Cell Combination Therapy. Disclosures

Transcription

1 Cell Combination Therapy Joshua M. Hare, M.D. Louis Lemberg Professor Senior Associate Dean Chief Science Officer Interdisciplinary Stem Cell Institute The Miller School of Medicine, University of Miami PACT WEBINAR June 19, 2018 Disclosures Research Grants Biocardia, Osiris UM Patent Consultant Kardia, Vestion Equity Kardia, Vestion, Heart Genomics, Biscayne Pharma, Longeveron 1

2 Background on the Development of Cell Combination Therapy (CCT) for HF Bone marrow MSCs lead to reverse remodeling in chronic ischemic cardiomyopathy and possible clinical benefits (being tested in phase 3 RCT) Mechanism of action Neovascularization Reduction of fibrosis Immunomodulation Stimulation of myogenesis Enhancement of effect Impact of MSCs on Scar Morphology Baseline 18 months Karantalis Circ Res 2014 Endocardial Length Scar Thickness Epicardial Cap Endocardial Length P=0.002 Baseline 18 months Scar Thickness P=0.005 Baseline 18 months Epicardial Cap P<0.001 Baseline 18 months 2

3 TAC-HFT Trial Scar Reduction and Regional Function %Change from Baseline * ** ** * *** ** Ecc in the Injected Zone * ** Pre 3M 6M 12M Pre 3M 6M 12M Time Post-TESI MSCs BMCs Placebo Time Post-TESI MSCs BMCs Placebo *p<0.05, **p<0.01, ***p<0.001 Heldman et al. JAMA 2014 *p<0.05, **p<0.01 Results of Trials of Cell Based Therapy in Chronic Heart Failure: Emerging evidence for clinical efficacy Trial name Δ 6MWT MLHFQ MI SIZE EF Williams et al. (n=8) 18±8.3% SCIPIO (n=21) ±3.5g ( 30%) % MESOBLAST (n=60) m* +5.2±9.3%* CADUCEUS (n=25) m g ( 42%) POSEIDON (n=30) m % g +2.0%* C CURE (n=33) m ±10* +7.0% TAC HFT (n=59) m g ( 32.9%) MSC HF (n=59) 4.4±5.1 g +5.5±3.8% *Not significant vs control. Not significant within group. EHJ million mesenchymal precursor cell group. Sanina C. et al. Mesenchymal Stem Cells as a Biological Drug for Heart Disease: Where Are We With Cardiac Cell Based Therapy? Circ Res 2015 Jul 17;117(3): doi: /CIRCRESAHA

4 Major dilemma that has plagued the field: Long-term engraftment is minimal to absent Endogenous repair Mechanism of action: C Kit+ Cells and cell cycle activity in MSC treated hearts Hatzistergos et al. Circ Res

5 Ex vivo co-culture enhances CSC proliferation and lineage commitment Hatzistergos. Circ Res 2010 Targeting Endogenous Regeneration Cardiomyocyte renewal rates are 0.5 to 2% per year in adult humans Renewal rates increase following injury Olaf Bergmann et al. Science 2009;324:

6 Interventions that Stimulate Endogenous Regeneration Injury Exercise Ventricular Geometry Cell-therapy Impact of human ckit+ cardiac stem cell (hcsc) and bone marrow mesenchymal stem cells (hmsc) therapy on delayed enhancement cmri scar size Acute Myocarial Infarction Pre-injection 4 week post-injection Pre-injection 4 week post-injection 20.7% 13.5% 20.9% 16.6% ckit+ hcsc and hmsc 21.6% 15.3% hmsc 18.4% 17.5% ckit+ hcsc Placebo (*p<0.05 within group ANOVA; p<0.05 vs. placebo at 4 weeks post-injection and p<0.05 vs. hcsc alone and hmsc alone at 4 weeks post-injection) 6

