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Pacific Life Re

FOR INTERNAL USE ONLY |

PRIVATE & CONFIDENTIAL

Transplantation –To infinity and beyond

July 2018

Dr Bill Monday

Pacific Life Re



Topics covered in this presentation

— Overview —

01 Overview of transplantation in Australia

02 Solid organ transplantation

03Stem cell transplantation

04 Bio-printing

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Aim of talk:

— Overview —

1.To make you all organ donors ☺ …. ( https://register.donatelife.gov.au/decide)

2.To get a feel for transplants in Australia

3.To note use of stem cell transplantation in MS

4.To ensure you don’t change your home printer into a bio-printer yet…..

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Transplantation

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Overview of transplantation in Australia

- Section 01 -

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Transplants performed in Australia from deceased donors.

6

http://www.anzdata.org.au/anzod/updates/20180606_ANZODMonthlyReport_2018May.pdf

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7http://www.anzdata.org.au/brochures/brochure_2016v1.0_20180417.pdf

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http://www.anzdata.org.au/anzod/updates/20180606_ANZODMonthlyReport_2018May.pdf

Jan May- 2018 Number of transplants

Kidney 385

Liver 127

Heart 57

Lung 184

Pancreas 18

Stomach and intestine 0

Multi-organTransplant

Jan –May2017

Heart and lungs 3

Kidney and Heart 4

Kidney and Liver 5

Kidney and Lungs 1

Kidney and Pancreas 16

Total 29

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Survival of Graft 1997-2016

http://www.anzdata.org.au/brochures/brochure_2016v1.0_20180417.pdf

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Solid Organ Survival Australia

1 Year 5 Year 10 Year

Kidney 99-97% 96-90% 83-74

Heart 87% 81% 70%

Lung 93% 70% 32%*

Pancreas 96% 92% 82%

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* USA survival data

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Common causes of renal disease leading to renal transplant.

• Diabetes- 31%

• Chronic Glomerulonephritis 28%

• Polycystic Kidney Disease-12%

• Nephrosclerosis 9%

• Lupus 3%

• Interstitial Nephritis 3%

• Other 14%

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Outcomes after transplants

Standardised mortality per 100 patient years:

• Dialysis 6.3

• Cadaveric transplant 3.8

• Living Donor transplant 2.0

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Causes of death in renal transplant patients

14tp://www.anzdata.org.au/anzdata/AnzdataReport/40thReport/chapter03_mortality_2016_v1.0_20180411.pdfht

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Long term complications of transplantation

• Cardiovascular disease (Death With a Functioning Graft- DWFG) 7.6% chance of MI or

coronary revascularization after 5 years.

• Why?

• More calcification in arteries

• More LVH.

• Caution esp in-

• Diabetics,

• CVS disease during dialysis

• Ongoing proteinuria.

• Renal function post transplant also NB with a 16% increase in CVS events for every

5ml/min/1.73m2 decrease below a eGFR of 45ml/min/1.73m2

• Immunosuppression including steroids increase BP and increase dyslipidaemia.

15https://academic.oup.com/bmb/article/106/1/117/322190. Update on long term complications of renal transplantation Mathew J Bottomley et at British Medical Bulletin 02 May 2013

https://academic.oup.com/bmb/article/106/1/117/322190

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Long term complications of transplantation

• Cancer (DWFG)

• Cardiovascular disease and cancer account for 47% of all deaths with a functioning

graft with 27% of death being due to cancer)

• Majority of cancers are Non Melanoma Skin Cancers (NMSC)

• Lymphomas higher than the general population

• Kaposi’s Sarcoma more common in transplanted patients



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Long term complications of transplantation- Cancer



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Immunosuppresssion

• All kidney transplants require life long immunosuppression to prevent T cell rejection. It’s

a bit of a balance as you need to:

• Prevent acute and chronic rejection.

• Minimize drug toxicity and rates of infection and malignancy

Complications include:

• Rejection

• Nephrotoxicity of certain immunosuppressive drugs such as Cyclosporin and Tacrolimus

• Recurrence of native kidney disease

• Acute rejection occurs in first 6 months (15% of cases)

• Chronic rejection occurs more than a year after transplantation

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Complications of common Transplant drugs

Complications CVS Carcinogenesis Other Nephrotoxicity

Ciclosporin ↑BP, ↑ Lipids,↑ Diabetes risk

Yes, carcinogenic Pancreatitis, All transplants have impaired function ( even if biochemically normal) . To avoid any medication that may effect the kidney such as NSAIDs, Certain antibiotics such as Aminoglycosides

Tacrolimus ↑BP, ↑ Lipids,↑ Diabetes risk

No carcinogenesis InsomniaHeadaches

Azathioprine No effect Yes, carcinogenic Low White cell count

Mycophenolate ↑ Lipids Possible, some evidence

Teratogenic

Sirolimus ↑ Lipids Possible, some evidence

Pneumonititis, oedema

Everolimus ↑ Lipids Possible, some evidence

Pneumonititis, oedema

Corticosteroids ↑BP, ↑ Lipids,↑ Diabetes risk

Limited evidence19

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Underwriting considerations of transplanted patient- Kidney.

Deceased or living donor in case of kidney

Present renal function- preferably eGFR, Creat below 150 as rule of thumb

Presence of proteinuria , hypertension

Cardiovascular, cancer and diabetic risk

Medication and side–effects of medication.



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Stem Cell Transplantation.

