Current Status of Pancreas Versus Islet

TransplantationPros and Cons

UCSF Mini-Medical SchoolNovember 2019

Peter Stock MD PhDDepartment of SurgeryUniversity of California

San Francisco

IMPROVEMENTS IN RESULTS:

PANCREAS TRANSPLANTS

ISLET TRANSPLANTS

LONG TERM SUCCESS:

INSULIN INDEPENDENCE

NORMALIZATION OF HGB A1C

ABROGATION OF SECONDARY COMPLICATIONS

Rationale for ß-cell therapyRationale for ß-cell therapy

Relative Risk

15

13

11

9

7

5

3

1HbA1c, %

7 8 9 10 11 12

Neuropathy

Nephropathy

Retinopathy

DCCT Research Group. N Engl J Med. 1993;329:977-986.

Relationship of HbA1c to Risk of Microvascular Complications

Relationship of HbA1c to Risk of Microvascular Complications

John D. Pirsch, Jon S. Odorico & Hans W. Sollinger

Indications for Pancreas TxIndications for Pancreas Tx Diabetes Mellitus (T1 or T2) with:

Renal failure requiring simultaneous kidney transplant (SPK). 75-80%Functioning kidney transplant already on

immunosuppression (PAK). 5-10%Brittle diabetes with hypoglycemic

unawareness (PTA). 10-15%

IPTR/UNOS

International Pancreas Transplant Registry

PTR/UNOSIPTR/UNOSI

5-Year Unadjusted Patient SurvivalUSA Primary DD Pancreas Transplants, 1 /1/1982 – 12/31/2018

PTR/UNOSIPTR/UNOSI

5-Year Pancreas/Kidney Graft FunctionUSA Primary DD Pancreas Transplants, 1 /1/1982 – 12/31/2018

UCSF Evolution in Immunosuppression for Pancreas/Kidney Transplantation

UCSF Evolution in Immunosuppression for Pancreas/Kidney Transplantation

1989-Current (>500 pancreas tx)ERA 1-3 : OKT3 Induction

ERA 4 : Thymoglobulin InductionMaintenance Incidence of rejection of either

kidney or pancreasERA 1: CSA/AZA/PRED 80%ERA 2: CSA/MMF/PRED 50%ERA 3: TACROLIMUS/MMF/PRED 15-20%

ERA 4: STEROID AVOIDANCE 10-15%Thymoglobulin Inductionlow dose tacrolimus/sirolimus/MMF

Typical Demographics for PancreasTransplant Recipients

Typical Demographics for PancreasTransplant Recipients

Recipients:Primary TxNon-highly sensitizedType 1 diabetic recipients <55 years of age BMI <30

Can we push the limits without impacting outcomes?

PTR/UNOSIPTR/UNOSI

1 Yr Pancreas Graft Function by Recip. Age

70

75

80

85

90

95

100

PAK

PTA

SPK

P<0.0001

P<0.0001

P<0.0001

20-29 30-39 40-49 50-59 60-69

USA Primary Pancreas Transplants in Type 1 DM 1/1/2010 – 12/31/2016

Age at Transplant [Yrs]

First World Consensus Conference on Pancreas TransplantationPTR/UNOSI05/17

US Pancreas Transplants 1/1/1996 – 12/31/2018

Patients with Type 2 Diabetes 

PTR/UNOSI

SPK Patient Survival by Diabetes TypeUSA Primary DD SPK Transplants 1/1/2013 – 12/31/2017

P = 0.49

DM Type n 1Yr Surv.Type 1 3,143 97.5% Type 2 537 96.8%

PTR/UNOSI

SPK Pancreas Graft Function by Diabetes Type

USA Primary DD SPK Transplants 1/1/2014 – 12/31/2018

DM Type n 1Yr Surv.Type 1 3,143 89.7% Type 2 537 88.3% P = 0.25

PTR/UNOSI

SPK Kidney Graft Function by Diabetes Type

USA Primary DD SPK Transplants 1/1/2014– 12/31/2018

P = 0.71

DM Type n 1Yr Surv.Type 1 3,143 96.1% Type 2 537 95.5%

PTR/UNOSIPTR/UNOSI

African American RecipientsUSA Primary DD Pancreas Transplants 1/1/1994 – 12/31/2018

2/16

0

5

10

15

20

25

30

35%

Transplant Year

PAK

PTA

SPK

PTR/UNOSI

SPK (n=7) and PAK (n=1)in people with Type 1 diabetes,

ESRD, and HIV infected

SPK (n=7) and PAK (n=1)in people with Type 1 diabetes,

ESRD, and HIV infected Standard immunosuppression for all SPK recipients

Thymo-induction, maintenance with TAC, MMF, Pred

Mean follow-up >4 years

Patient and Graft survival 100% at 1 and 3 years

2 deaths at 4 and 7 years secondary to cardiac events

2 pts with BK viremia – resolved with IS reduction

All recipients maintained insulin independence follow pancreas tx

THE PRO’S OF SUCCESSFUL PANCREAS TRANSPLANT

THE PRO’S OF SUCCESSFUL PANCREAS TRANSPLANT

Single organ tx

Euglycemia without the need for exogenous insulin

Prevents hypoglycemia

Normalizes HgbA1c

Improves patient quality of life

Reverses peripheral neuropathy

Prevents recurrent diabetic nephropathy (kidney damage) in transplanted kidneys

May prolong life

CONS OF PANCREAS TRANSPLANTATION:Cardiovascular risks

Why Transplant Islets?Are they replacing whole

organ transplants?

