Milestones in the History of Stem Cell TransplantationStem Cell Transplantation

John Barrett MDJohn Barrett MD

Transplant prehistory

Ulster, Ireland circa 500 BC

Indication: major traumaSt ll b t ftStem cell source: bos taurus xenograftOutcome: died d+ 7 (major trauma)

Reference: Tain Bo Cuialnghe (The g (cattle raid of Ulster)

Thereupon Fingin the prophetic physician asked of Cuchulain a vat of marrow wherewith to heal and to cureCethern son of Fintan. Cuchulain proceeded to the camp

Is and-sin conattacht Fingin Fathliaig smirammair for Coinculaind do ícc & do leigess Chethirn meic Fintain. Tanic Cuchulaind reme i n dúnud & illongphort fer nCethern son of Fintan. Cuchulain proceeded to the camp and entrenchment of the men of Erin, and whatsoever he found of herds and flocks and droves there he took away with him And he made a marrow mash of their flesh and

Tanic Cuchulaind reme i n-dúnud & illongphort fer n-hErend, & na fúair d'almaib & d'éitib & d'indilib and, tuc leis ass íat. Acus dogní smirammair díb eter with him. And he made a marrow-mash of their flesh and their bones and their skins; and Cethern son of Fintan was placed in the marrow-bath till the end of three days and

d, uc e s ss . cus dog s d b e efeóil & chnámaib & lethar, acus tucad Cethern mac Fintain sin smirammair, co cend teora lá & teora n-three nights. And his flesh began to drink in the marrow-bath about him and the marrow-bath entered in within his stabs and his cuts, his sores and his many wounds.

aidche. Acus ra gab ac ól na smiramrach imme. Acus ra luid in smirammair and eter a chnedaib & eter a h ht ib d ált ib & d il ib A d istabs and his cuts, his sores and his many wounds.

Thereafter he arose from the marrow-bath at the end of three days and three nights. It was thus Cethern arose, with a slab of the chariot pressed to his belly so that his

chrechtaib, dar a áltaib & dar a ilgonaib. And-sin atracht-som assin smiramair i cind teora lá & teora n-aidche. Acus issamlaid attracht & clár a charpait rewith a slab of the chariot pressed to his belly so that his entrails and bowels would not drop out of him. aidche. Acus issamlaid attracht & clár a charpait re broind, ar ná tuitted a fobach & a inathar ass.

Aspects of stem cell transplant history

1Introduction of new therapeutic agents

th ti t

1960 1970 1980 1990 2000

fludarabinecyclophosphamide busulfan

therapeutic agents

antilymphocyte globulin cyclosporinetacrolimus sirolimus

campath

whole body irradiation

imidazole antifungals

campathOKT3methotrexate

acyclovir ganciclovir/foscarnet

Figure1 Milestonesinthedevelopmentofbloodandmarrowstemcell transplantationandintroductionofimportanttherapeuticagents1950-2000Figure 1 Milestones in the development of blood andmarrowstemcell transplantationandintroductionof importanttherapeuticagents19502000

Organizations

A th N l F dAnthony Nolan Fund

1940’s The origins of modern stem cell transplantation

The chronological history

1940 s

1950’s

The origins of modern stem cell transplantation

The first human marrow transplants

1960’s Breakthroughs in immunology

1970’s

1980’s

Clinical bone marrow transplantation takes off

Widening indications widening donor choices1980 s

1990’s

Widening indications widening donor choices new drugs

N t ll i di ti1990’s New stem cell sources, new indications, New conditioning regimens

Improved outcomes, older patients, the rise of cord blood, cell therapy………………………..

2000’s

The 1940sThe atomic bomb precipitated researchleading to stem cell transplantation

BMT OVERVIEW

Jacobsen’s radiation protection experiments

1000 rads Spleencells

Shield hind limb Inject spleen cells

died protected protected

Why did the mice survive? Ford’s experiments

marrow cellsmarrow cellsWith marker chromosome

Humoral theory

Cellular theory

Inject spleen cells

Chromosome analysis

repopulated marrow 100% marker

Surviving micechromosome

Primary disease and secondary disease

IsologousdonorNo cells Homologous

donor

s r i alsurvivalDeath - 7 days:Primary disease

Secondarydisease

Death - 14 days

Graft- versus -leukemia (Barnes and Loutit 1956)

Isologous marrow Homologous marrow

leukemialeukemialeukemia

Death d 14Death from leukemia

Secondarydisease

Death d 14 no leukemia!!

