Cara East MD, Director

Cara East MD, Director The team of SCRC research physicians and staff Soltero CV Research Center, Baylor Research Institute Baylor Jack & Jane Hamilto...
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Cara East MD, Director The team of SCRC research physicians and staff Soltero CV Research Center, Baylor Research Institute Baylor Jack & Jane Hamilton Heart & Vascular Hospital Baylor University Medical Center Texas A&M College of Medicine

 Alexander Alexandrowitch

Maximow  Born 1874 St Petersburg, 

Russia  He first theorized that all 

hematopoetic cells develop  from 1 precursor cell (the  stem cell)  Professor of Anatomy at the  University of Chicago  Died 1925 of coronary  atherosclerosis 

Sea stars may reproduce asexually by fragmentation. Each arm can regenerate an entire organism. Thus, early fisherman who cut up the creatures who ate their oysters actually created many more. Wikipedia 2010

We know the body repairs  Blood vessels: vessels repair minor cuts frequently  Bone marrow: marrow your red cells, which carry

oxygen, are completely l t l replaced l d every 21 days d  Liver Liver: after injury or infection  Bones Bones: grow and change slowly over the years  Starfish Starfish: can regenerate an arm

Sources of Stem Cells • All tissues have some stem cells present

for local repair (including the heart and brain). • Only the bone marrow regularly produces

stem cells for export into the blood. • Adipose tissue is rich in stem cells, which

are likely present to participate in local repair, which is one major role for fat in skin.

Sources of Stem Cells for therapeutic purposes  Bone marrow: marrow Requires aspiration and at least some

processing (to remove blood cells and bone elements).  Adipose tissue tissue: Requires Adi ti R i collection ll ti (liposuction) (li ti ) andd

some processing.  Blood Blood: Larger number of stem cells can be mobilized

using manufactured cytokines (and specifically GCSF).  Both cord blood and menstrual blood are rich in stem

cells.

PI:  Barron Hamman MD PI:  Barron Hamman Poupak Moshayedi MD Cara A East MD Johannes Kuiper MD Robert F Hebeler Robert F  Hebeler MD Luis A Pineiro Luis A  Pineiro MD Hal C  Hal C Urschel Urschel Jr MD

Aastrom Surgical Trial  For treatment of dilated cardiomyopathy (ischemic and 

nonischemic).

 Patients who have congestive heart failure in spite of    



use of maximal medication therapy and biventricular  implanted defibrillators Bone marrow, 50 mL, was collected from the patient. It was then processed over 2 weeks in a closed  incubation system to expand the preferred cell types. Placed directly into the left ventricular muscle using a  left lateral thoracotomy, beating heart, no heart‐lung  bypass machine needed. FDA study phase 2

