Stamceltechnologie: Mythe of Realiteit

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1 Stamceltechnologie: Mythe of Realiteit
Dr C. Dubois, Prof. S. Janssens Afdeling Cardiologie UZ-Gasthuisberg Leuven Emeritiforum KULeuven, 26 april 2007

2 Cardiale Regeneration in 2007: “the stem cell approach”
Caulfield et al . Circ 1976 Infarct size (% LV mass) 48% 28% Shock, Death CHF Pfeffer et al . NEJM 2003 40 years later: VALIANT study (14,703 post-MI pts with reduced EF or CHF ) 1 y mortality: 13% 1 y death, reMI, rehosp CHF: 26%

3 Full Regeneration of Myocardium in Zebrafish
Poss et al., Science 2002;298; 2188

4 Cardiac Regeneration in 2007: the (stem) cell paradox?
Different cell types with uniform benefit on cardiac function: - skeletal myoblasts ( ) - fibroblasts (2000) - smooth muscle cells (2003) - endothelial progenitor cells (2001) - mesenchymal stem cells (2005) - hematopoietic stem cells ( ) - other BM-derived cells (2005) - cardiac progenitor cells (2005) - ES cell-derived CMC (2005) ………. ( What are options for cardiac regeneration in 2006?) ( Depends on setting: experimental vs clinical )

5 Cell Therapie voor AMI in 2007?
1. Lessen uit 4 RCT in 2006 met mononucleaire BM cellen en 6 RCT met mobilisatie strategieën? Is cardiale regeneratieve geneeskunde mogelijk? Toekomstperspectieven? Trial design: welke patiëntenpopulatie - eindpunten?

6 Cel Types voor Cardiaal Herstel
Acuut MI Endothelial Progenitor Cells Hematopoietic SCs Mesenchymal SCs Hemangioblasts SP cells MAPC Sca-1+ cells Myoblasts SP cells Mesenchymal SCs SPcells PLURIPOTENT Chronisch MI: MAGIC phase II Stabiele Ischemie Embryonic stem cells are immunogenic and tumorigenic Sca-1+ cells c-Kit + cells SP cells Cel Types voor Cardiaal Herstel (adapted from Dimmeler et al. , JCI 2005)

7 Future for Cardiac Resident (Stem) Cells?
Embryonic stem cells are immunogenic and tumorigenic Sca-1+ cells c-Kit + cells SP cells Cardiospheres Future for Cardiac Resident (Stem) Cells?

8 Spontaneous Mobilization and Homing in Acute - Chronic Ischemia
VEGF, FGF2 SDF-1, IL-8,…. G-CSF Mobilization: CD34+/CxCR4+/CD117+, c-met+ (Wojakowski, Circ 2004) CD133+ (Ott, EHJ 2006) CD34+ (Crea, EHJ 2005) Mes SC (Kastrup, EHJ 2006) EPC (Shintani, Circ 2001, George EHJ 2004, Massa, Blood 2005….) …………. So the question we asked in the beginning (how to optimize cell transfer?) might be rephrased in a way that would certainly please Helmut Drexler, How can we boost any …….. ?

9 G-CSF RCT Trials in Acuut Myocard Infarct
Kuethe et al. (Am Heart J 2005;150:115) Ince et al. (FIRSTLINE-AMI, Circ 2005;112: 3097) Valgimigli et al. (Eur Heart J 2005;26:1838) Ripa et al. (STEMMI, Circ 2006;113:1983) Zohlnhofer et al. (Revival 2, JAMA 2006;295:1003) ----> geruststellend veiligheidsprofiel -----> niet superieur tov placebo voor herstel LV functie -----> timing, dosis, directe versus indirecte cellulaire effecten?

10 BOOST: LV-Ejection Fraction after 6 and 18 Months
Controls BMC-Transfer LVEF [%] 0.7% 6.7% 2.4% -0.8% (Circulation 2006;113: )

11 UZ-Leuven Ervaring met BMC Transfer na AMI: design (2001)
1. Patiëntenpopulatie en Design van de Studie? 2. Cel product? 3. Timing voor Cel Transfer? 4. Primair eindpunt?

