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Stamceltechnologie: Mythe of Realiteit

Stamceltechnologie: Mythe of Realiteit. Dr C. Dubois, Prof. S. Janssens Afdeling Cardiologie UZ-Gasthuisberg Leuven. Emeritiforum KULeuven, 26 april 2007. Infarct size (% LV mass). 40 years later: VALIANT study (14,703 post-MI pts with reduced EF or CHF ) 1 y mortality: 13%

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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. Infarct size (% LV mass) • 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% 48% 28% Shock, Death CHF Caulfield et al . Circ 1976 Pfeffer et al . NEJM 2003 Cardiale Regeneration in 2007: “the stem cell approach”

  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 (1998-2001) - fibroblasts (2000) - smooth muscle cells (2003) - endothelial progenitor cells (2001) - mesenchymal stem cells (2005) - hematopoietic stem cells (2001-04) - other BM-derived cells (2005) - cardiac progenitor cells (2005) - ES cell-derived CMC (2005) ……….

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

  7. 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….) • ………….

  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. 6.7% 0.7% -0.8% 2.4% BOOST: LV-Ejection Fraction after 6 and 18 Months Controls BMC-Transfer LVEF [%] (Circulation 2006;113:1287-94)

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

  13. ASTAMI (n=87) REPAIR-AMI (n=187) (NEJM 2006; 355:1199-1221) LVEF - angio (%) LVEF - MRI (%) 4-mo 6-mo 4-mo 6-mo CON BMSC CON BMSC + 3.0% + 5.5% + 4.2% + 1.2%  = +2.5% (P<0.05)  = -3% (P=NS) Bone Marrow Cell Transfer Post-AMI(randomized controlled trials 2006) Leuven AMI (n=67) (Lancet 2006; 367:113-121) LVEF - MRI (%) 4-mo 4-mo CON BMSC + 2.2% + 3.4%  = +1.2% (P=NS)

  14. 20 10 0 -10 -20 Bone Marrow Cell Transfer Post-AMIDoes infarct size matter? Change EF (%) Plac BMC P=0.002 P=0.81 (52) (41) (40) (54) Baseline EF >48.9% Baseline EF <48.9% NEJM 2006; 355:1210-21

  15. (n=36) LV-EF (%) 46 (8) 47 (9) P=NS 3-4 d 4 mo LV-EDV (mL) 162 (33) 175 (43) P=0.014 3-4 d 4 mo Bone Marrow Cell Transfer Post-AMIDoes timing matter?  LV-EF (%) 20 10 0 -10 >4 d <4 d -20 Time after PCI (days)

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

  17. BMSC Treatment Effect* on Infarct Size 28% treatment effect* Infarct size (g) P=0.036 ** ** * Expressed as ratio’s of adjusted squares means (ANCOVA) with 95% CI. Lancet 2006; 367:113-121

  18. BMSC Treatment Effect* on Infarct Size 28% treatment effect* Infarct size (g) P=0.036 23% ** ** * Expressed as ratio’s of adjusted squares means (ANCOVA) with 95% CI.

  19. Regional Function AnalysisTDI: End-systolic Strain Time Profile Control ES Strain (%) Infarcted segments BMSC (n=232) -20 * * -15 -10 Treatment Effect p < 0.001 * -5 0 Baseline 5 d 2 mo 4 mo 1 yr

  20. Adverse Events during 1-year Follow-up

  21. Kaplan-Meier event-free survival analysis Schachinger, V. et al. Eur Heart J 2006 27:2775-2783

  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

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

  25. 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 10 g Biopsie GMP Cell Processing Cel suspensie

  27. The MAGIC Trial End Points Safety - 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 30-35 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: 15-20 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. High dose group Low dose group Placebo group 30 days 6 months High dose vs placebo p = 0.12 p = 0.87 Low dose vs placebo p = 0.43 p = 0.09 Summary of Time to First MACE High dose group Low dose group Placebo group

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

  31. 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. Sca-1+ cells 60,000 - 100,000 Isotype control Sca-1 Sca-1+ cells c-Kit + cells SP cells Cardiospheres Total %Sca-1+ 3500 89.97 Future for Cardiac Resident (Stem) Cells?

  34. Regenerative Potential of Biopsy-derived Human Cardiospheres Smith, R. R. et al. Circulation 2007;115:896-908

  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): Q3 2007 (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

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