Current Status of Pancreas and Islet Transplantation

1

• Current Status of Pancreas and Islet
  Transplantation

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The Problem
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Diabetes Mellitus in the U.S.

• 18.2 million people are diabetic (6.2 of
  population)
• 13 million diagnosed
• 5.2 million undiagnosed
• new cases per year 1.3 million people aged 20
  years or older
• 6th leading cause of death (heart disease most
  common)
• Leading cause of ESRD
• Leading cause of blindness
• Direct medical cost for DM in 2003
• Total(direct and indirect) 132 billion

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Geographic variations in adjusted incident rates
of ESRD due to diabetes whites, 1992 Figure
2.11
Incident ESRD patients. Per million population,
by HSA, adjusted for age gender.
illi
illi
lla
lla
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Geographic variations in adjusted incident rates
of ESRD due to diabetes whites, 2002 Figure
2.11 (continued)
Incident ESRD patients. Per million population,
by HSA, adjusted for age gender.
illi
illi
lla
lla
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Acute complicationsHypoglycemia

• The limiting factor in the management of type 1
  diabetes
• 25 of patients practicing intensive insulin
  therapy suffer at least one episode of severe,
  temporarily disabling hypoglycemia, often with
  seizure or coma, in a given year
• 4 of deaths of people with type 1 diabetes have
  been attributed to hypoglycemia

Philip E. Cryer, Diabetes 1994
7
Participants were selected by excluding those
with a history of severe hypoglycemia, long
duration of diabetes and other factors known to
increase the risk of severe hypoglycemia
Glycated Hb ()
NEJM 1993 329 977-86
DCCT. NEJM 1993
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NEJM Feb 12, 2004
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Beta-cell Replacement Therapy for Diabetes An
Integrated Approach with Pancreas and Islet
Transplantation
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PURPOSE OF BETA CELL REPLACEMENT THERAPY

• Improve quality of life by establishing
  insulin-independent, normoglycemic state
• Prevent/ameliorate secondary complications of
  diabetes

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THREE BROAD CATEGORIES of ß-CELL REPLACEMENT
inPANCREAS (P) or ISLET (I) TRANSPLANT (T)
RECIPIENTS

• -Simultaneous(S) kidney (K) transplant
• SBK (SPK or SIK)
• -After(A) kidney transplant
• BAK (PAK or IAK)
• -B-cell transplant alone
• BTA (PTA or ITA)

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• The immunosuppression needed to prevent rejection
  is of the same magnitude for either approach.

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• Pancreas Transplant
• Highly efficient but major surgery
• Islet Transplant
• Minimally invasive but less efficient

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Pancreas Transplantation
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Pancreas Transplants Worldwide
Total n 24,974 ? Non USA n 6,346 ?
USA n 18,628
3/06
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Pancreas Transplant Categories
USA SPK, PAK and PTA Transplants
3/06
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Outcome
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5-Year Patient Survival
USA DD Primary Pancreas Transplants, 1 /1/1988
12/31/2000
10/05
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SPK Pancreas Graft Function
USA DD Primary Pancreas Transplants, 10/1/1987
12/31/2005
Year HLmos
11/05
22
PAK Pancreas Graft Function
USA DD Primary Pancreas Transplants, 1/1/1988
12/31/2005
Year HLmos
11/05
23
PTA Pancreas Graft Function
USA DD Primary Pancreas Transplants, 10/1/1987
6/ 6/2004
Year HLmos
11/05
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Early Technical Pancreas Graft Failures
USA DD Primary Pancreas Transplants, 1/1/1988
12/31/2005
3/86
25
1-Year Immunological Graft Loss
USA DD Primary Pancreas Transplants, 10/1/1988
12/31/2005
3/06
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Risk FactorsforPatient Death
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Hazard Ratio for SPK Patient Death
USA DD Primary Pancreas Transplants, 1/1/2000
6/6/2004
Higher
Risk
Lower
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SPK Patient Survival
USA DD Primary Pancreas Transplants 1/1/2000
6/6/2004
Graft Status n 1Yr Surv. PxFx/KiFx 3,016 97
PxFx/KiFld 118 83 PxFld/KiFx 368 92
PxFld/KiFld 105 72
p 0.0001
8/04
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Pa Tx vs. Waiting-list Mortality
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Waiting List Death RatesPercent Deaths Per
Patient Waiting 2003 - 2005
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Patient Survival while Waiting
UNOS Pancreas Waiting List 1/1/1995 5/31/2003
Survival Cat. n 1Y
r 4Yrs ? PAK 2942 97.2 81.7
PTA 1207 96.6 87.3 ? SPK 12478 93.4 58.7
2/04
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Patient Survival after Tx
UNOS Pancreas Waiting List 1/1/1995 5/31/2003
Survival Cat. n 1Y
r 4Yrs ? PAK 1714 95.3 88.3
PTA 647 97.0 90.5 ? SPK 6995 95.0 90.3
2/04
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Relative Hazard Ratios
UNOS Pancreas Waiting List 1/1/1995 5/31/2003
Wait-Listed Patients
equal risk
8/04
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Summary