7 Pressure Volume Loop Hemodynamics Improved diastolic function after combination hmsc and hcsc therapy Pre-injection Post-injection Placebo Combo MSC/CSC Therapy Williams et al. Circulation (*p<0.05 within group and **p<0.05 between groups) Antifibrotic Effects of Cell Therapy: Chronic Ischemic Cardiomyopathy Post MI Placebo 3m post TESI Placebo TESI P< Scar size(de): 7.4g Scar size (DE): 8.9g MSCs MSCs Scar size(de): 9.7g Scar size (DE): 5.9g Combo Combo % Scar Mass as % LV Mass ** ** -50 3m post MI 1m 2m 3m P< * * ** % Viable Tissue Mass Scar size(de): 8.9g Scar size (DE): 5.8g *P< way ANOVA, **P< way ANOVA multicomparison test combo vs placebo, + P<0.05 multicomparison test MSCs vs placebo JACC

8 Combined engraftment enhances repair in an autologous model of chronic ischemic cardiomyopathy Karantalis et al. JACC, 2015 The Cardiovascular Cell Therapy Research Network The CONCERT -CHF Trial: Combination Of c-kit cells and mesenchymal cells: a Novel, dual Cell study Evaluating Regenerative properties for Treatment in Chronic Heart Failure Study Chair: Roberto Bolli, MD Professor, Director of Cardiology University of Louisville, Louisville, KY 8

9 Sample Size and Treatment Groups 144 subjects will be randomized 1:1:1:1 36 subjects/group to 1 of 4 treatment groups: 1. Combo: Target dose is a mixture of 150 million MSCs and 5 million CSCs 2. MSCs: Target dose is 150 million MSCs 3. CSCs: Target dose is 5 million CSCs 4. Placebo: Cell free PlasmaLyte A medium Run in phase (n=16) Each subject will receive 15 injections, each of 0.4 ml volume (cells or placebo) 17 Organizational Structure: NHLBI Cardiovascular Cell Therapy Research Network (CCTRN) PRC NHLBI Ebert Chair Simari DSMB Cell Processing QC Lab Univ of Miami PDCs Steering Committee Data Coordinating Center UTSPH Moyé P & P Biorepository & Core Labs RC Core MD Core RC Core MD Core Texas Heart Institute U Florida Minneapolis Heart Inst. U Louisville U Miami Stanford Indiana U 9

10 A ckit + myocardial lineage emerges on ~E9.5 ckit CreERT2 /IRG Tam E :: Analysis E18.5 A B C D EGFP DsRed Dapi E F Hatzistergos et al. Circulation Research

11 C-Kit Cell Expansion Endomyocardial Biopsy Digestion Cell Expansion CD117+ Cell Sorting Further Cell Expansion Expansion Expansion P0 Adherence to surface of cell culture flasks Sorting C-kit+ Cells P2-P3 Expansion C-kit+ Cells P1-P2 Cell Growth 2.6E E E+07 Cell Count 4.1E E E E E+04 *DCM 037, only 5million cells were Plated at P2, if 20million Plated, recovery 80million DCM 033 DCM 035 DCM 036 DCM 037 *DCM E E Days in culture Khan and Hare, Unpublished,

12 Cell Characterization DCM 037 ckit ab Ckit APC (ebioscience ) Ckit APC (ebioscience ) DCM 036 ckit ab Ckit APC (ebioscience ) Ckit APC (ebioscience ) DCM 035 ckit ab Ckit APC (Abcam ab130410) Ckit APC (ebioscience ) Khan and Hare, Unpublished, 2015 New Ongoing Efforts: Staged surgical palliation for patients with hypoplastic left heart syndrome. I Norwood II bidirectional III total cavopulmonary (Fontan) Brody Wehman, and Sunjay Kaushal Circulation Research. 2015;116: Copyright American Heart Association, Inc. All rights reserved. 12

13 Conclusions and Implications MSCs reduce scar tissue tissue by 30 50% The replaced tissue is unequivocally contractile Regeneration in the human heart, likely due to increased abundance of endogenous c kit cells and cell cycle activity Lineage tracing studies show that MSCs activate myocardial c kit cells Three studies show unequivocal evidence of c kit differentiation into cardiac myocytes (BMP regulation) The interaction of MSCs and c kit cells forms the basis for a novel therapeutic principle cell combination therapy which is in clinical trial Soffer Family Foundation, Starr, Marcus 13