs

SCIPIO

Phenotype of CSCs

SCIPIO:

Phenotype

of CSCs

Telomere Length


SCIPIO: Results

Ejection Fraction at 4 Months After CSCs

Absolu

te E

F U

nits

Baseline 4 months Pre-CSC 4 months

Controls (n=7) CSC-treated (n=14)

0

20

40

60

30.3±1.9

38.5±2.8

P=0.001

30.1±2.4 30.2±2.5

0

5

10

15

20

SCIPIO: Results

Change in Ejection Fraction After

CSC Treatment

4 months

P=0.001

8.2±2.0

12.3±2.1

Absolu

te E

F U

nits

P<0.001

12 months

n=14 n=8

0

10

20

30

40

50

60

70

80

90

0

10

20

30

40

50

60

70

80

90

0

10

20

30

40

50

60

70

80

90

0

10

20

30

40

50

60

70

80

90

0

10

20

30

40

50

60

70

80

90

0

10

20

30

40

50

60

70

80

90

Ejection Fraction (MRI) After CSC Therapy

4 months 12 months Pre-CSC

n=8 n=8 n=5

27.5

35.1

41.2

Absolu

te E

F u

nits

SCIPIO: MRI Results

P=0.004

P=0.013

0

5

10

15

20

25

Change in Ejection Fraction (MRI)

After CSC Therapy

n=5 n=8

P=0.004

7.7±1.8

P=0.013

13.6±3.2

ΔE

F (a

bsolu

te E

F u

nits)

4 months 12 months

0

5

10

15

20

25

0

5

10

15

20

25

SCIPIO: MRI Results

Baseline EF:

27.5%

0

10

20

30

40

0

10

20

30

40

-40

-20

0

20

40

60

80

-40

-20

0

20

40

60

80

-40

-20

0

20

40

60

80

-40

-20

0

20

40

60

80

-40

-20

0

20

40

60

80

-40

-20

0

20

40

60

80

Regional Ejection Fraction in Infarct-Related

Segments After CSC Therapy

n=8 n=8 n=5

10.3

24.5 21.5

Pre-CSC 4 months 12 months

Absolu

te E

F u

nits

4 months 12 months

n=5 n=8

P=0.008

14.2±3.9

P=0.085

17.9±7.9

ΔE

F (a

bsolu

te E

F u

nits)

SCIPIO: MRI Results

0

10

20

30

40

0

10

20

30

40

50P=0.008

n=8

24.5±6.4

10.3±6.9

Pre-CSC 4 months

P=0.085 n=5

21.5±7.3

3.5±6.7

Pre-CSC 12 months

Absolu

te E

F u

nits

Regional Ejection Fraction (MRI) in Infarct-

Related Segments After CSC Therapy

SCIPIO: MRI Results

0

20

40

60

80

-40

-20

0

20

40

Regional Ejection Fraction in Dyskinetic Segments

After CSC Therapy


n=7 n=7 n=4

-20.6

3.9 7.9

Absolu

te E

F u

nits

ΔE

F (a

bsolu

te E

F u

nits)

n=4 n=7

P=0.014

24.5±7.1

P=0.030

35.7±9.1

4 months 12 months

SCIPIO: MRI Results

0

20

40

60

80

0

20

40

60

80

-100

-80

-60

-40

-20

0

20

40

60

80

Regional Ejection Fraction in the Least Functional

Segment After CSC Therapy


n=8 n=8 n=5

-32.7

-7.1 2.7

Absolu

te E

F u

nits

ΔE

F (a

bsolu

te E

F u

nits)

n=5 n=8

P=0.020

25.6±8.5

P=0.023

40.2±11.3

4 months 12 months

SCIPIO: MRI Results

0.0

0.5

1.0

1.5

2.0

2.5

3.0

SCIPIO: Results

Global Wall Motion Score Index 4 Months

After CSC Treatment



P=0.005

1.91 1.73

1.89 1.88

0

1

2

3

4

5

Global WMSI After CSC Treatment in Patients

Who Have Completed 12 Month Follow-up

4 months Pre-CSC 12 months

P=0.010

P=0.008

n=8

1.99±0.08 1.73±0.10 1.68±0.12

SCIPIO: Results

SCIPIO:

