Autologous S tem Cell Therapy In Patients with Non- - - PowerPoint PPT Presentation

Autologous S tem Cell Therapy In Patients with Non- Reconstructable Critical Limb Ischemia

Karl R S tark MD F ACS North Kansas City Hospital

DIS CLOS URES

• Karl R. Stark, M.D. has disclosed that he is an

investigator for Harvest and LifeCells Therapy with no personal relevant financial relationship.

DIS CLOS URES

The following listed CME Advisory Committee members have disclosed that they do not have any relevant financial or other pertinent relationships with proprietary entities producing healthcare goods or services related to the content of this activity.

• Michael W. Farrar, M.D., Chair
• Gary L. Carter, M.D.
• Iris A. Comes, M.D.
• S

arah J. Hon, D.O.

• Jay W. Kimball, M.D.
• James L. S

tewart, M.D.

• Todd P

. Hill, D.O. has disclosed that he is listed on the S peaker’s Bureau for Teva, Forrest Pharmaceuticals, and Otsuka Pharmaceuticals.

• William W. Pingleton, M.D. has disclosed that he is a Consultant for Oncimmune.

OVERVIEW

• Define Critical Limb Ischemia; (CLI)
• Natural history of CLI
• Treatment option for patients with CLI
• Patients with no reconstruction options
• Types of stem cell therapy, and what type is used

clinically

• Evolution of stem cell therapy in patients with CLI
• Two current autologus stem cell therapies being used at

NKC Hospital

CRITICAL LIMB IS CHEMIA

• Define as limb threatening ischemia of the

lower extremity that has been present for several weeks if not months. It is the most severe form of peripheral arterial disease.

• S

eparate it from acute limb ischemia; in the duration of the process; and the underlying etiology is different. Acute limb ischemia is usually embolic or thrombotic occlusion of the arteries of the leg.

TREATMENT OF ACUTE LIMB IS CHEMIA

• Intervention
• Use combination of endovascular and open

techniques to restore flow.

• Unless flow can be immediately successfully

restored the limb will be lost.

• Common presentations are embolic sources

from the heart such as in atrial fibulation, or thrombosis of underlying arterial disease.

CHRONIC PERIPHERAL ARTERIAL DIS EAS E

• In Europe and North America 27 million people

affected; worldwide 202 million.

• 23.5%

increase in incidence in the last 10 yrs.

• Most patient have mild if any symptoms; 1 in 4

are symptomatic.

• The severity of patient’s P

AD directly correlates with the risk of cardiovascular events and death.

P ATIENT PRES ENTED WITH S EVERE FOOT P AIN

Patient has palpable DP pulse around the ankle area

TYPICAL APPEARANCE OF LOWER EXTREMITIES IN A P ATIENT WITH CHRONIC S ERVERE ARTERIAL INS UFFICENCY

• Thin, pale appearing

skin

• Patchy, irregular areas
• f marginally viable

tissue distinguish embolization from a more generalized severe arterial flow pattern

TYPICAL APPEARANCE OF IS CHEMIA FROM EMBOLIZATION

Appearance shows splotchy areas of ischemia, rather than diffuse distal tissue involvement seen in purely arterial-ischemic patients

RANGE OF S EVERITY OF PERIPHERAL ARTERIAL DIS EAS E

• S

everal classification scales range from no symptoms to non-salvageable limbs.

• Appropriate treatment is based on the severity
• f the disease
• All patients receive medical therapy
• Intervention is reserved for more severely

affected patients

MEDICAL THERAPY FOR P ATIENTS WITH PERIPHERAL ARTERIAL DIS EAS E

• S

moking Cessation

• S

upervised Walking Programs

• S

tatin Therapy

• Antiplatelet Therapy
• Weight Loss Therapy
• Diabetes Management
• These Therapies and Others to Lower the

Overall Cardiovascular mortality Risk

DO THES E THERAPIES CHANGE OUTCOMES ?

• S

moking cessation alone doubles the life-span compared to a patient with peripheral arterial disease that smokes.

• For patients undergoing interventions for peripheral

arterial disease, the risk of failure is three times greater for those who continue to smoke.

• Quick found in 244 patients with claudication, 8%

progression to CLI in patients who quit smoking and a 79% progression in those who did not. * S tatins have a much more profound affect then simply helping lipid profiles. S tatin therapy reduces the risk of progression of disease, as well as increases walking distance in patients with claudication

CRITICAL LIMB IS CHEMIA: CLI MOS T S EVERL Y AFFECTED P ATIENT

• 25%
• f patients with CLI die in one year

Greater then 40% by five years.