• For 2000-2005 cases, patient and graft survival
  rates continue to improve due to further decline
  in TF and rejection rates
• Immunological graft losses remain higher for PTA
  PAK
• The risk of death is not higher for transplanted
  vs wait-listed recipients of solitary pancreas
  transplants

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Islet Transplantation
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Obstacles to Islet Allotransplantation
Donor shortage
At least 50 loss of islet mass during isolation
Difficulties in monitoring rejection
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Human Islets Transplantation Cumulative burden of
immune and environmental stress
Reduced Islet Mass Islet Cell Death Islet Cell
Dysfunction
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Decline in islet function over time - Reasoning

• Intrinsic limitations of islets to repair injury,
  replicate, and survive
• Chronic rejection? Autoimmune recurrence?
• Does immunosuppression interfere with islet
  replication/neogenesis?
• Serial systematic graft biopsies?
• Is the liver an appropriate islet implantation
  site?

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Human Islet Allotransplantation

• ImmunosuppressionNo steroids. Daclizumab
  Rapamycin Tacrolimus
• Donor tissue
• Deceased donor islets from 2-4 pancreata/recipient
  

Shapiro et al., NEJM 2000
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Percutaneous transhepatic approach
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Islet transplant activity (1999-2004)
Edmonton (67)
Miami (30)
Milan (35)
Minneapolis (20)
Brussels (35)
Philadelphia (12)
Giessen (27)
Vancouver (12)
Geneva/GRAGIL (28)
Houston (11)
Nordic Network (24)
Harvard (10)
Leuven (20)
Northwestern (8)
Innsbruck (11)
St Louis (8)
Zurich (10)
NIH (6)
Sydney (6)
Cincinnati (6)
Kyoto (5)
Seattle (6)
Budapest (4)
Emory (6)
Kings (UK) (2)
City of Hope CA (5)
Chiba (1)
Memphis (3)
Sao Paulo (2)
Tokyo (1)
UCSF (2)
U Mass (2)
Shanghai (1)
43 institutions 530 patients
U. Maryland (1)
Red ITA Blue ITA and SIK/IAK Black SIK/IAK
Columbia NY (1)
Carolina Med Ctr (1)
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ITN Multicenter Trial of Edmonton
ProtocolMinnesota Cases
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Issues

• Of 2,000 candidates only 149 (7) fulfilled
  criteria
• Rec mean BW 62kg, mean BMI 22
• Mean IE 13,400 only 45 of isolations were txed
• Lack of stringent criteria for definition of
  adequate glycemic control (HgA1clt6.5, fasting
  BSlt140, postprandBSlt180)
• 25/36 recs underwent more than 1 islet tx (33
  had 3)
• Graft survival disappointing (44, 31)
• Adverse events intraabd bleed, partial portal
  vein occlusion, bile leak, mild hepatic steatosis
  (4/13 at 2 yrs),change in IS in 25
• Evolving therapy for highly selected pts

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Single-donor Islet Transplantation
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Single-donor 7 strategies16 of 18 insulin-free
with 11 transplant

• Young, LARGE donors
• Short cold storage
• High islet graft potency
• Pretransplant islet culture
• Potent immunosuppression
• Posttransplant insulin treatment
• Minimizing diabetogenic side effects

