Funding NIH/NIDDK; Beta-Cell Biology Consortium Larry L. Hillblom - - PDF document

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Funding NIH/NIDDK; Beta-Cell Biology Consortium Larry L. Hillblom - - PDF document

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Options for Cell Replacement in Diabetes Michael German MD Division of Endocrinology Department of Medicine UCSF Funding NIH/NIDDK; Beta-Cell Biology Consortium Larry L. Hillblom Foundation The Leona M. and Harry B. Helmsley Charitable

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Options for β Cell Replacement in Diabetes

Michael German MD Division of Endocrinology Department of Medicine UCSF NIH/NIDDK; Beta-Cell Biology Consortium Larry L. Hillblom Foundation The Leona M. and Harry B. Helmsley Charitable Trust Nora Eccles Treadwell Foundation Juvenile Diabetes Research Foundation American Diabetes Association Neuroendocrine Tumor Research Foundation Justine K. Schreyer Endowed Chair in Diabetes Research Iacocca Family Foundation Stock in Viacyte, Inc. Patents on Nkx2.2, Nkx6.1, Neurog3, Rfx6 and β cell production

Disclosure Funding

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Patient History

58yo woman referred for management of Type 1 Diabetes Mellitus. Diabetes history:

  • Dx at age 13, presented with DKA.
  • No family history of T1DM.
  • Treated initially with BID insulin, started

multiple injections in her 20’s, pump in her 40’s, back to multiple injections in 50’s. Currently Humalog and Lantus ~22 u/day. >6 FSBG/day.

  • Last HbA1C 8.0

Patient History

Complications: Developed neuropathy, retinopathy, microalbuminuria in 40’s. Over the past decade, increasing blood glucose fluctuations, serious hypoglycemic events, hypoglycemia unawareness. Meds: Insulin, HCTZ, Lisinopril Other: Hypertension, Graves’s disease at age 37

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Patient History

Exam: Ht: 5’ 5” Wt: 122 BMI: 20.4 BP: 117/68 P: 96 HEENT: retina: photocoagulation scars neck: mild thyromegaly Neuro: loss of sensation to 10g monofilament toes and plantar foot bilaterally

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β Cell Replacement for Type I Diabetes

  • Insulin Injection:
  • Multiple injections
  • Pump
  • CGM
  • Closed loop (in trials)
  • Transplant
  • Pancreas Transplant
  • Islet Transplant
  • Stem Cell Transplant
  • β Cell Regeneration

Pancreas Transplant

  • Simultaneous Pancreas/Kidney (SPK)
  • Pancreas after Kidney(PAK)
  • Pancreas Transplant Alone (PTA)
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John D. Pirsch, Jon S. Odorico & Hans W. Sollinger

1-Year Pancreas/Kidney Graft Function

USA Primary DD Pancreas Transplants, 10/1/1982 – 12/31/2014

2/15

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5-Year Pancreas/Kidney Graft Function

USA DD Primary Pancreas Transplants, 1/1/1984 – 12/31/2014

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UCSF Evolution in Immunosuppression for Pancreas/ Kidney Transplantation

1989-Current (n=462) ERA 1-3 : OKT3 Induction ERA 4 : Thymoglobulin Induction

Maintenance Incidence of rejection of either kidney or pancreas ERA 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 Induction low dose tacrolimus/ sirolimus/MMF

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Effect on Secondary Complications

✦ Difficult to demonstrate an impact on disease

progression because patients often present with far advanced disease.

✦ Progression of retinopathy halted. ✦ Progression of nephropathy halted; some

improvement in pathologic changes.

✦ Some reversal of neuropathy: Peripheral >

Autonomic.

✦ Reduced hypoglycemia.

Effect on Quality of Life

✦ More positive perception of health. ✦ Less pain. ✦ More flexibility. ✦ Greater ability to function socially. ✦ Patients with failed grafts return for

retransplantation.

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Worldwide Pancreas Transplants

Pancreas Transplants 12/16/1966 – 12/31/2014

■ USA:

n = 29,128

■ Non US

n = 19,164

Why Are Transplant Rates Decreasing?

✦ Decreased/delayed nephropathy ✦ Improvements in insulin delivery technologies ✦ Increased BMI of recipients ✦ Increased BMI, age and DM in donors

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Why Transplant Islets? Are They Replacing Whole Organ Transplants?

