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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. No disclosures. Madrid , April 24 th , 2008. 30 years later: VALIANT study (14,703 post-MI pts EF<35%, clin CHF).

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

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  1. Cardiovascular Cell Therapy: What’ s New?On Clinical Scenarios and Clinical Trials Stefan P. Janssens, MD, PhD Department of Cardiology University of Leuven, Belgium No disclosures Madrid, April 24th, 2008

  2. 30 years later: VALIANT study (14,703 post-MI pts EF<35%, clin CHF) Infarct size (% LV mass) 26% 13% 48% 28% Shock, Death CHF 1 y mortality 1 y death, re-MI, CHF rehosp Caulfield et al . Circ 1976 Pfeffer et al . NEJM 2003 Cardiac Regeneration in 2008: the stem cell approach Premise: myocyte deficit contributes to dysfunctional phenotype?

  3. Stem Cells: from Bench to Bedside Clinical Scenarios • Acute Myocardial Infarction with significantly impaired LV function: • - is safety & efficacy sufficiently established to start a Phase III • randomized, controlled outcome trial? • or • - are additional innovative, mechanistic Phase II studies required?

  4. Stem Cell Therapy in Post-MI Patients with Depressed LV Function is Safe (Adapted from Arnesen et al. Lancet 2007;369,2142) # unrelated to BMC

  5. RC Trials using Intracoronary BMC post MI MI size ND ND + 2.8% (P=n.s.)* P=n.s. ND -28% (P=0.03) LEUVEN-AMI * 18-months follow-up

  6. Stem Cells: from Bench to Bedside Clinical Scenarios What does an increase in global LVEF of a few % points mean?

  7. Infarct Size Reduction (%) Infarct Size Reduction in Reperfused STEMI Small Infarcts (<17% LV mass) Large Infarcts (>17% LV mass)

  8. Change in LV-EF (%) SWT (mm) Infarct Border Infarct Border Δ+ 3% P=0.003 Infarct Size Determines Global and Regional Functional Recovery in Reperfused STEMI P=0.003 P=0.01 P=NS P=NS P=NS Small Infarcts (<17% LV mass) n=29 Large Infarcts (>17% LV mass) n=29 Small Infarcts (<17% LV mass) n=29 Large Infarcts (>17% LV mass) n=29

  9. Bone Marrow Cell Transfer Post-AMI Infarct size and Coronary Flow Reserve (Doppler) Δ EF (%) Plac BMC P=0.002 20 P=0.81 10 0 (n=30) (n=28) -10 (52) (41) (40) (54) -20 >48.9% <48.9% Baseline EF (%) (Erbs et al., Circulation 2007) (Schachinger et al., NEJM 2006; 355:1210-21)

  10. Large Infarcts (>20% LV mass, n=20) Infarct Size Determines Global Functional Recovery in Reperfused STEMI Change in LV-ESVI (mL) Change in LV-EF (%) P=0.06 for interaction P=0.07 for interaction 48 CON 45 44 43 BMSC Baseline 1 year Baseline 1 year

  11. 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) Wall Motion Score Index and Ejection Fraction for Risk Stratification after AMI (Moller et al. Am Heart J 2006;151:419-25)

  12. Strain Septum 4 months (%) base Baseline Strain Septum (%) AVO AVC mid AVO AVC apex 0 0 -10 -10 -20 -20 Time (ms) -30 -30 0 200 400 600 800 1000 200 400 600 800 Powerful MRI and TDI Analysis of Biological Signals: Infarct Transmurality & Segmental Contraction LV Coronary occlusion 20 min 60 min 3h >6h

  13. Improved Regional Contraction in Dysfunctional Segments indicates BMC Functional Repair 0-25% 0-25% 26-50% 26-50% 51-75% 51-75% 76-100% 76-100% Improved contraction (%) 80 Infarcted segments P<0.05 for interaction ES Strain (%) (n=232) (29 of 53) Control (33 of 63) (9 of 18) 60 BMSC (6 of 13) (14 of 32) -20 * (9 of 25) (25 of 83) *** *** 40 -15 * -10 (10 of 87) 20 -5 0 0 Baseline 5 d 2 mo 4 mo 1 yr CONTROL BMC Lancet 2006; 367:113-121

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

  15. VALIANT study (14,703 post-MI pts EF<35%, clin CHF) 26% 13% 1 y mortality 1 y death, re-MI, CHF rehosp Pfeffer et al . NEJM 2003 Cardiac Regeneration in 2008: Clinical Scenarios Power calculations for Outcome study: Significant Reduction in combined Clinical EP (death, recurrent MI, CHF hospitalizations) requires ± 1,200 pts

  16. lack of cardiac muscle regeneration limited progenitor cell functionality in sick patients 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 IC injection 18F-FDG labeled BMSC: 1.3 - 2.6% homing infarct region (Hofmann et al. Circ 2005)