Clinical Stem Cell Transplantation and the beginnings of HLA typingg g yp g

• 1957-Thomas – Safe infusion of marrow into humans

1959 M thé• 1959-Mathé– First bone marrow transplants for radiation accident

victims.1958 Dausset• 1958-Dausset– First HLA antigen described (A2)

• 1963-Mathé– First successful complete engraftment and survival of over

1 year, description of acute and chronic GVHD in men• 1968-van Rood/Terasaki

M d HLA l i i il bl– Modern HLA serologic typing available – Secondary disease-runting syndrome-GVHD

• 1968-Good (Minneapolis) De Vries (Leiden)– First successful HLA-matched sibling transplant for SCID

Transplanters hall of fame

Georges Mathé E Donnall Thomas JJ van Rood

Jean Dausset Robert Good Paul Terasaki

The 1970’sThe 1970 s

B M T l t ti t k ff!!Bone Marrow Transplantation takes off!!

Blood. 1977 Apr;49(4):511-33. LOne hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation.Thomas ED, Buckner CD, Banaji M, Clift RA, Fefer A, Flournoy N, Goodell

i k O G i S l G S d SiBW, Hickman RO, Lerner KG, Neiman PE, Sale GE, Sanders JE, Singer J, Stevens M, Storb R, Weiden PL.

94 patients were engrafted and only one patient rejected 94 patients were engrafted and only one patient rejected the graft. ……

Thirteen patients are alive with a marrow graft, on no maintenance antileukemic therapy, and without recurrent leukemia 1-4.5 yr after transplantation.

This observation, coupled with the observation that some patients may be cured of their disease, indicates that marrow transplantation should now be undertaken earlier marrow transplantation should now be undertaken earlier in the management of patients with acute leukemia who have an HLA-matched sibling

1975Tracking and documentingtransplants

Europe

20092009

Tracking transplants world-wide IBMTR - CIBMTRIBMTR CIBMTR

Mortimer M. Bortin

Scientific Director

Mary M. Horowitz

Scientific Director,Scientific Director,

IBMTR 1972-1991

Scientific Director,

IBMTR 1991-

IBMTRIBMTR• Established in 1972 to monitor and study

outcomes of bone marrow transplants; moved to MCW 1980moved to MCW ~1980

• Maintains a database of clinical information on recipients of autologous and allogeneicon recipients of autologous and allogeneic hematopoietic stem cell transplants in ~450 centers in 47 countries

• Provides scientific and statistical support for analyzing those data

Annual Numbers of H t i ti St C ll T l tHematopoietic Stem Cell Transplants

Worldwide 1970-2003

an

ts

35 000

40,000

45,000

f Tra

nsp

la

25,000

30,000

35,000

Autologous

um

ber

of

10 000

15,000

20,000

All iNu

0

5,000

10,000

1970

Allogeneic

1975 1980 1985 1990 1995 2000

Year

1970 1975 1980 1985 1990 1995 2000

INDICATIONS FOR BLOOD AND MARROW TRANSPLANTATIONTRANSPLANTATION

(BMT) IN NORTH AMERICA 2002 (IBMTR)

4,500Allogeneic (Total N = 7,200)Autologous (Total N = 10,500)4,000

3 500

PLAN

TS

2,500

3,000

3,500

TRAN

SP

1 000

1,500

2,000

0

500

1,000

BreastNHLMultipl AML ALL CMLMDS / CLL OtherHodgkin NonBreastCancer

NHLMultipleMyeloma

AML ALL CMLMDS / Other

Leukemia

CLL OtherCancerNeuroblastoma

HodgkinDisease

Non-MalignantDisease

Barriers for stem cell transplantation

The 1980’s: Extending the indications

The 1990’s: Older and debilitated patients

Extending the donor pool

The last decade: Safer transplants

The next decade: More cures

The 1980’sExtending the indicationsg

1970s 1980s 1990s

Acute leukemiaCML

MyelomaCLLmyeloma

lymphomaMDS

C

Aplastic anemia and immunodeficiency diseases

Cancer

H l bi thiHemoglobinopathiesInborn errors

committed stem cells

aplastic anemia reticular dysgenesis Fanconi anemia

Correction of genetic disorders by replacement with hematopoietic stem cells and their prtogeny

pluripotent stem cellsstem cells

common lymphoid

B cell

T and B cell i d fi i

common myeloid T cell

immune deficiencydiseases

congenital t i

SCID

monocyte-

Gaucher disease

PRCAamegakaryocytic thrombocytopenia

neutropenia

neutrophils

monocyte-macrophages

CGD osteo- exported enzyme

megakaryocyte

red cellsCGD

hemoglobinopathy

petrosisexported enzymefrom mature marrow-derived cells

megakaryocyte

Glamzmann's thrombocythemia mucopolysaccharidoses

other inborn metabolic errors 6

Allogeneic SCT for Renal Cell CancerPre-tx D 180 D 270

Childs et al NEJM 1999

Barriers for stem cell transplantation

The 1980’s: Extending the indications

The 1990’s: Older / debilitated patients

Extending the donor pool

The last decade: Safer transplants

The next decade: More cures

Limitations to successful cure

INTENSIVE MYELOABLATIVE

REGIMEN IMMUNOSUPPRESSION

TRANSPLANT RELATED MORTALITY

REGIMEN IMMUNOSUPPRESSION

RRT INFECTION

TRANSPLANT-RELATED MORTALITY TRM

GVHD+ + RELAPSE

10-30% 10-60%

Restricts SCT to patients <60y in good condition.H t t l t ld l f l ?How to transplant older people safely?