Am J Transplantation 2004, and JAMA 2005
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Transplant Protocol 1
10,302 2,594 IE/kg
Am J Transplantation 2004
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Transplantation of Cultured Islets from
Two-Layer Preserved Pancreases in Type 1 Diabetes
with Anti-CD3 Antibody

• 4 of 6 recipients achieved insulin independence
  after single-donor islet transplantation
• Induction immunotherapy with the anti-CD3 mAb
  hOKT3g1 (Ala-Ala) may facilitate minimization of
  maintenance immunosuppression

Am J Transplantation 2004
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Long-Term Follow-Up
MN Protocol 1
Partial Function
Insulin Independence
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Feb 16, 2005
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JAMA Protocol RATG Etanercept Rapa
Tac?MMF
MN Protocol 2
Time Point of Subsequent Tx
Graft Failure
Feb 16, 2005
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Issues

• Mean D/R weight 101/60, BMI 34/23
• Mean IE/kg 7,200
• 8/18 isolations resulted in tx
• Donors lt50yrs, cold storagelt8hrs, 2-layer
  preservation, islet cultures, etarnercept peritx

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RATG Etanercept CsA RAD
MN Protocol 3
Hering BJ et al., WTC 2006
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Insulin independence after 11 transplant
19/22 (86) became insulin-independent 17/22
(77) off insulin with islets from 1 donor 19/22
(86) 3 U/d with islets from 1 donor
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• FDA
• License

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• Phase II Pilot and Phase III Licensure Clinical
  Trials
• Univ. of Minnesota, Miami, Pennsylvania, Alberta,
  and Uppsala

www.citisletstudy.org
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NIH Consortium for Clinical Islet
Transplantation(Miami, Minnesota, Penn, Alberta,
Uppsala)
Two Phase III Registration Trials
1. Islet-Transplant-Alone Trial
2. Islet-after-Kidney CMS Demonstration Project
Primary Endpoint Proportion of subjects with
HbA1c lt6.5 and no episodes of severe
hypoglycemia at 1 yr after initial transplant
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CIT-07 (Phase 3 ITA n48/6-12)
Primary Endpoint Proportion of subjects with
HbA1c lt6.5 and free of severe hypoglycemic
events at 1 yr after the first islet cell infusion
Sirolimus
-2 -1 0 1
2 10 365

Days after transplant
Donor Islet Isolation
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CIT-06 (Phase 3 IAK n65/12)
Primary Endpoint Proportion of subjects with
HbA1c lt6.5 and free of severe hypoglycemic
events at 1 yr after the first islet cell infusion
Tac-based Immunosuppr. (Tac-Rapa or Tac-MMF)

-2 -1 0 1
2 10 365

Days after transplant
Donor Islet Isolation
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Secondary Efficacy EndpointsAt 75 5 days
following the first infusion

• The proportion of insulin-independent subjects
• The percent reduction in insulin requirements
• HbA1c
• Mean amplitude of glycemic excursions (MAGE)1
• Glycemic lability index (LI)
• Clarke hypoglycemia awareness score
• Ryan hypoglycemia severity (HYPO) score
• Basal (fasting) and 90-min glucose and C-peptide
  derived from the mixed-meal tolerance test (MTT)
• Ryan ß-score
• C-peptideglucose creatinine ratio
• Acute insulin response to glucose (AIRglu),
  insulin sensitivity, and disposition index
  derived from the insulin-modified
  frequently-sampled intravenous glucose tolerance
  (FSIGT) test
• Glucose variability and hypoglycemia duration
  derived from the continuous glucose monitoring
  system (CGMS)
• Quality of life measures (DQOL, HSQ 2.0,
  Hypoglycemia Fear Survey-HFS)

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Inclusion CriteriaPatients who meet all of the
following criteria are eligible for participation
in islet transplant trials

• Male and female patients age 18 to 65 years of
  age.
• Ability to provide written informed consent.
• Mentally stable and able to comply with the
  procedures of the study protocol.
• Clinical history compatible with type 1 diabetes
  with onset of disease at lt 40 years of age and
  insulin-dependence for gt 5 years at the time of
  enrollment.
• Absent stimulated C-peptide (lt0.3ng/ml) in
  response to a mixed meal tolerance test (Boost 6
  ml/kg body weight to a maximum of 360 ml another
  product with equivalent caloric and nutrient
  content may be substituted for Boost) measured
  at 60 and 90min after the start of consumption.
• Involvement in intensive diabetes management
  defined as self monitoring of glucose values no
  less than a mean of three times each day averaged
  over each week and by the administration of three
  or more insulin injections each day or insulin
  pump therapy. Such management must be under the
  direction of an endocrinologist, diabetologist,
  or diabetes specialist with at least 3 clinical
  evaluations during the previous 12 months.