12 Can BMSC Transfer Improve LV Recovery
after Acute Myocardial Infarction? AMI + documented LV dysfunction post PCI Informed consent TTE Acetate-PET scan Bone marrow aspiration + randomization 24 hours BMSC or placebo transfer in open IRA Aborted infarction ( < 2h)!!! Admission (7 d) cine MRI - LE Echo / TDI Follow-up (4 mo) cine MRI - LE Acetate-PET scan Follow-up (1 y) Echo TDI

13 Bone Marrow Cell Transfer Post-AMI (randomized controlled trials 2006)
Leuven AMI (n=67) LVEF - MRI (%) REPAIR-AMI (n=187) ASTAMI (n=87) + 3.0% + 5.5%  = +2.5% (P<0.05) + 4.2% + 1.2%  = -3% (P=NS) CON BMSC 4-mo 6-mo LVEF - angio (%) (NEJM 2006; 355: ) (Lancet 2006; 367: ) LVEF - MRI (%) 4-mo 4-mo CON BMSC + 2.2% + 3.4%  = +1.2% (P=NS)

14 Bone Marrow Cell Transfer Post-AMI Does infarct size matter?
Change EF (%) P=0.002 Plac BMC 20 -20 10 -10 P=0.81 0.3% difference in EF> median (3.7% vs 4.0 % in BMC) 5.0% difference in EF<median (2.5% vs 7.5% in BMC) (52) (41) (40) (54) Baseline EF <48.9% Baseline EF >48.9% NEJM 2006; 355:

15 Bone Marrow Cell Transfer Post-AMI Does timing matter?
46 (8) 47 (9) (n=36) LV-EF (%) P=NS 3-4 d 4 mo Bone Marrow Cell Transfer Post-AMI Does timing matter?  LV-EF (%) 20 10 LV-EDV (mL) P=0.014 162 (33) 175 (43) 3-4 d 4 mo -10 >4 d <4 d -20 Time after PCI (days)

16 Paracrine or autocrine effects
MRI and TDI Analysis Post-AMI: Infarct Transmurality & Segmental Contraction LV Paracrine or autocrine effects of transferred cells? ? Coronary occlusion 20 min. 60 min. 3hrs. >3-6hrs. Reperfusion Reversible injury Irreversible injury

17 BMSC Treatment Effect* on Infarct Size
(g) P=0.036 ** ** Overall, We used an analysis of covariance to compare the infarct size in the two groups with BMSC treatment as the main factor and infarct size at baseline as a covariate. To evaluate the treatment effect on change in infarct size over time, differences in adjusted squares means were calculated based on the ANCOVA model. Overall, BMSC reduce infarct size over the course of 4 months by 35% in control pts and by 50% in BMSC treated pts and that difference , due to the treatment is statistically significant (28.3%) * Expressed as ratio’s of adjusted squares means (ANCOVA) with 95% CI. Lancet 2006; 367:

18 BMSC Treatment Effect* on Infarct Size
(g) P=0.036 23% ** ** Overall, We used an analysis of covariance to compare the infarct size in the two groups with BMSC treatment as the main factor and infarct size at baseline as a covariate. To evaluate the treatment effect on change in infarct size over time, differences in adjusted squares means were calculated based on the ANCOVA model. Overall, BMSC reduce infarct size over the course of 4 months by 35% in control pts and by 50% in BMSC treated pts and that difference , due to the treatment is statistically significant (28.3%) * Expressed as ratio’s of adjusted squares means (ANCOVA) with 95% CI.

19 Regional Function Analysis TDI: End-systolic Strain
Time Profile Control ES Strain (%) Infarcted segments BMSC (n=232) -20 * * -15 -10 Treatment Effect * p < 0.001 -5 Baseline 5 d 2 mo 4 mo 1 yr

20 Adverse Events during 1-year Follow-up
BMSC Tx (n=31) Control group (n=34) Ventricular tachycardia (Holter) - 1 Life threatening arrhythmia’s 1 (ICD) Death 1 (suicide) Myocardial reinfarction Recurrent ischemia, PCI 2 4 Congestive Heart Failure Others: depression PAD (claudication) 31 ipv 32 BMSC pts (1 moved to Senegal, Africa) Explain cause of death in 1 BMSC pt: suicide Recurrent ischemia and rePCI: ONLY ONE IN STENT STENOSE in Control pt (R/ DES)

21 Kaplan-Meier event-free
survival analysis Schachinger, V. et al. Eur Heart J :

22 Conclusies IC transfer van autologe BMSCs is veilig en leidt niet tot laattijdige significante nevenwerkingen. Na tijdige reperfusie van een myocardinfarct met een matige graad van ventrikel schade hebben BMSCs variabele effecten op herstel van globale LV functie, doch verbeteren ze op significante wijze de regionale functie (waar schade is opgetreden). De uitdaging voor de toekomst bestaat erin om na te gaan hoe de geobserveerde paracriene effecten van BMSC kunnen vertaald worden tot een klinische meerwaarde voor AMI patienten met een ernstigere initiele linker ventrikel beschadiging.