J l (Sl i )

RIC - a conceptual wavefront of the 90’s

Jerusalem (Slavin)

Houston (Giralt)

Spitzer / Sykes

Bethesda(Childs / Barrett)

SeattleSeattle(Storb)

GenovaGenova(Carella)

Diversity in 40 published reduced intensity conditioning regimens

Flu/Bu Flu/Cy Flu/Mel TBI-based

Dose variable or not given

Fludarabine

10 y

9 9 12

Fludarabine

Busulfan

Cyclophos

M l h l

irradiation

Melphalan

other

100

Busulfan-based regimens look most promising!100

90

Bu10410

Mel8

612

TBI12

1052

Cy9

172

% RegimenNumber of studiesNumber of patients

80

70

60

50

>1.5y PFS

40

30>1yr TRM

30

20

1010

0

Can we make SCT available to more patients who do not have

a matched sibling?g

UnrelatedCord bloodCord blood

haploidentical

NMDPNMDP

• 1986 – U.S. government appropriated funds to establish the National Bone Marrow Donorestablish the National Bone Marrow Donor Registry (Donor Panel)

• 1988 – U.S. Organ Transplant Amendments Act d t d ll ti t d t (R i i t– mandated collecting outcome data (Recipient

Registry); also collects donor outcomes• ~150 transplant centers and 90 donor centers150 transplant centers and 90 donor centers • Repository with matched recipient/donor blood

samples

Related and unrelated SCT meet less th h lf th d f dthan half the need for donors

Percentage of patients needing donors

100%

g p g

CBT21,000 no unrelated donor

CBT

Haplo transplant

4,000 unrelated30%

42%

11,000 related

30%

Matched Unrelated Donors

5,335,4656,000,000 60,000

, ,

4 000 000

5,000,000

40 000

50,000

adult30,874

3,000,000

4,000,000

30,000

40,000adult

2,000,000 20,000cord

1,000,000

0

10,000

YearYEARS1985 2006

Cord Blood Transplantation

Laughlin M, NEJM 344:1815, 2001Laughlin M, NEJM 344:1815, 2001

The CBT learning curveg

Increase stem cell dose byydouble (triple?) CBTT depleted haplo sibling plus CBTex vivo expansionex-vivo expansion

Increase immune effectSSalvaged cord lymph expansionpooled Tregsantigen-specific T cell expansiong p p

Increase cord banks to provide better matches

Haploidentical transplants

• Henslee-Downeyn: 72

•Aversa (NEJM 1998)–n: 43

• Henslee-Downey72

•Aversa (NEJM 1998)43– n: 72

– Engraftment: 88%A t GVHD 16%

–n: 43–Engraftment: 100%

Acute GVHD: 0%

– n: 72– Engraftment: 88%

–n: 43–Engraftment: 100%

– Acute GVHD: 16%– Chronic GVHD: 8%

2 i l

–Acute GVHD: 0%–Chronic GVHD: 0%

TRM: 40%

– Acute GVHD: 16%– Chronic GVHD: 8%

–Acute GVHD: 0%–Chronic GVHD: 0%

– 2 year survival:• High risk: 27%

Lo risk 55%

–TRM: 40%–18 mo F/U: 12/43 alive and well

– 2 year survival:• High risk: 27%

–TRM: 40%–18 mo F/U: 12/43 alive

• Low risk: 55% and well• Low risk: 55% and well

Barriers for stem cell transplantation

The 1980’s: Extending the indications

The 1990’s: Older and debilitated patients

Extending the donor pool

The last decade: Safer transplants

The next decade: More cures

TRANSPLANTS ARE GETTING SAFERHLA IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FORHLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR

LEUKEMIA Registered with the IBMTR, 1975-2002

100

ITY,

%

80

RO

BA

BIL

60≥1995 (15,126) 56%

PR

401985-1994 (14,755) 48%

1975-1984 (N=2,334) 35%

0

20( , )

P = 0.00010

YEARS

0 1 2 3 4 5

Why are transplants getting safer?Why are transplants getting safer?

