Stem cell therapy for myocardial repair Birgit Assmus The heart is - PowerPoint PPT Presentation

Stem cell therapy for myocardial repair Birgit Assmus

The heart is regenerating ! Undisputable Evidence from DNA Integration of C-14 – generated during nuclear bomb testing during cold war - expected observed The heart muscle is younger than the body! Bergmann O et al., Science 2009; 324:98-102

Cells for functional cardiac repair Cells for functional cardiac repair Embyronic-like stem cells (iPS) 4 genes: Oct4, Klf4, Sox2, myc somatic cells (skin fibroblasts) Cardiac stem cells Modified from Dimmeler et al, JCI 2005

Clinical evolution of BMC therapy for cardiovascular diseases Phase I/II clinical trials Phase III trials Cell enhancement, Bone marrow-derived cells target region preconditioning - Shock waves for enhancing cell CD34 + CXCR4 + Bone marrow engraftment mononuclear CD34 + cells (BMC) - Factors to enhance cardiac Mesenchymal differentiation CD133 + Stromal Cells - Repeated administration 2001/ 2006 2008 2009 2013 2002 Adipose Cardiac stem tissue- cells derived c-kit + cells Cardiospheres cells stopped end 2013

Cell therapy in cardiovascular diseases Acute Myocardial Infarction Acute Myocardial Infarction Refractory Angina Refractory Angina Peripheral arterial occlusive disease Peripheral arterial occlusive disease Chronic post- -infarction heart failure infarction heart failure Chronic post

Cell Therapy in Acute Myocardial Infarction: therapeutic targets Adverse LV Adverse LV Remodeling Remodeling   Acute Chronic Acute Chronic Acute Chronic Myocardial Myocardial Heart Heart Myocardial Heart Infarction Failure Infarction Failure Infarction Failure infarct chronic infarct chronic expansion LV- - dilatation dilatation expansion LV Vascularization  Apoptosis  BMC/CPC BMC/CPC Paracrine Ischemia factors Cytokines, e.g. Cardiac VEGF, SDF-1 Regeneration

Cell Therapy for STEMI The patient population at risk post- -AMI AMI The patient population at risk post Effects of cell therapy in patients at risk Effects of cell therapy in patients at risk Derivation of the clinical benefit Derivation of the clinical benefit

LV contractile recovery within 1 week after successful reperfusion determines clinical outcome in STEMI There is no linear correlation between mortality and ejection fraction after AMI ! Volpi et al., Circulation 1993; 88: 416-429

Enhanced contractile recovery by BMC is confined to patients with failed initial recovery 12 months data MRI 4 months data LV angiography N Engl J Med 2006 Repair-AMI: n= 204 patients; 1:1 multicentre double-blind randomized intracoronary placebo or BMC infusion 3 -7 days after successful acute reperfusion therapy

Do beneficial effects of BMC therapy on adverse remodeling translate into clinical benefit ?   ? ? … reduce adverse … reduce adverse Therapies preventing Therapies preventing cardiovascular events cardiovascular events adverse remodelling… adverse remodelling… ACEI , ARB, ß-Blocker, Aldosteron-Ant., CRT

BMC therapy post-AMI Improved clinical outcome in meta-analysis N = 2625 patients from 50 studies Jeevanantham et al, Circulation, 2012

Baseline LVEF determines 5-year survival in Repair-AMI 5-year survival Assmus et al; Eur Heart J 2014

Factors influencing function of autologous BMC

Selection of clinical BMC Trials in AMI EU- Ficoll isolated BMC trials Study Number of Cells Heparin in Final Primary Effects pts. Cell Product Endpoint ASTAMI 100 i.c.; BM-MNC vs. 5 U/ml LVEF (SPECT) (-) after 6 / 12 months standard therapy BONAMI 101 i.c.; BM-MNC vs. No heparin Vitality (+) vitality after 3 months standard therapy (SPECT) (-) LVEF FINCELL 80 i.c.; BM-MNC vs. heparinized serum LVEF (QLVA, (+) LVEF after months medium echo) HEBE 200 i.c.; BM-MNC vs. 20 U/ml reg. LV-function (-) after 4 months peripheral MNC vs. (MRI) standard therapy Janssens-Trial 67 i.c.; BM-MNC vs. NaCl No heparin LVEF (MRI) (+) reduction infarct size + serum (+) regional LV function Plewka et al 60 i.c.; BM-MNC vs. ? LVEF (echo) (+) LVEF after 6 months standard therapy REGENT 200 i.c.; BM-MNC vs. No heparin LVEF (MRI) ((+)) LVEF after 6 months CXCR4 + BM-MNC vs. in cell treated groups standard therapy REPAIR-AMI 204 i.c.; BM-MNC vs. No heparin LVEF (QLVA) (+) LVEF after 4 months medium (+) after 12 & 24 months

Migratory / Invasion Capacity of BMC: Effects of Heparin BMC/CPC BMC/CPC in-vitro migration assay Ischemia SDF-1 24 hours Cytokines, e.g. VEGF, SDF-1 Homing of BMC in Migration ear wound model