Safer, Simpler Procedure than Pancreas Transplant

Graft Survival (insulin independence)

Islet Transplant Registry

  • 87%

Edmonton

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Naftanel, M. A. & Harlan, D. M. Pancreatic islet

  • transplantation. PLoS medicine 1, e58; quiz e75, doi:

10.1371/journal.pmed.0010058 (2004). Illustration by Giovanni Maki

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Results: HbA1c

Ryan EA Diabetes 54:2060-2069, 2005

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The Islet Transplant Experiment: Time for a Reassessment

  • J. S. Bromberg, B. Kaplan, P. F. Halloran and R. P. Robertson

American Journal of Transplantation 2007; 7: 2217–2218 Blackwell Munksgaard

Publication of the initial results of the Edmonton protocol in 2000 (1) raised hopes that many of the technical and immunologic hurdles of islet transplantation had finally been solved and that a new era for the treatment and cure of type 1 diabetes had arrived. Unfortunately, while shortterm results utilizing this specific protocol were repeatedby other groups around the globe, long-term follow-up revealed that islet transplantation with this particular protocol is far less successful than originally hoped (2,3). Thus, although 5 years after transplantation 85% of recipients had measurable plasma C-peptide, well-controlled HbA1c levels, significant diminution in amount of daily insulin required, and virtually no clinical hypoglycemia (3), only 10%

  • f patients experienced freedom from exogenous insulin use. While this still may

represent partial success in alleviating the debilitating symptoms that brought them to islet transplant in the first place, such a claim needs to ultimately be established in a controlled trial, like other medical advances. Moreover, toxicities from the calcineurin inhibitors combined with sirolimus used for immunosuppression produced worrisome trends in renal function (4). Given continued insulin dependence, the shortage of donor organs, the complications of immunosuppression, and the great expense of this procedure, sober reassessment of the clinical applicability of this protocol and particular experiment is needed.

✦ Rejection? ✦ Autoimmunity? ✦ Drug toxicity? ✦ No precursor cells?

Decay in Islet Function

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✦ Used for treatment of chronic pancreatitis, benign

pancreatic tumor, trauma.

✦ Low rates of DM immediately post surgery (~50%)

and long term, despite low islet yields.

✦ Pancreas transplant post pancreatectomy can also

prevent exocrine deficiency, but requires donor pancreas and immunosuppression.

✦ Therefore, allo- and/or autoimmunity are the cause

  • f long term failure of islet transplants for T1DM.

Total Pancreatectomy and Islet Autotransplantation (TPIAT)

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Better outcome with more aggressive induction immunosuppression

Centers with 5-Yr Insulin Independence ≥ 50%

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Costimulation/Adhesion Blockade

Vincenti, AJT 2002

Efalizumab (Raptiva)

LEA29Y

(Belatacept, CTL4-Ig)

  • ­‑ ¡Used ¡successfully ¡in ¡kidney ¡(both) ¡and ¡liver ¡transplanta8on ¡(belatacept) ¡

¡-­‑ ¡Allow ¡reduc8on ¡of ¡Calcineurin ¡inhibitors ¡w/o ¡increased ¡rejec8on ¡

¡

Adverse ¡Effects ¡ ¡-­‑ ¡Both ¡increase ¡risk ¡of ¡Post-­‑transplant ¡lymphoprolifera8ve ¡ ¡ ¡ ¡ ¡ ¡ ¡disorder ¡(PTLD) ¡if ¡used ¡at ¡high ¡doses ¡ ¡ ¡-­‑ ¡Both ¡increase ¡risk ¡of ¡Progressive ¡mul8focal ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡leukoencephalopathy ¡(PML, ¡fatal) ¡ ¡ ¡-­‑ ¡Rap8va ¡taken ¡off ¡market ¡5/09 ¡(4 ¡cases ¡PML/40,000pts) ¡

¡

Immunosuppressive Protocols

¡ ¡

SIROLIMUS (Target trough 8-12 ng/L) (substitute mycophenolate if not tolerated) EFALIZUMAB 1 mg/kg/wk 0.5mg/kg/wk Drug withdrawn in all pts on May, 2009 ATG *

  • 2

+2 +4 +7 10 28 90 180 27 365

1yr +90 1yr +180 1 yr +270 2 yr 2yrs +90 2 yrs +180 2 yrs +270 3 yrs

SIROLIMUS (Target trough 8-12 ng/L) (substitute mycophenolate if not tolerated) Belatacept (10mg/kg/mo) 5mg/kg/mo 5mg/kg/2mos ATG *

  • 2

+2 +4 +7 10 28 90 180 27 365

1yr +90

1yr

+180 1 yr +270 2 yr 2yrs +90 2 yrs +180 2 yrs +270 3 yrs

Solumedrol Days relative to Transplant Days relative to Transplant Solumedrol

Efalizumab Belatacept

Txp Txp

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Graft Function in EFA and BELA Treated Patients

365 730 1095 1460 1825 EFA-5 EFA-4 EFA-3 EFA-2 EFA-1 BELA-5 BELA-4 BELA-3 BELA-2 BELA-1 Time from initial transplant (days)

Insulin Independent Partial Use Full Use

Tx # 2 (day 750) Tx # 2 (day 445) Tx # 2 (day 442) Tx # 2 (day 400)

* * * * *

* EFA d/c’ed

Pancreas Txp Pancreas Txp

HbA1c Levels after Islet Transplantation

4.0 5.0 6.0 7.0 8.0 9.0 10.0 30 75 120 180 270 365 455 545 730

Time from Transplant (d) HbA1c (%)