• Better antifungalsBetter antifungals• Better antivirals, pre-emptive treatments• Treatments for EBV LCLTreatments for EBV LCL• Treatments for steroid-resistant GVHD• Effective antibiotics• Effective antibiotics• Cell dosing• Selection of regimen intensity• Selection of regimen intensity• Improvement in competence levels worldwide

Improved competencep p

• Standardized supportive care• Standardized supportive care– IV lines, prophylaxis, transfusions

• Stadardized treatments of high risk• Stadardized treatments of high-risk complications– VOD IP CMV EBV etcVOD, IP, CMV, EBV, etc

• Education and training widely disseminated and availableand available

• More people doing more transplants!

Voriconazole

Treatment of severe acute GVHD using MSC

Le Blanc et al, Lancet 363, 1439-41, 2004

Barriers for stem cell transplantation

The 1980’s: Extending the indications

The 1990’s: Older and debilitated patients

Extending the donor pool

The last decade: Safer transplants

The next decade: More cures

TRANSPLANTS ARE NOT MORE CURATIVE%

)HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS

ADVANCED LEUKEMIA* IBMTR, 1975-2002100%

(%

80

AB

ILIT

Y,

60

SE P

RO

BA

20

40

1985-1994 (2299) 60%

1975-1984 (451) 62%

REL

APS

NS

0

20

0 1 2 3 4 5

≥1995 (2261) 62%

* Not in remission for AML or ALLBlast phase for CMLYEARS

0 1 2 3 4 5

GVL comes of age!

Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, Rimm AA, Ringdén O, Rozman C, Speck B, et al.

Graft-versus-leukemia reactions after bone marrow transplantation.transplantation.Blood. 1990 Feb 1;75(3):555-62

DLIKolb HJ, Mittermüller J, Clemm C, Holler E, Ledderose G, Brehm G, Heim M Wilmanns W

DLI

Heim M, Wilmanns W.

Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients.y g p pBlood. 1990 Dec 15;76(12):2462-5Blood. 1990 Dec 15;76(12):2462-5.

The GVL effect is T cell linked

Allogeneic non T cell depleted Relapse risk %

44

17

no GVHD

aGVHD

90

141

20

aGVHD

cGVHD 28

1541

a+cGVHD

Syngeneic

84

12

34Allogeneic T depleted 84

Horowitz et al, Blood 1990,75:555.

NK cells also have a GVL effect

Attacks host DC

BLOCKS GVHDDonor-recipientKIR MHC I BLOCKS GVHDKIR-MHC Imismatch

Alloreacting NK

Attacks host le kemiaLYSIS

Attacks host leukemia

GVL

Attacks host T cells

ENGRAFTMENT Ruggeri et al Semin Cancer Biol. 2006

Suicide gene therapydonor

GVHD GVHDGVHD

GVLGVHDmodulated

HSZ-Tk geneinserted intoproliferating ganciclovir

transplanted patientproliferatingdonor PBMC

ganciclovir

Haplo identical SCT for advanced leukemiaHaplo-identical SCT for advanced leukemia

107 CD3+TK+ cells/kg full immune recon broad repertoirepRelapse prevented in 2/3 patientsmultiple doses of ganciclovir abrogated GVHD

Ciceri et al Cytotherapy 2005

Gene Modified T cells

CMML patient

Leukemia-specific T cell lines

Irrad CML+Donor MNC

restimulatesplit Select and expand

growing clones

IL-2

10 X 96 well platesTest

select

10 X 96 well plates

6-8 weeks

Pool active and specific

Give DLI to relapsed CML patient

6 8 weeks

CTL linesto relapsed CML patient

Falkenburg et al

NK infusionsHaploidentical NK cells proliferate in recipientsp p p

and show cytotoxicityRequirement for lymphodepletion(IL15 driven expansion)

92% of lymphocytesof donor origin(IL15 driven expansion) of donor origin and show NK cytotoxicity

Miller et al Blood 2005

GVH GVL

Selective DepletionSelective DepletionRecipient non-leukemic cells

Anti-CD25 immunotoxin

CD25MLR

Donor

Third-party stimulatorsReactive

Recipient pleukemic cells

1. Irradiated non-leukemic stimulators: activated/expanded T cells• Sufficient numbers

RecipientSufficient numbers

• Efficient antigen presentation

Combined GVL strategies for the perfect stem cell allograft

Selective5 x 106 /kgPBSCT

No immunosuppression !Block T reg function (Ontacc?)

CD34CD3 allodepletionvaccinate

Boost NK recovery

survival

HLA-matched /

vaccinate

y

Mismatched:Select NK alloreactive

TXPTInfuse leukemia-specific CTL

0 1 2 3 4 5

relapse

Anti-leukemia +immunoablation

0 1 2 3 4 5YEARS

The future of allogeneic SCT

Small moleculesCombinationchemotherapy

Early chemotherapyy py

Selective immune reconstitution

High dose chemotherapy and marrow rescue

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