Aastrom Surgical Trial Heart Attack

1

Healthy Heart H lth H t

2

Infarcted Myocardium

3

Fibrosis/Scar Formation

Heart Failure

4 20

Dilative Cardiomyopathy

Aastrom Surgical Trial Analysis of this Phase 2 trial showed: Stem‐‐cells Stem

Usual care

• Adverse events         

25

• NYHA FC 12 mo’s better

13

15 5

• NYHA FC 12 mo’s no change

2

2

• 6 minute walk 12 mo’s better

13

5

• 6 minute walk 12 mo’s no change       1

0

• No significant change in EF Amit Patel MD, University of Utah

Aastrom Surgical Trial  Safety and Efficacy of Ixmyelocel‐T, an Expanded Patient‐Specific Mixed Cell Product in Dilated  Cardiomyopathy (IMPACT‐DCM) Amit N. Patel, Baron L. Hamman, Brian Bruckner, Omar M. Lattouf, Nicholas G. Smedira, Cara East, David A.  Bull; Ronnda L. Bartel, Sharon Watling. HFSA Annual Meeting, September, 2011  Safety and Efficacy of Ixmyelocel‐T, An Expanded Patient‐Specific Mixed Cell Product, in Dilated  Cardiopyopathy (IMPACT‐DCM) Brian Bruckner, Amit N. Patel, Baron L. Hamman, Omar M. Lattouf, Nicholas G. Smedira, Ronnda L. Bartel, and  Sharon Watling. Sharon Watling International Society for Heart and Lung Transplantation, International Society for Heart and Lung Transplantation November 2011  Ixmyelocel‐T, A Unique Mixed Cellular Therapy for the Treatment of Vascular Diseases Associated  with Endothelial Dysfunction KJ Ledford, EN Murphy, F Zeigler, RL Bartel,  AHA Arteriosclerosis, Thrombosis and Vascular Biology 2013  Scientific Sessions, May 2013  Ixmyelocel‐T Therapy Alternatively Activated Macrophages Potentially Exert Atheroprotective Effects KJ Ledford, C Parrish, F Zeigler, RL Bartel. Keystone Symposia on the Molecular Basis of Vascular Inflammation  and Atherosclerosis in Big Sky, Montana, starting Sunday, March 2012 

Safety and Efficacy of Ixmyelocel‐T, A Patient‐Specific Expanded Multicellular Therapy, in Dilated  Cardiomyopathy Timothy D. Henry, Jay H. Traverse, Rod Badger, Marco Costa, Patricia Mitchell, Kristen Kolsch, Ronnda L. Bartel,  Sharon Watling, Amit N. Patel. Society for Cardiovascular Angiography and Interventions (SCAI), May 2012

Aastrom Surgical Trial Challenges: • Surgery is required to deliver stem cells.  Thus, not 

justified to do a randomized, blinded study. • The surgery though is a left lateral thoracotomy, so  Th    th h i    l ft l t l th t    

patient home in 3 days and no complications of the  heart‐lung machine. • The endpoint of VO2 max on a metabolic stress test is 

a hard endpoint, as are hospitalizations for CHF and  death. • Where we first noted the phenomenon of “stem cell 

high.”

J ff y Schussler PI:  Dr Jeffrey  PI:  Dr Jeffrey Schussler Dr Paul  Dr  Paul Grayburn Grayburn Dr Luis Pineiro Dr Cara East Dr Carlos Velasco

Baxter RENEWTrial  Intractable angina.  No further revascularization options.  Area(s) of ischemia that could benefit. Area(s) of ischemia that could benefit  Stem cells, CD34+,  mobilized into the blood 

using G‐CSF, collected by apheresis, and  cleaned.  Stem cells implanted using the NOGA system.  FDA study phase 3

Baxter RENEW Trial Challenges: • Mapping being used to direct injections. • Apheresis A h i takes 4 hours and a large IV. k    h   d   l  IV • Training of the physician researchers. • Takes 2 physicians to keep the NOGA injection 

catheter pressed on the LV wall correctly. • Endpoints will be time to angina on ETT and 

angina diaries (so, soft endpoints).

PI:  Dr Jeffrey  PI:  Dr Jeffrey Schussler J ff y Schussler Dr Paul  Dr  Paul Grayburn Grayburn Dr Luis Pineiro Dr Cara East Dr Carlos Velasco

Safety and Efficacy of Ixmyelocel Ixmyelocel--T, A Patient--Specific Expanded Multicellular Patient Therapy, in Dilated Cardiomyopathy  An increasing number of patients have ongoing 

congestive heart failure symptoms despite optimal  medical and device therapy.  Current options include left ventricular assist devices 

or cardiac transplantation.  There are not enough hearts for transplantation for all 

who need them.  Cell therapy is an attractive alternative Timothy D Henry MD, Minneapolis Heart Institute

45000

Cytokine Seccretion (pg/mL)

40000 35000 30000 25000 Basal 20000

+LPS

15000 10000 5000 0

IL‐10

IL‐1ra

TNFα

IL‐1β

IL‐12

Aastrom Cath Trial Challenges: • Cells collected from the bone marrow and 

grown in vitro for 12 days at an off‐site location. grown in vitro for 12 days at an off site location • Training of the physician researchers. • Takes 2 physicians to keep the NOGA injection 

catheter pressed on the LV wall correctly. • Endpoints will be hard endpoints (EF, serious 

adverse events, 6 minute walk)

PI:  Dr Jeffrey  PI:  Dr Jeffrey Schussler J ff y Schussler Dr Paul  Dr  Paul Grayburn Grayburn Dr Luis Pineiro Dr Cara East Dr Carlos Velasco

 A plasmid, called JVS-100, has been developed that

contains a construct of the SDF-1 gene.  The SDF-1 gene is a chemokine that attracts endothelial

progenitor cells from the bone marrow.  When present, circulating stem repair cells stop and enter

the tissues expressing the SDF-1 gene.