23 Toekomstperspectieven: Optimaliseren van Stam Cel Transfer?
Grote, multicenter studie in ernstig AMI - klinisch eindpunt Centraal hematologie core faciltieit SOPs cel bereiding Q-control, financiele ondersteuning,…. Gefocuseerde klinische studies en parallele preklinische studies - Boost 2 - NL interuniversity study - Poland (cell comparison) - Leuven/Frankfurt meta-analysis - Leuven homing studies short reference to high number of uncontrolled studies submitted to EHJ and recent task force document in EHJ Retain driver’s seat - avoid Gelsinger-like mishaps. Straightforward design Simple execution and logistics

24 Cell Sources for Cardiac Repair
Sca-1+ cells Myoblasts SP cells Ischemic Cardiomyopathy (EF<35%) MAGIC phase II Embryonic stem cells are immunogenic and tumorigenic Cell Sources for Cardiac Repair (adapted from Dimmeler et al. , JCI 2005)

25 Suggestion of efficacy (EF, NYHA, WMSI) Cave: arrhythmogenicity
MAGIC Phase 1 Study To assess the feasibility and safety of autologous skeletal myoblasts in pts with ischemic heart failure. Single center (F): n=10 Suggestion of efficacy (EF, NYHA, WMSI) Cave: arrhythmogenicity

26 MAGIC Phase 2: Studie Procedures
Biopsie GMP Cell Processing Cel suspensie

27 The MAGIC Trial End Points Safety Efficacy
- MACE : All deaths, MI, congestive HF, resuscitated sudden death & stroke - Ventricular arrhythmias (ICD implanted in all patients before hospital discharge) Efficacy - Primary : Recovery of contractility of previously akinetic segments & change from baseline to month 6 in LVEF as assessed by echocardiography (Core Labs) ± MUGA - Secondary : LV volumes

28 Skeletal Myoblast Transplantation
Infarct Zone (Scar) Total of injections Injections in a grid with  5 mm between injections  equally divide in scar and in peri-infarct zone Injection volume 200 uL from 1 mL syringe Total injection volume 6 mL Total injection time: min X X X X X X X X X X X X X X X X X X X X X X X X X Peri-Infarct Zone

29 Summary of Time to First MACE
High dose group Low dose group Placebo group High dose group Low dose group Placebo group p = 0.09 p = 0.43 Low dose vs placebo p = 0.87 p = 0.12 High dose vs placebo 6 months 30 days

30 Summary of Time to First Ventricular Arrhythmia
High dose group Low dose group Placebo group p = 0.23 p = 0.20 Low dose vs placebo p = 0.12 p = 0.30 High dose vs placebo 6 months 30 days Death treated as censored event

31 Patients with Qualitative Echo Data at Baseline and Month 6
The MAGIC Trial Regional Wall Motion Patients with Qualitative Echo Data at Baseline and Month 6 High dose Low dose Placebo Number of patients 26 28 31 Recovery in at least one segment Yes (%) 12 (46) 13 (46) 18 (58) No (%) 14 (54) 15 (54) 13 (42) Recovery in at least two segments Yes (%) 8 (31) 10 (36) 12 (39) No (%) 18 (69) 18 (64) 19 (61)

32 LV End-Diastolic Volume
mL p=0.006 p=0.62 n=27 -9.0 (-33.0;25.0) n=30 +9.0 (-21.0;28.0) n=26 -23.0 (-42.0;0.0) Data are given as median (interquartile range)

33 Future for Cardiac Resident (Stem) Cells?
Isotype control Sca-1 Sca-1+ cells 60, ,000 Total %Sca-1+ Embryonic stem cells are immunogenic and tumorigenic Sca-1+ cells c-Kit + cells SP cells Cardiospheres Future for Cardiac Resident (Stem) Cells?

34 Regenerative Potential of Biopsy-derived Human Cardiospheres
Smith, R. R. et al. Circulation 2007;115:

35 Cel Therapie voor Ischemische Dysfunctie in 2007: Droom of Realiteit?
Isolatie, amplificatie en intramyocardiale administratie van Sca-1 positieve CSC (muis) en c-kit positieve CSC (rat, varken) en humane cardiospheren (RV biopsie) Intramyocardiale administratie van CSCs in geinfarceerd myocard verbetert regionale systolische functie (TTE) First in men (veiligheid, haalbaarheid per CABG): Q (US)

36 Stamcelbehandeling: Fontein van de Eeuwige Jeugd?
Lucas Cranach (olie op canvas 1546)

37 Acknowledgments Gasthuisberg University Hospital & CTG, VIB-3
University of Leuven, Belgium Departments of Cardiology, Hematology, Radiology, Nuclear Medicine, Radiopharmacy, Biostatistics Leuven Coordinating Center (LCC) Referring Cardiology Sites