Milestones in the History of Stem Cell Transplantation

John Barrett MD

Transplant prehistory

Ulster, Ireland circa 500 BC Indication: major trauma St Stem cell ll source: bos b taurus t xenograft ft Outcome: died d+ 7 (major trauma) Reference: Tain Bo Cuialnghe g (The ( cattle raid of Ulster)

Is and-sin conattacht Fingin Fathliaig smirammair for Thereupon Fingin the prophetic physician asked of Cuchulain a vat marrow wherewith to heal and to cure Coinculaind doof cc & do leigess Chethirn meic Fintain. Cethern son of Fintan. Cuchulain proceeded to the camp Tanic Cuchulaind reme in n-d dnud & illongphort fer n nand entrenchment of the men of Erin, and whatsoever he hErend, & na fair d'almaib & d'itib & d'indilib found of herds and flocks and droves there he took away and, d,him. tuc uc And leis e s ass ss made at. . Acus cus dog dogn mash smirammair s b e eter e with him he a marrow-mash marrow of their d flesh and feilbones & chnand maib &skins; lethar, acus tucad son Cethern macwas their their and Cethern of Fintan Fintain smirammair, teora l & days teoraand nplaced insin the marrow-bath co till cend the end of three three nights. And his flesh to drink in imme. the marrowaidche. Acus ra gab ac l began na smiramrach Acus bath about him and the marrow-bath entered in ra luid in smirammair and eter a chnedaib &within eter ahis stabs and his cuts, his sores and his many wounds. chrechtaib, h ht ib d dar a ltaib lt ib & dar d a il ilgonaib. ib And-sin A d i Thereafter he arose from the marrow-bath at the end of atracht-som assin smiramair i cind teora l & arose, teora nthree days and three nights. It was thus Cethern aidche. Acus issamlaid r a charpait with a slab of the chariotattracht pressed & to cl his belly so that re his broind,and ar n tuitted a fobach & aout inathar ass. entrails bowels would not drop of him.

Aspects of stem cell transplant history

Introduction of new therapeutic agents

1960 1970 1980 1990 2000
flu da rab ine

th e ra p e u ti a tic g e n t ts
cy clop h os ph am id e w ho lebo d yirrad iation tacrolim u s an tily m p ho cy teglo bu lin m eth o trex ate cyc lo sp o rine cam pa th O K T3 im id azo lean tifu n ga ls a cyc lo vir ga nc ic lo vir/fo sca rn et b us ulfan

siro lim u s

F igu re1 re 1M ile ston esinth es inth ed e d evelo pm en to t o f blo odan od an dm arrowste mcelltran splan tatio nandintro du ctionofim ctionof im po rtan tth erap eu ticag en ts19 50 502 -2 00 0

Organizations

Anthony Nolan A th N l Fund F d

The chronological history 1940s 1940 s 1950s 1960s 1970s 1980s 1980 s The origins of modern stem cell transplantation The first human marrow transplants Breakthroughs in immunology Clinical bone marrow transplantation takes off Widening indications widening donor choices new drugs New stem N t cell ll sources, new indications, i di ti New conditioning regimens Improved outcomes, older patients, the rise of cord blood, cell therapy..

1990s

2000s

The 1940s
The atomic bomb precipitated research leading to stem cell transplantation

BMT OVERVIEW

Jacobsens radiation protection experiments

1000 rads Spleen cells

Shield hind limb

Inject spleen cells

died

protected

protected

Why did the mice survive? Fords experiments

marrow cells With marker chromosome

Humoral theory Cellular theory

Inject spleen cells Chromosome analysis

repopulated marrow 100% marker chromosome Surviving mice

Primary disease and secondary disease

No cells Isologous donor Homologous donor

Death - 7 days: Primary disease

s r i al survival

Secondary disease

Death - 14 days

Graft- versus -leukemia (Barnes and Loutit 1956)

Isologous marrow Homologous marrow

leukemia leukemia

Death from leukemia

Secondary disease

Death d 14 no leukemia!!

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

1957-Thomas
Safe infusion of marrow into humans

1959-Math 1959 M th
First bone marrow transplants for radiation accident victims.