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Inclusion Criteria (Contd)Patients who meet all
of the following criteria are eligible for
participation in islet tx trials

• At least one episode of severe hypoglycemia in
  the past year defined as an event with symptoms
  compatible with hypoglycemia in which the subject
  required the assistance of another person and
  which was associated with either a blood glucose
  level lt 50 mg/dl 2.8 mmol/L or prompt recovery
  after oral carbohydrate, intravenous glucose, or
  glucagon administration).
• Reduced awareness of hypoglycemia as defined by a
  Clarke score of 4 or more and a HYPO score
  greater than or equal to the 90th percentile
  (1047) within the last 6 months prior to
  randomizationORMarked glycemic lability
  characterized by wide swings in blood glucose
  despite optimal diabetes therapy and defined by a
  glycemic lability index (LI) score greater than
  or equal to the 90th percentile (433
  mmol/l2/hwk-1) within the last 6 months prior to
  randomizationORA composite of a Clarke score
  of 4 or more and a HYPO score greater than or
  equal to the 75th percentile (423) and a LI
  greater than of equal to the 75th percentile
  (329) within the last 6 months prior to
  randomization.

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Critical Issues in Islet Tx

• Long-term results are disappointing, short-term
  results trail those of Pa Txs
• Primary study end-points must include
  insulin-independence

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5-Year Pancreas Graft Function
USA DD Primary Pancreas Transplants, 1/1/1988
12/31/2003
8/04
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542060-2069, 2005
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Insulin-independent islet allograft
survivalEdmonton Miami - Minnesota
n 118 1-yr survival 82
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Endocrine Function

• Islet transplants fail to release glucagon during
  hypoglycemia and do not restore epinephrine
  responses and symptom recognition. This indicates
  suboptimal hypoglycemic hormonal
  counterregulation, in contrast to pancreas
  transplants.

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Critical Issues in Islet Tx

• UNOS registry for transparency and accountability

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Islet Registries and Study Groups

• International Islet Transplant Registry (Giessen)
• Collaborative Islet Transplant Registry (CITR)
• Consortium for Islet Transplantation (CIT)
• Islet Cell Resource Program (ICR)

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CITR Annual Report Exhibits
CITR Annual ReportExhibitsPrepared byCITR
Coordinating CenterThe EMMES CorporationRockvill
e, MDSponsored byNational Institute of
Diabetes Digestive Kidney DiseasesNational
Institutes of HealthBethesda, MDDatafile
Closure April 3, 2006
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Number of Islet Transplant Programs Transplanting
and Number Reporting Information to CITR by Year
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Total Number of Islet Allograft Infusion
Procedures Performed in North America as Reported
to the Registryand Number Contained in the
Annual Report
The Islet Transplant Summary (ITS) questionnaire
is completed by all North American islet
transplant programs regardless of their
participation in the Registry. Of 42 North
American islet transplant programs polled, all
have provided this information through 2005.
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Total Number of Islet Allograft Infusion
ProceduresReceived Per Participant (All
Participants, N225)
81
Participants Insulin Status at Follow-upPost
First and Last Infusion
82
Participants Insulin Status at Follow-Up Post
Last Infusion by Total Number of Infusions
Received
83
Percent of Participants Ever Achieving Insulin
Independence
84
Critical Issues in Islet Tx

• SACs need to be revisited

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Organ Acquisition Issues

• Organ acquisition costs for DD Pa graft
  20-30,000 (irrespective if used for clinical tx
  or for research only)
• Only for IAK reimbursement by CMS (if within CIT)
• UNOS Pa committee charged by HRSA to increase
  donor pancreata utilization
• What to do about pancreata acquisition costs if
  the islet preparation is unsuitable for tx
  (variability among OPOs)?
• SAC same for whole organ vs. islet (cellular)
  txs? (different SACs for recovery of a heart vs.
  heart valves)