CONS OF PANCREAS TRANSPLANTATION:Cardiovascular risks

Why Transplant Islets?Are they replacing whole

organ transplants?

Safer, Simpler Procedure

than Pancreas Transplant

Graft Survival (insulin independence)Islet Transplant Registry

• 87%Edmonton

Ryan EA Diabetes 54:2060-2069, 2005

5-Year Insulin Independence5-Year Insulin IndependenceAuthor Center Immunosu-

ppressionReference Year 5-Year

Hering et al25

Minnesota Anti-CD3, Thymo, Etanercept

AJT 2012 50%

Shapiro et al26

Edmonton Thymo, Tacro, MMF

CJD 2012 79%

Szot et al UCSF Thymo/Efa or Bela, SRL+ MMF

ATC 2012 80 % (4 years)

Berney et al37

GRAGIL Basiliximab, SRL+ Tacro

Diabetes Care

2015 75%

Qi et al38 UIC Daclizumab, SRL + Tacro, +/-

Etancercept/Exenatide

ActaDiabetol

2014 60%

Pattou et al39

Lille Daclizumab, Basiliximab,Tacro + SRL

AJT 2018 58%

Islet recipient 3 years post transplant

modified from Vanthygem JCEM 2012

Glu

cose

(mg/

dL)

Glu

cose

(mg/

dL)T1DM patient on

intensive insulin tx

TitleTitle

crossover study (6 yrs)

Retinopathy progression

Nephropathy ∆GFR (ml/min/BSA/yr)

NeuropathyNerve conduction velocity (m/s)

Insulin 10/82 eyes -3.53 -0.0607

Islet tx 0/51 * -1.49 * 0.1179

modified from Thompson Transplantation 2012

Limitations of CNI and Steroid-Based IS in Islet Transplant

Limitations of CNI and Steroid-Based IS in Islet Transplant

Belatacept (Nulojix)Belatacept (Nulojix)

Belatacept (CTLA4‐Ig)IgG1‐Fc/CTLA4 fusion protein 

binding CD80/86Competitive antagonist of 

CD28 costimulationImproved long‐term outcomes 

(43% reduction of death or graft loss at 7yrs) with BELA in renal transplant recipients relative to cyclosporine.

Efalizumab (Raptiva)Efalizumab (Raptiva)

Efalizumab (anti‐LFA‐1)CNI‐free ISanti‐CD11α (LFA‐1)- Prevents T‐cell trafficking and 

activationPrevious efficacy 

demonstrated in kidney transplant recipients

Linked with PML in several psoriasis patients (4/40,000); withdrawn from market 5/2009

0 365 730 1095 1460 1825 2190 2555 2920 3285 3650

EFA-5EFA-4EFA-3EFA-2EFA-1

BEL…BEL…BEL…BEL…BEL…

Ten Year Outcomes: Insulin Independence

Ten Year Outcomes: Insulin Independence

Time From Initial Transplant

Tx #2 (Day 442)

Tx #2 (Day 400)

Panc Tx

Panc Tx

Tx #2 (Day 689)

Tx #2 (Day 750)

Tx #2 (Day 445)

Panc Tx

HbA1c Levels after Islet TransplantationHbA1c Levels after Islet Transplantation

4.0

5.0

6.0

7.0

8.0

9.0

10.0

0 30 75 120 180 270 365 455 545 730

Time from Transplant (d)

HbA

1c (%

)

EFA-1

EFA-2

EFA-3

EFA-4

EFA-5

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

0 30 75 120 180 270 365 455 545 730

Time from Transplant (d)

HbA

1c (%

)

BELA-1

BELA-2

BELA-3

BELA-4

BELA-5

EfalizumabBelatacept

C-peptide Responses to a Mixed Meal Tolerance Test

C-peptide Responses to a Mixed Meal Tolerance Test

0

1

2

3

4

5

6

7

8

9

-10.0 -5.0 0.0 15.0 30.0 60.0 90.0 120.0

Time (minutes)

C -

Pept

ide

(ng/

ml) EFA 1

EFA 2

EFA 3

EFA 4

EFA 5

0

1

2

3

4

5

6

7

8

9

10

-10.0 -5.0 0.0 15.0 30.0 60.0 90.0 120.0

Time (minutes)

C -

Pept

ide

(ng/

ml) BELA 1

BELA 2

BELA 3

BELA 4

BELA 5

EfalizumabBelatacept

Glomerular Filtration Rates after Islet Transplantation

Glomerular Filtration Rates after Islet Transplantation

0

20

40

60

80

100

120

140

0 180 365 0 180 365Time from Transplant (days)

GFR

(ml/m

in/1

.73m

2 )

Belatacept Efalizumab

T Reg Kinetics in Islet RecipientsT Reg Kinetics in Islet Recipients

0

10

20

30

40

50

60

70

0 30 60 90 120 150 180 210 240 270 300 330 360

Time from Transplant (days)

% F

oxP3

+ of

CD

4+ T

cel

ls

EFA-1EFA-2EFA-3EFA-4EFA-5

0

10

20

30

40

50

60

70

0 30 60 90 120 150 180 210 240 270 300 330 360

Time from Transplant (days)

% F

oxP3

+ of

CD

4+ T

cel

ls

BELA-1BELA-2BELA-3BELA-4BELA-5

BelataceptEfalizumab

EFA-4: A Case of Operational Tolerance?