Infarct Regression

Before CSCs 24 months after CSCs

-30

-25

-20

-15

-10

-5

0

10

20

30

40

50

0

10

20

30

40

50

0

10

20

30

40

50

0

10

20

30

40

50

0

10

20

30

40

50

SCIPIO: MRI Results

Change in Infarct Size by CMR Using a Semi-

automated (FWHM) Method After CSC

Treatment

0

10

20

30

40

50

-30

-25

-20

-15

-10

-5

-30

-25

-20

-15

-10

-5

n=6 n=9

P=0.003

-15.2±2.8

-44.8%

P<0.001

-13.3±2.3

-38.1%

4 months 12 months 4 months 12 months Pre-CSC

Mass

(g)

Change

in m

ass

(g) n=9 n=9 n=6

34.9

21.6 18.7

-30

-25

-20

-15

-10

-5

SCIPIO: MRI Results

Change in Non-Viable Tissue by CMR After

CSC Treatment

0

10

20

30

40

50

60

0

10

20

30

40

50

60

0

10

20

30

40

50

60

0

10

20

30

40

50

60

0

10

20

30

40

50

60

0

10

20

30

40

50

60


Mass (

g)

n=9 n=9 n=6

24.1

12.1 10.4

Change in m

ass (

g)

-30

-25

-20

-15

-10

-5

-30

-25

-20

-15

-10

-5

-12.0±2.5

P=0.001

-49.7% -14.8±3.9

P=0.013

-58.6%

n=9 n=6

4 months 12 months

0

10

20

30

40

50

60

70

0

50

100

150

200

250

300

SCIPIO: MRI Results


Mass (

g)

Change in m

ass (

g)

4 months 12 months

n=9 n=9 n=6

151.1 162.6 177.8

n=9 n=6

0

20

40

60

0

20

40

60

7.6% 11.6±5.2

P=0.055

21.5% 31.5±11.0

P=0.035

Change in Viable Tissue by CMR After CSC

Treatment

0

1

2

3

4



P=0.172 P=0.003

0

1

2

3

4

0

1

2

3

4

0

1

2

3

4

0

1

2

3

4

2.0±0.0 1.7±0.2

New York Heart Association Score 4

Months After CSC Treatment

2.2±0.2

1.6±0.2

SCIPIO: Results

0

1

2

3

4

5

6

NYHA Score After CSC Treatment in Patients



P=0.024

P=0.004

n=10

2.4±0.22

1.8±0.20 1.5±0.17

SCIPIO: Results

0

20

40

60

80

0

20

40

60

80

0

20

40

60

80

0

20

40

60

80

0

20

40

60

80

Pre-CSC 4 months Baseline 4 months


P<0.001

MLHFQ Score 4 Months After

CSC Treatment

38.1±10.5

40.4±9.2 46.4±5.2

26.7±4.9

SCIPIO: Results

MLHFQ After CSC Treatment in Patients


0

20

40

60

80

0

20

40

60

80

0

20

40

60

80

0

20

40

60

80


P<0.001

P=0.007 n=10

41.7±7.5

27.7±6.9 23.5±8.0

SCIPIO: Results

i) Feasibility and safety

The initial results of SCIPIO indicate that, in patients

with ischemic cardiomyopathy:

1. Isolation, expansion, and infusion of a highly pure

population of c-kitpos CSCs are feasible in virtually

all cases.

2. It is possible to obtain viable CSCs with high

telomerase activity and telomeres >7 kbp.

3. Intracoronary infusion of autologous CSCs is not

associated with appreciable adverse effects.

SCIPIO: Summary

ii) Efficacy

The initial results of SCIPIO indicate that:

4. Infusion of CSCs results, 4 months later, in a

reduction in infarct size, an increase in viable

myocardium, and a marked improvement in LV

EF, NYHA functional class, and quality of life

(MLHFQ).

5. These effects persist and are even more pronounced

at 1 year.

SCIPIO: Summary

The initial results of SCIPIO suggest that administration of

autologous c-kitpos CSCs is feasible and safe and produces

a sustained increase in viable myocardium, LV systolic

function, and functional capacity in patients with ischemic

cardiomyopathy.

Larger, Phase II studies are warranted.

SCIPIO: Conclusions

Acknowledgments Xian-Liang Tang Yiru Guo Gregg Rokosh Qianghong Li Atul Chugh John Loughran Sohail Ikram Marcus Stoddard Steve Wagner Garth Beache Mark Slaughter

Boston group Piero Anversa Annarosa Leri Jan Kajstura


Thank You

c-kit stem cell therapy of ischemic cardiomyopathy/media/clinical/pdf-files/... · 11/8/2011 ·...

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