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Allocation Issues in Pancreas and Islet
Transplantation
87
Most deceased donor pancreases that are suitable
for beta-cell replacement are currently used as a
solid organ immediately vascularized graft.The
reason Islet isolation yield is variable and the
incidence of being insufficient to induce
insulin-independence is higher than the incidence
of technical failure of a pancreas allograft.
Integrated approach for Pa and Islet Tx tailored
to the need of individual patients
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Should Have a Common Waiting List for Pancreas
and Islet Transplant Candidates

• Stratified according to insulin requirements or
  donor BMI
• Examples
• Pancreas from a large donor, allocate first for
  islet transplantation to candidates with low
  insulin requirements
• Small or normal size donors allocate first for
  Immediately-vascularized organ transplantation to
  candidates with normal or high insulin
  requirements who have no contraindications to
  major surgery
• Candidates could be ranked by wait time, match,
  medical urgency, etc.

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Complications after transplant divided by donor
BMI
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OBESE DONORS ARE GOOD FOR ISLET ISOLATION
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Bottom Line

• -Pancreas TransplantHighly efficient but major
  surgery
• -Islet TransplantMinimally invasive but less
  efficient
• Do Islet Txs in Beta Cell Replacement candidates
  who would predictably become insulin-independent
  with a single donor using state-of-the-art
  isolation
• Do Px Txs in those who would predictably require
  re-transplants (multiple donors) for islets,
  unless candidate is willing to have long interval
  to achieve insulin-independence

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b-cell replacement therapy

• Growing demands
• Islet transplant preferable approach
• Eliminate surgical risks
• Less long-term complications
• Xenogeneic islet transplants could meet the
  demand of donor shortage

International pancreas transplant registry
(IPTR), Bretzel RG, 2004
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Areas of Improvements
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Five Factors that Determine Graft Survival

• Donor age and tissue quality
• Brain death
• Preservation and implantation injury
• Immune-mediated injury
• Stresses in the recipient environment

Halloran PF. Am J Transplant 2002 2 195-200
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240
r -0.536, P 0.004
220
200
180
160
140
Islet ATP Content (pmol/mg DNA)
120
100
80
60
40
20
10
20
30
40
50
60
70
Donor Age (yr)
99
Brain-Death is Associated with
Reduced Glucose-Stimulated and
Arginine-Stimulated Insulin Release in the
in-situ-Perfused Pancreas
Reduced b-Cell Survival Before Islet Isolation
Contreras JL et al. Diabetes 2004
100
Brain-Death is Associated with Decrease in Islet
Yields
Contreras JL et al. Diabetes 2004
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Islet Processing

• Progress in pancreas procurement, preservation,
  and processing will depend on the development and
  validation of reliable, preferably real-time
  assays of islet beta cell mass and potency
• Cellular composition (beta cells/kg)
• Oxygen consumption rate
• ATP

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Dual Chamber Oxygen Consumption Rate Apparatus
Small (210 mL) Stirred Chambers for Islets in
Suspension Custom Designed in Collaboration with
Instech Labs
Fiber optic cables
Spectrometer
Chamber plug
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Innate Immunity Posttransplant
Macrophages NKT Cells Neutrophils Endothelial
Cells Platelets
Donor Factors Hypoxia Hyperglycemia
NO, ROI Cytokines Complement
PNF Islet Death Adaptive Immunity
ROS
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Research in Islet Transplantation

• Alternative source
• Xenotransplant
• Stem cell
• Islet culture/expansion

• Immunotherapeutic strategies
• New immunosuppressive protocols
• Transplant tolerance
• Genetic modification, local factors...