Functional capacity of the applied BMC predicts clinical outcome at 5 years Eur Heart J 2014

BAMI Clinical Trial Design (ESC Cell Therapy Trial Consortium) ‚The effect of intracoronary reinfusion of bone marrow-derived mononuclear cells on all-cause mortality in STEMI‘ - 1:1 randomized, controlled, no placebo group - intracoronary BMC administration vs. standard care - approx. 3000 patients, event-driven trial design - primary endpoint: all-cause mortality - Inclusion criterion: LVEF < 45% 3-6 days after successful reperfusion by quantitative echo core lab analysis - Aim: to reduce 2-year mortality by 25% - anticipated mortality in control group: 11.5% at 2 years - 11 participating European countries - 6 core cell processing facilities across Europe - first patient in: Q3 / 2013

Patients with acute myocardial Visit plan infarction post primary PCI N = 3000 eligible AMI patients 3-6 days post primary PCI Central reading of echocardiography (EF ≤ 45%) Randomisation 1:1 Study flowchart Group 1: Control, n= 1500 Group 2: BM-MNC, n= 1500 No intervention Bone marrow aspiration Intracoronary infusion of BMCs 4-8 days post PCI Day 30 ± 7 days: Site visit follow-up Day 30 ± 7 days: Site visit follow-up Month 3: Telephone follow-up Month 3: Telephone follow-up Every 3 months: Telephone follow-up Every 3 months: Telephone follow-up Following observation of full no. of events: Following observation of full no. of events: End of study visit (on site) End of study visit (on site)

Cell processing centers and patient distribution - The Royal London Hospital, London, UK - Hospital Gregorio Maranon, Madrid, Spain - Rigshospitalet University Hospital, Copenhagen, Denmark - Universitaire Ziekenhuizen, Leuven, Belgium - BSD, Institute for Transfusion Medicine, Frankfurt, Germany potentially eligible patients @ day 4-5 post AMI (EF≤45) Start Sept 2013, 8 Sept 2014: n = 51 patients

Cell therapy in cardiovascular diseases Acute Myocardial Infarction Acute Myocardial Infarction Refractory Angina Refractory Angina Peripheral arterial occlusive disease Peripheral arterial occlusive disease Chronic post- -infarction heart failure infarction heart failure Chronic post

Challenges in Cell Therapy of Chronic Heart Failure Acute Infarction Reverse LV Remodeling Reverse LV Remodeling ? - ‘ ‘healed healed‘ ‘ infarction infarction - - established scar established scar - - lack of inflammation lack of inflammation - - remodeled LV remodeled LV - - chronically ill patient chronically ill patient - Impaired homing of progenitor Effects of i.c. administration cells in chronic heart failure of progenitor cells in CHF 10 7 (baseline – FU; %) Mean Indium activity Abs. delta LVEF 8 6 (%; AUC/time) 5 6 Pooled analysis LV- Dilatation 4 (N=70) 4 3 2 2 1 Chronic 0 0 Acute MI MI > 1 year Assmus et al, NEJM 2006 Heart Failure Kang et al, Circ 2006 Schächinger et al, Circ 2008

Need for novel cell sources or enhancement strategies for cell therapy in chronic heart failure Pretreatment Recruitment of progenitor cells in target tissue Bone Skeletal Adipose Cardiac Blood marrow muscle tissue stem cells Cell therapy ** * *** * ** * * * * * * * * * * * * * small genes Pretreatment of the molecules target region shock wave pretreatment shock wave pretreatment Repetitive nanofiber- -based delivery based delivery applications nanofiber Seeger et al, Nat Clin Pract Cardiovasc Med, 2007

Vrtovec B,…,Wu JC; Circ Res 2013

Shock Wave Application may Improve Cell Homing to Target Area Shock Wave Injection P<0.05 800 Pretreatment 3. of cells Number of Cells 600 (% of control) 400 1. 200 Homing 0 N = 6 7 8 6 Untreated 500 1000 2000 Target tissue limb Number of pulses 0.05 mJ/mm 2 Release of chemoattractant factors in target tissue 2. H 2 0 0 500 1000 2000 HLI after 24 h SDF-1 GAPDH VEGF VEGF VEGF & SDF-1 SDF-1 SDF-1 ( attraction & retention of BMC) (Aicher et al, Circulation 2006)

2-D-Echo-guided cardiac shockwave application Shockwave Source Power generator with • Coil High Voltage pulse Energy level control unit Flat coil • Membrane (Magnetic field) and ECG synchronization • Rapid membrane Membrane movement Acoustic lens • Shock wave produced in ECG Trigger water bellow Bellow • Shockwave focused by acoustic lens Patient Shockwave path Shockwave generator Live 2D integrated SW target area Ultrasound Imaging Custom build by Dornier Med Tech Systems Wessling, Germany Assmus et al., JAMA 2013

Primary endpoint: absolute change in LVEF at 4 months - pooled groups - 4 3 p=0.01 2 1 0 SW & Placebo SW & BMC N=33 N=37 Assmus et al., JAMA 2013