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 30 75 120 180 270 365 455 545 730

Time from Transplant (d) HbA1c (%)

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

Efalizumab ¡ Belatacept ¡

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C-peptide Responses to a Mixed Meal Tolerance Test

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 - Peptide (ng/ml) EFA 1 EFA 2 EFA 3 EFA 4 EFA 5 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 - Peptide (ng/ml) BELA 1 BELA 2 BELA 3 BELA 4 BELA 5

Efalizumab ¡ Belatacept ¡

Glomerular Filtration Rates after Islet Transplantation

20 40 60 80 100 120 140 180 365 180 365

Time from Transplant (days) GFR (ml/min/1.73m

2)

Belatacept Efalizumab

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T Reg Kinetics in Islet Recipients

10 20 30 40 50 60 70 30 60 90 120 150 180 210 240 270 300 330 360

Time from Transplant (days) % FoxP3+ of CD4+ T cells

EFA-1 EFA-2 EFA-3 EFA-4 EFA-5 10 20 30 40 50 60 70 30 60 90 120 150 180 210 240 270 300 330 360

Time from Transplant (days) % FoxP3+ of CD4+ T cells

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

Belatacept ¡ Efalizumab ¡

Cessation of All Immunosuppression – EFA4 case

✦

Single islet transplant, insulin independent for 8 years

✦

ATG induction, on EFA for 15 months, maintained on Sirolimus after EFA cessation

✦

Tregs increased to 70% one month after transplant

✦

No detectable T cell response

✦

Patient stopped taking all drugs on Sep 2012 due to PTLD

✦

Remains insulin independent

10 20 30 40 50 60 70

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

% FoxP3+ of CD4+ T cells

Time from Transplant (days)

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

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Transplantation Rates in US

Pancreas and Islet Transplantation .

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The Next Steps

Multicenter trials Single donor Tolerance New source 2000 2005 2010 2015

New Sources for β Cells

✦ Regeneration ✦ Replacement ✦ Protection

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Where do β cells come from?

Adult Loss

New Sources for β Cells

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Transplantation of hESC-Derived β Cells

✦ What stage of differentiation/maturation? ✦ How to protect them? Encapsulation or

drugs?

✦ Safety? ✦ Efficacy? ✦ First trial, phase 1/2, initiated 2014.

Summary

✦ Pancreas transplantation is an option for some

patients failing intensive medical therapies.

✦ Islet transplantation has similar outcomes in

selected patients.

✦ Newer immune modulating therapies may

have less morbidity and allow drug withdrawal.

✦ β cell replacement is also an option in T2DM,

MODY and Pancreatic DM.

✦ β cells from new sources are entering human

trials.

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German Lab

Islet Isolation Team: Florinna Dekovic, Vinh Nguyen, Vi Dang, Andrew Posselt, Greg Szot Clinical ¡and ¡Research ¡Team:

¡ Lynda ¡Frasse5o, ¡Kris9na ¡Johnson, ¡Bob ¡Kerlin, ¡Umesh ¡Masharani, ¡Joan ¡McElroy, ¡Debbie ¡Ramos, ¡ Tara ¡Rojas, ¡Mehdi ¡Tavakol, ¡Andrew ¡Posselt, ¡Peter ¡Stock, ¡Jeff ¡Bluestone ¡ ¡

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Publications

  • Choudhary, P. et al. Evidence-informed clinical practice recommendations for treatment of

type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care 38, 1016-1029, doi:10.2337/dc15-0090 (2015).

  • Seaquist, E. R. et al. Hypoglycemia and diabetes: a report of a workgroup of the American

Diabetes Association and the Endocrine Society. Diabetes Care 36, 1384-1395, doi: 10.2337/dc12-2480 (2013).

  • Moassesfar, S. et al. A Comparative Analysis of the Safety, Efficacy, and Cost of Islet

Versus Pancreas Transplantation in Nonuremic Patients With Type 1 Diabetes. Am J Transplant 16, 518-526, doi:10.1111/ajt.13536 (2016).

  • Redfield, R. R., Rickels, M. R., Naji, A. & Odorico, J. S. Pancreas Transplantation in the

Modern Era. Gastroenterology clinics of North America 45, 145-166, doi:10.1016/j.gtc. 2015.10.008 (2016).

  • Rezania, A. et al. Reversal of diabetes with insulin-producing cells derived in vitro from

human pluripotent stem cells. Nat Biotechnol 32, 1121-1133, doi:10.1038/nbt.3033 (2014).

  • Pagliuca, F. W. et al. Generation of functional human pancreatic beta cells in vitro. Cell

159, 428-439, doi:10.1016/j.cell.2014.09.040 (2014).

  • Russ, H. A. et al. Controlled induction of human pancreatic progenitors produces functional

beta-like cells in vitro. The EMBO journal 34, 1759-1772, doi:10.15252/embj.201591058 (2015).