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Minnesota BSM ?-CD154 RAD FTY720
LFM Emory/AB BSM ?-CD154 Rapa LEA29Y
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Pancreas Transplants by Category
Pancreas Transplants, U of MN 12/66 11/ 1/2004
PTA 472 (53 LRD)
PAK 634 (31 LRD, 1 LURD)
SPK 646 (30 LRD, 7 LURD)
SPL 1
TOTAL 1753
113
Estimated Half-Lives months
114
OUTCOME BY AGE AT DIAGNOSIS
115
Age at Diabetes Onset
USA Primary Pancreas Transplants 1/1/2000 6/
6/2004
116
Causes Px Graft Failure
USA DD Primary Pancreas Transplants 1/1/2000
12/31/2005

SPK
PAK
PTA
0-3 3-12 gt 12
0-3 3-12 gt 12
0-3 3-12 gt 12
Months Posttransplant
3/06
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Pancreatectomy with Islet Autotransplant

• Can it help us interpret islet allograft results?

118
Chronic Pancreatitis Etiology

• Idiopathic 59 (43)
• Alcohol 21 (15)
• Divisum 17 (13)
• Familial 15 (11)
• Biliary 14 (10)
• Iatrogenic 4 (3)
• Cystic Fibrosis 3 (1)
• Trauma 2
• Congenital cyst 1

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Pancreatectomy and islet autotransplantation

• The main objective is to relieve pain by the
  pancreatectomy and withdraw patient from
  narcotcis
• Prevention or amelioration of diabetes is a
  bonus, but beta cell preservation should nearly
  always be attempted.

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Islet Isolation
1977 2004 136 Cases U MN
122
Metabolic control

• Complete pancreatectomy (73 pts)
• Islet transplanted lt 2000 IEQ/kg
• Insulin dependent (22 pts, 30)
• Islet transplanted gt 2000 IEQ/kg
• Insulin independent (34 pts, 47)
• Intermittently insulin-treated (17 pts, 23)

1977 2004 136 Cases U MN
123
Ryan EA Diabetes 542060-2069, 2005
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Islet Transplantation At the Crossroads
Short-term
Long-term
Incremental Steps
Innovation
Anecdotal Success
Vital Therapy
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SiteSafetySource
Islet Transplantation At a Crossroads
Hepatic
Extrahepatic
Suppression
Regulation
Human
Porcine
126
All donors with BMI gt28 are first offered to
islet candidates ranked highest on the combined
beta cell replacement (BCR) list
127
Five Year Kaplan-Meier Survival Curves (Insulin
Independence from time of first transplant)
Survival ()
128
Living Donor Kidneys in PAK
USA Primary DD Pancreas Transplants 1/1/1988
12/31/2005
3/06
129
Number of Tx Centers and Number of Txs
USA Pancreas Transplants 1/1/1988 12/31/2005
Transplants
3/06
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Single-donor islet transplants will

• Promote overall availability of islet
  transplantation
• Reduce costs per patient by 75,000
• Allow ultimate validation of islet potency assays
  
• Facilitate evaluation of immunotherapeutic
  protocols
• Promote FDA approval and insurance coverage
• Promote donor pancreas allocation to islet
  patients

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Patients with Type II Diabetes
USA Pancreas Transplants 1/1/1994 9/ 1/2005
10/05
133
SPK Pancreas Graft Function
USA DD Primary Pancreas Transplants, 10/1/1987
6/ 6/2004
Year HLmos
8/04
134
Risk FactorsforPancreas Graft Loss
135
Hazard Ratio for SPK Pancreas Graft Loss
USA DD Primary Pancreas Transplants, 1/1/2000
6/6/2004
136
1-Year Pancreas Graft Function
USA DD Primary Pancreas Transplants 1/1/2000 6/
6/2004
8/04
137
1-Year Pancreas Graft Rejection Rate
USA DD Primary Pancreas Transplants 1/1/2000
6/ 6/2004
8/02
138
IMMUNOSUPPRESSIVEProtocols
139
SPK Induction Antibody Therapy
USA DD Primary Pancreas Transplants 1/1/2000
12/31/2005
3/06
140
Major Immunosuppressive Protocols
USA Primary DD Pancreas Transplants 1/1/2000
12/31/2005
3/06
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Operative Technique

• Patient placed in right lateral decubitus
  position as per standard laparoscopic nephrectomy
• Supine position for pancreatectomy
• 6-cm periumbilical incision for hand assist
  Gelport? (Applied Medical, Rancho Santa
  Margarita, CA)
• 2 12-mm ports in mid clavicular and left
  anterior axillary line