• One year amputation rate is 25%
• Mortality risk for BKA 5%

to 10% ; AKA 10% to 15%

• Quality of life generally falls with amputation
• Chances of independent living fall with an

amputation.

APPROPRIATE THERAPY FOR CLI

• Medical therapy
• Revascularization if possible.
• Non-viable extremities undergo early amputation.
• Overall mortality is less if the extremity can be

saved. * For revascularization; use a combination of endovascular and open techniques to improve arterial flow.

Patient with CLI and renal insufficiency

CO2 arteriogram identifies chronic superficial femoral artery occlusion

Results of intervention

S uccessful restoration of flow for treatment of patient’s CLI

FEMORAL-POPLITEAL BYP AS S FOR LIMB S AL VAGE

Bovine carotid artery conduit used when autologous vein is not available for bypass

NON-DIRECT REVAS CULARIZATION TREATMENT OPTIONS FOR P ATIENTS WITH CLI

Patients with CLI and no revascularization options

Pattern of Arterial Disease in Treated Patients

Typical arterial disease pattern in patients with non-reconstructable arterial disease with critical limb ischemia and threatened limb loss. CT arteriogram showing non flow limiting proximal disease and severe tibial and plantar disease with no named arteries in distal leg and foot.

Patient with CLI and no reconstructable arteries; treated with HBO

HYPERBARIC OXYGEN THERAPY FOR CRITICAL LIMB IS CHEMIA

• Group of patients with CLI and threatened

limbs that could not undergo revascularization

• The group that received HBO had a higher limb

salvage rate and were twice as likely to heal their ischemic wounds

• Mortality was also lower in the group that

received HBO

52% 30% 0% 20% 40% 60% 80% 100% Hyperbaric Oxygen Treatment Group Non-Treatment Group

Long Term Patient Survival

S URVIVAL OF P ATIENT WITH CLI AND NON- RECONS TRUCTABLE ARTERIAL DIS EAS E

EVOLUTION OF CELL THERAPY FOR ARTERIAL DIS EAS E: Inadequate results from other treatment modalities

• Treatment of a specific group of patients in

whom arterial reconstruction is not possible

• Other modalities used include compression

devices with limited success

• Infusion of prostaglandins (beraprost)
• S

ympathectomy

• S

pinal cord stimulation

• Vasodilators

GOAL: INDUCE ANGIOGENES IS

• Change the balance between angiogenesis and

angiostasis

• Introduce new factors to stimulate angiogenesis
• Induce arterial collateral formation
• Introduce new cells to develop arteries

ARTERIAL AND ANGIOGENES IS GROWTH F ACTORS

• Gene transfer by viral transfer, plasmid attachment, or

bare DNA

• Most used as intramuscular inj ections
• Factors used include fibroblast growth factor 1, vascular

endothelial growth factor, hypoxia-inducable factor 1, hepatocyte growth factor, and naked DNA forms of hepatocyte growth factor

• Meta–

analysis shows benefit from these factors

S TEM CELLS

• Primary stem cells are embryonic
• Embryonic cells are totipotent and may

differentiate into the three germ layers: ectoderm, endoderm and mesoderm

• Differentiation path is to multipotent stem

cells

• Multipotent stem cells are dedicated to

specific tissues and organs, and farther differentiate to progenitor adult stem cells

ADULT S TEM CELLS LOCATION

• Found in the postnatal bone marrow, blood,

skeletal muscle, fatty tissue, and heart

• Adult bone marrow contains differentiated cells,

such as monocytes, lymphocytes, fibroblast, adipocyte, chondroblasts, osteoblast, and

• steoclasts, as well as a group of undifferentiated
• cells. The extracellular matrix contains cytokines

and growth factors.

• Differentiated centrifugation can separate cells

into subgroups

• Now can separate even these stem cells into their

tissue specific types.