  17. Stem Cells: from Bench to Bedside Clinical Scenarios • Acute Myocardial Infarction with significantly impaired LV function: • - clinical outcome trial (phase III, confirmed safety & efficacy) • versus • - innovative, mechanistic studies (phase II) • Acute myocardial infarction with significantly impaired LV function: • - Focus on cell enhancement strategies • - Labeling and in vivo tracking of different progenitor cell populations • luciferase bioluminescence • Genetic or histochemical marker (GFP, Endorem, DiI, ..) • PET/CT: compare timing of delivery and route of administration

  18. Stem Cells: from Bench to Bedside Cell Enhancement Strategies Priming of Progenitor Cells Priming of Target Tissue Hostile target milieu: ~ oxidant stress ~ microvascular obstruction ~ transmigration - residency Impaired PC phenotype & non-responders: ~ CV Risk factors ~ progenitor cell modification

  19. Imaging of Bone Marrow Mononuclear Cell Homing in Ischemic Myocardium I/R injury Hypothesis WT FVB BMC and EPC cell transfer 3 hours after I/R L2G85 FVB

  20. Day 1 Day 2 Day 4 Day 6 Day 8 Day 10 Day 14 Day 21 I/R Sham

  21. LV-EF (%) Cx occlusion Persistent MVO Successful PCI 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 Reperfusion Therapy frequently Associated with Microvascular Obstruction (MVO) Incidence postPCI: >60% J. Bogaert & S. Janssens, Eur J Rad 2007

  22. Global LV Function Recovery in AMI Patientswith and without Microvascular Obstruction LV-EF (%) 62 60 No MVO 58 P = 0.05 BMSC (n=11) 56 CON (n=9) 54 52 50 P = 0.36 48 P = 0.63 46 P = 0.60 44 1 week 4 months +5.5% +3.5% MVO BMSC (n=17) CON (n=19) 12 months

  23. 2-[18F]fluorodeoxyglucose (FDG) • T1/2 = 109 min • Transport via GLUT • Phosphorylated by hexokinase • (= metabolic trapping) • Good labeling efficiency • Poor retention • Substrate for cardiomyocytes Direct Labeling of Stem Cells Using Positron Emission Tomography Radionuclides Heart 30 min post injection Liver Bladder 60 min post injection 90 min post injection (Ma et al. 2005)

  24. Hexadecyl-4-[18F]fluorobenzoate (HFB) Direct Labeling of Stem Cells Using Positron Emission Tomography Radionuclides 18F-HFB 30 min post injection Heart Liver Bladder 60 min post injection • T1/2 = 109 min • No transport, no enzymatic reaction • Incorporation in cell membrane • Good labeling efficiency • Good retention • No substrate for cardiomyocytes 90 min post injection (Ma et al. 2005)

  25. 18F-HFB BMCs vs Free label Injection post MI

  26. 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 Stem Cells: from Bench to Bedside Cell Enhancement Strategies Priming & Labeling of Progenitor cells Priming of Target Tissue Hostile target milieu ~ oxidant stress ~ microvascular obstruction ~ transmigration - residency Impaired EPC phenotype & non-responders ~ CV Risk factors ~ post MI cell modification

  27. Stem Cells: from Bench to BedsideInformative Cell Delivery Studies • REGENT Poland (NCT 00313339) - recruitment complete R, 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)

  28. 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 AMI Prim 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)

  29. Acute MI Chronic Ischemia Endothelial Progenitor Cells Hematopoietic SCs Mesenchymal SCs Hemangioblasts SP cells MAPC Sca-1+ cells Myoblasts SP cells Mesenchymal SCs SPcells PLURIPOTENT Anversa P.et al. Circulation 2007 • Revascularisation using CSC • US Kentucky (NCT 00474461) • - Ph I: n=40; • - RAA resection during CABG • - Reinfusion of CSC after 4 mo • if LVEF < 40% Cardiac Stem Cells Sca-1+ cells c-Kit + cells SP cells

  30. SCIL • - X. Liu, MD, PhD • P. Pokreisz, PhD • T. Vandendriessche - M. Chua • - K. Sipido, MD, PhD • C. Verfaillie, MD, PhD • M. Boogaerts, MD, PhD • L. Mortelmans, MD, PhD KUL & Univ Hospital • - C. Dubois, MD • G. Marsboom, PhD • O. Gheysens, MD • S. Vandenwyngaert, MSc • H. Gillijns, BSc • M. Pellens, BSc • F. Van de Werf, MD, PhD • G. Marchal, MD, PhD • J. Bogaert, MD, PhD • G. Bormans, PhD • A. Verbruggen, MD, PhD Acknowledgments Cardiology lab and CTG Stanford University - S. Gambhir, MD, PhD Harvard University - K. Bloch, MD

  31. 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.

  32. Stem Cells: from Bench to Bedside Cell Enhancement Strategies • 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)

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