Gelport
Operative port
Camera Port
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Operative Technique
Mobilization of the pancreas
Division of splenic artery
Division of splenic vein
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Operative Technique
Division of pancreatic neck
Pancreatic remnant
145
Port sites and midline incision 3 weeks post
laparoscopic distal pancreatectomy and left
nephrectomy. A midline incision for Gelport
placement, B 12-mm camera port, C- 12-mm
operative port
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Single-donor islet transplantation
Donor selection Islet processing
Pretransplant Islet Culture
Peritransplant Mgmt Contd
Young donors
IGF-1
Peritransplant Recipient Therapy
Heparin 70 U/kg PTT 50-60 48 hrs Enoxiparin 7
days Insulin 1st 30 days
lt8 hrs
152

• Safety

153
Adverse events

• Serious, unexpected, protocol-related 0/24
• Serious 11 (neutropenia 7,
  cholecystitis 2, ovarian cyst 1, rash 1,
  fever post orthopedic surgery 1)
• Severe
• Transient neutropenia 11/24
• Transient anemia 3/24
• Transient LFT elevations 4/24
• Pneumonia 1/24

No procedural complications
No deaths, no cancers, no PTLD, no CMV
154
Waiting List Deaths For Candidates Waiting
ForAll Organs Except Kidney and Liver (No
Intestine) 2003 - 2005
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www.citisletstudy.org
157

• Phase II Pilot and Phase III Licensure Clinical
  Trials
• Univ. of Minnesota, Miami, Pennsylvania, Alberta,
  and Uppsala

158
CIT-07 (Phase 3 ITA n48/6-12)
Primary Endpoint Proportion of subjects with
HbA1c lt6.5 and free of severe hypoglycemic
events at 1 yr after the first islet cell infusion
Sirolimus
-2 -1 0 1
2 10 365

Days after transplant
Donor Islet Isolation
159
CIT-03 (Phase 2 ITA n20/8-12)
Primary Endpoint The proportion of
insulin-independent subjects at day 75 ( 5 days)
following the first islet cell infusion
Deoxyspergualin
-2 -1 0 1
2 10 365

Days after transplant
Donor Islet Isolation
160
CIT-06 (Phase 3 IAK n65/12)
Primary Endpoint Proportion of subjects with
HbA1c lt6.5 and free of severe hypoglycemic
events at 1 yr after the first islet cell infusion
Tac-based Immunosuppr. (Tac-Rapa or Tac-MMF)

-2 -1 0 1
2 10 365

Days after transplant
Donor Islet Isolation
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162
Preclinical Islet Xenotransplantation
Streptozotocin
Intraportal infusion of 25,000 IE/kg
Adult, genetically unmodified donor pig
Rhesus/ Cynomolgus macaque
Immunosuppression
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March 2006
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Pig-to-NHP islet xenotransplantation
BSMFTY720RADABI793LFM
BSMFTY720RADABI793
BSMFTY720RAD
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Group B BSM FTY720 RAD ABI793
University of Minnesota
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Islet Transplantation At the Crossroads
August 23, 2006
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Islet Transplantation At the Crossroads
Short-term
Long-term
Incremental Steps
Innovation
Anecdotal Success
Vital Therapy
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SiteSafetySource
Islet Transplantation At a Crossroads
Hepatic
Extrahepatic
Suppression
Regulation
Human
Porcine
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INSULIN INDEPENDENCE ALL SUBJECTS
l Subjects maximum posttx time-point reached
while still insulin independent
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Long-term normoglycemia and protection from
severe hypoglycemia on small doses of exogenous
insulin (2 to 10 units/day)
Ryan EA Diabetes 542060-2069, 2005
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Important Exclusion CriteriaPatients who meet
any of these criteria are not eligible for
participation in the study

• BMI gt27 kg/m2 or patient weight 50kg.
• Insulin requirement of gt 0.8 IU/kg/day or lt 25
  U/day.
• HbA1c gt10.
• Untreated proliferative diabetic retinopathy.
• Blood Pressure SBP gt160 mmHg or DBP gt100 mmHg.
• Measured GFR of lt70 ml/min/1.73 m2 for females
  and lt80 ml/min/1.73 m2 for males.
• Presence or history of macroalbuminuria
  (gt300mg/d).
• Panel-reactive anti-HLA antibodies gt20 by flow
  cytometry.