- Section 03 -

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Stem cell transplants – Around a 1000/year in Australia

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Indications:

• Leukaemia

• Lymphoma

• Myeloma

• Amyloidosis

• Aplastic anaemia

• Some solid tumours (e.g testicular cancer, breast cancer)

• Some immune system disorders (scleroderma)

• MS

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Stem Cell Transplant.

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A stem cell transplant replaces blood forming cells in your bone marrow that have been

destroyed by chemotherapy or radiotherapy with healthy stem cells

A stem cell transplant can be your own stem cells ( Autologous 2/3 of cases ) or stem cells

from a donor ( Allogenic)

Stem cell transplants have 4 main phases

1)Stem cell collection from you or a donor (1-2 weeks)

2)Transplant treatment (Chemotherapy or radiotherapy – 1 week)

3) IV transfusion of healthy Stem cells (1 day)

4) Recovery 2-12 weeks

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Survival after Stem cell transplant

Survival improving due to better tissue matching, better supportive care and earlier referral

for transplantation.

Allogenic bone marrow transplants potentially curative with most deaths occurring in the

first 2 years post transplant. 5 Year survival 89% and 10 year survival 85%.

Causes of death-

– Age related

– Relapse of malignancy

– Chronic Graft Versus Host Disease ( GVHD)

– Second cancers ( 2-10% of deaths in late survivors)

Australia at the forefront creating blood stem cells in the lab. Used pluripotent stem cells to

create blood cells

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Graft Vs Host Disease

This can only occur in Allogenic transplants

The donated bone marrow/stem cells see the recipient’s body as foreign and attack,

Graft vs Host disease can be acute or chronic

GVHD can affect the skin, liver, eyes, mouth, lungs, GIT tract, neuromuscular system or

genitourinary system.

Immunosuppressives are prescribed thus increasing infection risk.

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Fairly predictable and favourable prognosis after 2 years of survival

27https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107742/

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Stem cell Transplantation in MS

- Section 02 -

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MS- Different subtypes.

Relapsing Remitting ( RRMS-85%)

Secondary Progressive MS ( SPMS- Rare)

Primary Progressive MS ( PPMS- 10%)

Progressive relapsing MS ( PRMS-5%)

29https://www.multiplesclerosis.com/us/treatment.php

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Types of MS

30

Relapsing

Remitting MS

Secondary

progressive

MS

Progressive

relapsing MS

Primary

Progressive MS

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MS- Treatment

Methylprednisolone (Solu-medrol)

Dexamethasone

Beta interferons

Glatiramer acetate

Fingolimod

Teriflunomide

Dimethyl fumarate

Mitoxantrone

Natalizumab

31https://www.multiplesclerosis.com/us/treatment.php

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MS- Cell based therapy

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Stem cell transplantation for MS.

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1. I/AHSCT. Intensive chemo to kill immune system- Immuno-Ablative Haematopoietic

Stem Cell Transplant. Cost $80,000

2. Mesenchymal Stem Cells +/- 2 million stem cells reintroduced with more normal

immune function. Rebooting the immune system without it attacking the body uses a

different kind of stem cell which is isolated from different tissue including bone marrow

and fat. Mesenchymal stem cells secrete chemicals that dampens the immune system

and a milieu that is more supportive for self repair of the central nervous system.

3. Use of oligodendrocyte progenitor cells

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Bio-printing- Section 04 -

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Bioprinting

Bio-printing

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Bio-printing

• Testing of Cosmetics and other consumer goods

• Drug screening

• Personalised medicine

• Regenerative Medicine (Bone and cartilage, skin, dental, vasculature, complex

organs)

• Cell-based Biosensors

• Food and other animal products

• Education

• Academic research

• Bionics

• Market expected to reach a value of $1.9 Billion by 2028.

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Bio-printing

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Bio-printing- Biomimicry

Biomimicry involves the identical reproduction of the cellular and extracellular components of a tissue or organ. An example would be the mimicking of the branching patterns of blood vessels.

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Bio-printing- Autonomous self assembly

This uses embryonic organ development as a guide. The early cells produce their own extra cellular matrix, appropriate cell signalling and autonomous organization to produce the right micro-architecture and functioning.

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Bioprinting- Mini- Tissues.

Organs and tissues comprise of smaller, functional building blocks-mini tissues. Mini tissues can be fabricated and assembled by rational design or self assembly or a combination of both

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1. Imaging- X-ray, CT, MRI2. Design approach-Biomimicry, self- assembly. Mini-tissues3. Material selection4. Cell selction –differentiated cells, multipotent stem cells5. Bio-printing-Inkjet. Micro-extrusion, laser assisted6. Application- Maturation, implantation, in vitro testing

Bio-printing- Multi-Stepped Approach

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PRIVATE & CONFIDENTIALBioprinting- ConsiderationsRejection remains a problem unless autologous cells used

Many primary cells are difficult to isolate and culture and have a finite life span.

Embryonic stem cells and pluripotent stem cells hold great promise due to indefinite

self renewal.

Still need increased resolution, speed and compatibility with biologically relevant

materials.

Cross linking of cells and the extracellular matrix are ongoing challenges

Building a vascular tree and perfusion remains challenging.

It is thought a Human D organ is around 1o -15 years away

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Reinvent

Thank You

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For more information, please contact:

NameDr Bill MondayPacific Life Re | CMO

T: +610282748634E: [email protected]

W: www.pacificlifere.com

ContactContact

The views contained in this document are confidential, do not constitute advice and are not intended to be relied upon as such. While this information has been prepared in good faith, no representation or warranty, express or implied, is or will be made and no responsibility or liability is or will be accepted in relation to the accuracy or completeness of the information contained herein and any such liability is expressly disclaimed.

http://www.pacificlifere.com/

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