PROBLEMS WITH EMBR YONIC S TEM CELLS US E IN THERAPY

• Moral issues surrounding fetal source of cells
• Potential for uncontrolled differentiation can

lead to neoplasms

• Use can lead to graft vs. host reaction;

immunosuppression is required

• Currently, use not supported by FDA

EVOLUTION TO CELL THERAPY

• Early trials show greater potential then factor

use

• Religious and moral beliefs direct research

toward autologous source of stem cells

• Cell culturing risk: decreasing the activity of

the desired beneficial effect, and risk development of the undesired side-effects

• FDA has directed research toward autologous,

non-cultured cells

CULTURED ADULT S TEM CELLS

• FDA

’s general position is that with culturing cells, their effect may change

• Can lead to ineffectivity for original therapy

goal

• Can lead to undesirable changes in cell

function

CURRENT S TEM CELLS FOR TREATMENT OF CLI

• Autologous bone marrow source
• S

pecifically the patient receives their own stem cells

• Avoid moral, and neoplastic issues with

embryonic cells

• S

tudies have shown this line of cells to be safe for patient treatment

ADMINIS TRATION OPTIONS FOR S TEM CELL THERAPY FOR CLI

• Intramuscular
• Intra-arterial
• Combination of intramuscular and intra-arterial
• Attempt to deposit the cells in the neuro-vascular

bundle

INTRAMUS CULAR ADMINIS TERED BONE MARROW CELLS

• S

everal trials showed improved limb salvage rates in treated patients (60% )

• Improved measured limb profusion as measured by ankle

brachial index and TCO2

• Trend in all treatment modalities for CLI patient that

limb salvage is associated with decreased mortality

PROVAS A TRIAL

• Randomized trial of intra-arterial infusion of

either autogenous bone marrow derived mononuclear cells vs. placebo

• S

ignificant improvement in ischemic rest pain and ulcer healing in the treated group

CURRENT ONGOING AUTOLOGOUS S TEM CELL TRIALS FOR NON-RECONS TRUCTABLE ARTERIAL DIS EAS E

• Harvest trial: interim data shows improvement in

amputation rest pain and ulcer healing

• It is an intramuscular inj ection protocol of autologous

bone marrow derived cells

• North Kanas City Hospital is the number three enroller

in the nation for this trial

• It is approaching 50%
• f the enrollment goal
• Can only treat more advanced ischemia in this trial

LIFECELLS PROTOCOL

• New protocol that using a combination of

intra-arterial and intramuscular inj ection

• Cells are separated to pure cells to allow for

arterial infusion of a portion of the bone marrow derived cells.

• Can treat ischemic rest pain as well as more

advanced ischemia with tissue loss

• This a newer trial
• HAS

GREAT POTENTIAL

MORAL PROBLEM OF THE PLACEBO ARM IN THES E TRIALS

• Harvest has a two treated patients to one

placebo treatment protocol

• For the enrolled patients, this is a treatment
• ption of last resort
• Our initial filing with the FDA suggests a strong

positive effect of treated patients in the Lifecells treated patients.

• FDA now is going to have us move forward for

the next 24 patient without a placebo arm

TREATMENT FOR THE P ATIENT IN THE HARVES T TRIAL

• Arrive on the day of the procedure to the OR.
• Taken to surgery, and under sedation the bone

marrow aspiration is done.

• The aspiration is prepared in the OR room
• Then I arrive; blinded whether the patient is going

to receive the aspirate or placebo.

• I inj ect the solution along the desired growth tract
• Patient is observed, then discharged.
• We then follow the patients with a series of

vascular laboratory studies, blood work, eye evaluations, and clinical observations

LIFECELLS PROTOCAL

• The patient has the bone marrow aspiration in

a procedure area in the early morning.

• They have a baseline MRI that day
• The bone marrow aspirate is taken off site and

prepared; (this takes approximately six hours).

• I then take then take the patient to the
• perative angiosuite and infuse a portion of

the cells into the arterial system above the

• cclusion, and a portion along the desired cell

growth tract.

Review

• Peripheral arterial disease is relatively common;

the incidence has increased over the last ten years; and with the aging of the population that trend will continue

• A small number of affected patients advance in

disease severity to CLI where the threat of limb loss is significant; and mortality is increased

• further. Around 25%

in the first year.

• Direct revascularization is the treatment of choice

for these patients if possible

• In a small number of these patient that is not
• possible. For them the search has been for

alternate therapy.

REVIEW CONTINUED

• HBO and other modalities has been helpful in some

patients, but had limited success.

• Exploration for other treatments led first to factor

administration; and subsequent to direct cell inj ection therapy.

• S

tem cell therapy used today is directly from the patient’s bone marrow and an adult stem cell population.

• Currently we are studying two treatment protocols:
• Harvest-a direct intramuscular inj ection treatment; and
• Lifecells-that is a combination of intravascular and

intramuscular inj ection protocol.