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Protocol for Phase III Trial
Feb 16, 2005
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Secondary Efficacy EndpointsAt 365 50 days
following the first infusion

• The proportion of insulin-independent subjects
• The percent reduction in insulin requirements
• HbA1c
• MAGE
• LI
• Clarke score
• HYPO score
• Basal (fasting) and 90-min glucose and C-peptide
  (MTT)
• ß-score
• C-peptideglucosecreatinine ratio
• QOL (DQOL, HSQ 2.0, HFS)
• The proportion of subjects receiving a second
  islet infusion
• The proportion of subjects receiving a third
  islet infusion

174

• The overall rate of SH was 1.3 episodes/patient
  year and episodes were reported by 37 of
  patients
• 5 of subjects accounted for 54 of all episodes
• In a subgroup selected to be similar to the DCCT
  cohort, the rate of SH was 0.35 episodes/ patient
  year
• Severe hypoglycemia remains a significant
  clinical problem in type 1 diabetes

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UNOS Data

• of registrations for pa/kd tx (9/16)
  2487
• of registrations for pa tx
  297
• of pa/kd txs (2005)
  903
• of pa txs
  541

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• 5 of patients die annually while waiting for a
  pancreas/kidney transplant.
• The number of patients on the waiting list is
  more than twice as high as the number of
  transplants. The waiting list continues to grow
  by gt15 annually.
• Morbidity and mortality are higher and quality of
  life is lower for diabetic (vs. non-diabetic)
  patients on dialysis. Transplant priority is not
  given to diabetic patients.

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Pancreas TransplantsfromLiving Donors
178
Long Term Outcome
UNIVERSITY OF MINNESOTA , 7/1978 6/2004
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ID Twin Pancreas Transplant Experience
UNIVERSITY OF MINNESOTA, 1/79 - 5/02
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Caveats from Recurrence of Disease Story

• The fact that immunosuppression prevents means
  that it should also prevent progression in de
  novo autoimmune diabetes if applied early enough.
• Immunosuppression done late does not allow beta
  cell regenerationno examples in diabetic kidney
  transplants alone immunosuppressed for up to
  decades

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Centers Participating in CITR (Coll. Islet Tx
Registry)
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Allocation

• Until we have an unlimited source of islets (e.g,
  xenografts are succesful), or until islet and
  pancreas allo-transplantation have equal
  efficiency in inducing insulin-independence in
  the recipients, we must link organ allocation to
  the two BCR techniques by an algorithm that
  allows the maximum number of recipients to become
  insulin-independent while minimizing the
  magnitude of the surgery in as many as possible.

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ACRGlu IE Txd/Donor Age
1.8
r 0.914 P 0.004
1.6
1.4
1.2
1.0
ACRGlu (ng/mL)
0.8
0.6
0.4
0.2
0.0
5000
10000
15000
20000
25000
IE Transplanted / Donor Age (yr)
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Stresses in the Recipient Environment
HIGHER CONCENTRATION OF IS DRUGS
SUBOPTIMAL OXYGEN LEVELS / REVASCULARIZATION
TOXIC PRODUCTS FROM GI ENDOTOXINS
PRO-INFLAMMATORY MICROENVIRONMENT
CHRONIC IMPAIRMENT OF ISLET FUNCTION
EARLY GRAFT LOSS PNF - IBMIR
CHALLENGES RELATED TO BIOPSIES AND NON
RETRIEVABILITY
GLUCO AND LIPOTOXICITY
POTENTIAL RISK FOR DISSEMINATED INTRAHEPATIC
INFECTIONS OR CANCER
HIGH GLUCAGON ALTERED a-CELL FUNCTION
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"I like pigs. Dogs look up to us, cats look down
on us, but pigs see us as their equals."
-Winston Churchill
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• Replace insulin producing cellsCAD, LD, XD,
  precursor cell-derived islets
• Restore self-tolerance andRegenerate islet beta
  cells in native pancreas
• Retire to a decent place

188
Minimally invasive surgery is desirable.For BCR,
the proportion of cases done by the two
techniques (pancreas vs. islet transplantation)
is influenced by their relative efficiency.
Currently pancreas is dominant.
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