STOP HF Trial Challenges: • It is an advantage to be able to simply take a gene 

product from the freezer.

• Gene products have the disadvantage that the body 

will eventually remove the added gene.

• The Biocardia catheter is bulky and cannot be placed 

inside hearts with moderate aortic stenosis.

• The Biocardia system is easily handled by 1 

cardiologist.

• Endpoints will be hard endpoints (EF, serious adverse 

events, 6 minute walk).

PI:  Gregory J Pearl MD K Blaire  K Blaire Kerwin Kerwin BS Cris D Molina BS Pamela J Coker  Pamela  J Coker RN RN Luis A Pineiro Luis A Pineiro MD Harold C Urschel Harold C  Urschel Jr MD Cara A East MD

Harvest BMAC Trial  This is a treatment for critical limb ischemia for patients 

for whom other therapies have not worked, who have some  tissue loss, and thus are being watched expectantly for  probable amputation.  The stem cells are collected from the bone marrow in the 

operating room (240 mL).  Processing of the stem cell product takes about 30 minutes 

and also takes place in the operating room.  Cells are injected along the vessels below critical 

obstruction, using sonographic guidance.  FDA study phase 3

RANDOMIZATION FLOWCHART

SALINE

A

BLOOD

RANDOMIZED TO CONTROL N = 14

INVESTIGATOR BLINDED TO INJECTATE

RANDOMIZE

• 40 injections

B

• 1 mL per injection

RANDOMIZED TO TREATMENT N = 34

BONE MARROW

Amputation Rates by trial

Randomized controlled trials Randomized controlled trials

302 subjects – 302 subjects  – 213 BMAC

1

Harvest BMAC Trial Challenges: • Complete bone marrow is used, so this includes 

any local cytokines. any local cytokines • A large volume of bone marrow of 240 mL must be 

collected. • Delivered locally, but with sonographic guidance to 

place the cells in peri‐vascular locations. • Endpoints of healing of sores and amputation are 

hard end‐points.

There are many questions still to be  asked and answered.

Uses and advantages of cord blood stem cells  First Cord Blood transplant in 1988 for a case of

Falconi anemia.  Since Si usedd for f treatment off leukemia l k i andd immune i

deficiencies.  Less HLA matching required (75% match with

siblings).  Less Graft vs Host Disease.  4000 patients have been treated to date

Disadvantages of cord blood stem cells  May not be wise to use to treat autoimmune diseases or

leukemia, as the systemic genes associated with the disorder di d are still till present. t  The 75 mL volume collected likely cannot be used

singly to treat a normal-sized adult.  Higher rates of relapse due to lack of graft vs host

disease.

California Stem Cell Agency to Allocate $70M for Clinical Trials  The California Institute of Regenerative Medicine’s board

signed off on the allocation of $70M to begin setting up clinics and to bring a number of developing stem cell therapies into clinical trials.  The network, called the Alpha stem cell clinics network,

will consist of 5 sites at established academic institutions and a coordinating center that will help streamline patient enrollemtn, management of regulatory procedures, and data sharing.

Thank  you for joining us today.

Bone marrow has shown regenerative potential in various applications

Multipotent Stem Cells Progenitor Cells Accessory Cells Signal Cells

HARVEST TECHNOLOGIES CORP.

Stem cells  What kind of stem cells should we use?   How are the stem cells collected?  From a tissue, 

like bone marrow or muscle, or from the blood.  Which stem cells?  Do we use separate out 

specific cell types or use a wide collection of cells?  How do we deliver them to the tissues we want to 

repair?  If stem cells work, how long will they continue to 

work?

 Fig. 2 Unipolar voltage map (color range, 6.7–12 mV). 

Scarred areas (unipolar voltages, 

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