EFA-4: A Case of Operational Tolerance?

Long‐term insulin independence without immunosuppression Single islet transplant, insulin‐independent for 10 years.  ATG induction, on EFA for 15 months, maintained on 

sirolimus and MMF after EFA cessation.- Stopped all IS Sept 2012 following an episode of PTLD Tregs increased to 68% one month after transplant No detectable T‐cell response until 24 months, when both 

effectors and Tregs re‐expanded. Remains insulin‐independent without immunosuppression, 

despite demonstrable alloreactivity in vitro.

Beta Cell Replacement for PreuremicType 1 Diabetic Patients

Moassesfar, Stock, Posselt et al, 2016, AJT

Islet transplantation Whole pancreas transplantation

COST : PANCREAS TX ($ 134,748.08)ISLET TX ($ 138,872.27)

Beta Cell Supply is Severely Limited

Bruin, Rezania, KiefferScience Translational Medicine Dec 2015

From Kushner et al. Cell Stem Cell 2014

Engraftment Site for stem cell derived beta cell clusters

Potential Engraftment Sites

OmentumIntramuscular

Liver

SUBCUTANEOUS/INTRAMUSCULAR

Massive rejection-independent loss of islets

KC SQ

d0

d7

Luciferase‐expressing mouse isletsin syngeneic recipients

0

20

40

60

80

100

0 5 10 15 20%BLI o

f day 0

days

Kidney capsuleSubcutaneous

Faleo G, Tang Q

Stem cell-derived beta cells are also vulnerable

Russ, Hebrok et al EMBO 2015

Faleo G, Tang Q

Faleo G, Tang Q et al

Stem cell-derived beta cells are also vulnerable

KC SQ

d0

d7

Russ, Hebrok et al EMBO 2015

0

20

40

60

80

100

0 5 10 15 20

%BLI o

f day 0

days

Kidney capsuleSubcutaneous

Faleo G, Tang Q et al

Stem cell-derived beta cells are also vulnerable

KC SQ

d0

d7

Russ,Hebrok et al EMBO 2015

0

20

40

60

80

100

0 5 10 15 20

%BLI o

f day 0

days

Kidney capsuleSubcutaneous

0

20

40

60

80

100

120

0 5 10

% BLI

Days after Transplant

SQ – nakedSQ ‐ encapsulated

Faleo G, Tang Q et al

Making the Desert

Bloom….• Oxygenation• Nutrients• Pancreas-like niche• 3-dimensional

Scaffold• Parathyroid Tissue

Adult human islet: Minimal mass leads to reversal of diabetes in SQ

1000 human IEQ, 1/4 hPTG

Increased viability of Stem Cell Derived Beta Cell Cluster with

Parathryoid Gland Intra-Muscular (IM)

(5/5) NSG mice, 200 SCIPC’s; hPTG (1/4 gland) per mouse

Co-transplantation of Stem Cell Derived Beta Cell Clusters with PTG leads to diabetes reversal in IM after

6 weeks

0100200300400500600700800

Week4

Week6

Week10

Week12

Hum

an C

-pep

tide

(pg/

ml)

SCIPC SCIPC+PTG

(5/5) NSG mice, 1000 SCIPC clusters, 1/4 hPTG

InsulinDAPI

Translational Opportunities FACILITATED BY SUCCESSFUL

SUBCUTANEOUS/INTRAMUSCULAR SITE

- Allotransplantation

- Auto-islet transplantation

- Stem-cell based transplantation

- Xenotransplantation

PTR/UNOSIPTR/UNOSI

P < 0.0001

Waitlist Survival for Diabetic Patients USA Wait-List for Primary DD Transplants, 1/1/2005 –12/31/2018

ß‐cell replacement algorithm in ESRD based on current state of the art*

Type 1 DM with ESRD

Low insulin requirement/small 

habitus

Islet or pancreas transplant

High insulin requirement/large 

habitus

Low CV risk Pancreas transplant

High CV risk Consider islet transplant?

*2018; algorithm will change pending availability of unlimited ß‐cell source and improved engraftment sites

ß‐cell replacement algorithm based on current state of the art in preuremic

patients*

Preuremic type 1 DM

Life‐threatening complications (e.g. 

severe hypoglycemia)

High CV risk Islet transplant?

Low CV risk/small habitus

Islet or pancreas transplant

No life‐threatening complications

Continue medical management

*2018; algorithm will change pending availability of unlimited ß‐cell source and improved engraftment sites