1958-Dausset 1958 Dausset

First HLA antigen described (A2)

1963-Math
First successful complete engraftment and survival of over 1 year, description of acute and chronic GVHD in men

1968-van Rood/Terasaki
Modern M d HLA serologic l i typing i available il bl Secondary disease-runting syndrome-GVHD

1968-Good (Minneapolis) De Vries (Leiden)

First successful HLA-matched sibling transplant for SCID

Transplanters hall of fame

Georges Math

E Donnall Thomas

JJ van Rood

Jean Dausset

Robert Good

Paul Terasaki

The 1970s 1970 s B Bone M Marrow T Transplantation l t ti takes t k off!! ff!!

Blood. 1977 Apr;49(4):511-33. L One 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 BW, Hickman i k RO, O Lerner KG, G Neiman i PE, Sale S l GE, G Sanders S d JE, Si Singer J, Stevens M, Storb R, Weiden PL.

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 in the management of patients with acute leukemia who have an HLA-matched sibling

Tracking and documenting transplants Europe

1975

2009

Tracking transplants world-wide IBMTR - CIBMTR

Mortimer M. Bortin Scientific Director, Director IBMTR 1972-1991

Mary M. Horowitz Scientific Director, IBMTR 1991-

IBMTR
Established in 1972 to monitor and study outcomes of bone marrow transplants; moved to MCW ~1980 1980 Maintains a database of clinical information on 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 Hematopoietic t i ti Stem St Cell C ll Transplants T l t Worldwide 1970-2003

45,000

Nu umber of f Transpla ants

40,000 35 000 35,000 30,000 25,000 20,000 15,000 10 000 10,000 5,000 0 1970 All Allogeneic i Autologous

1975

1980

1985

1990

1995

2000

Year

INDICATIONS FOR BLOOD AND MARROW TRANSPLANTATION (BMT) IN NORTH AMERICA 2002 (IBMTR)
4,500 4,000 3 500 3,500 3,000 2,500 2,000 1,500 1 000 1,000 500 0
Non MultipleNHL AML Hodgkin ALL MDS / CML Multipl CLL BreastOther NonDisease Other Cancer Cancer Malignant Myeloma Neuroblastoma Leukemia Disease Allogeneic (Total N = 7,200) Autologous (Total N = 10,500)

TRANSP PLANTS

Barriers for stem cell transplantation

The 1980s: Extending the indications

The 1990s: Older and debilitated patients Extending the donor pool The last decade: Safer transplants The next decade: More cures

The 1980s g the indications Extending

1970s Acute leukemia CML CLL Myeloma myeloma lymphoma MDS C Cancer Aplastic anemia and immunodeficiency diseases H Hemoglobinopathies l bi thi Inborn errors 1980s 1990s

Correction of genetic disorders by replacement with hematopoietic stem cells and their prtogeny aplastic anemia reticular dysgenesis Fanconi anemia pluripotent stem cells

committed stem cells common lymphoid T and B cell i immune d fi i deficiency diseases

B cell

SCID common myeloid congenital neutropenia t i

T cell Gaucher disease

amegakaryocytic thrombocytopenia

PRCA

monocytemacrophages neutrophils CGD red cells hemoglobinopathy megakaryocyte Glamzmann's thrombocythemia mucopolysaccharidoses other inborn metabolic errors

osteopetrosis

exported enzyme from mature marrow-derived cells

Allogeneic SCT for Renal Cell Cancer

Pre-tx D 180 D 270

Childs et al NEJM 1999

Barriers for stem cell transplantation

The 1980s: Extending the indications

The 1990s: 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 TRANSPLANT RELATED MORTALITY TRM RRT + GVHD + INFECTION RELAPSE

10-30%

10-60%

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

RIC - a conceptual wavefront of the 90s

J Jerusalem l (Sl i ) (Slavin) Houston (Giralt)
Spitzer / Sykes

Bethesda (Childs / Barrett) Seattle (Storb)

Genova (Carella)

Diversity in 40 published reduced intensity conditioning regimens

Dose variable or not given

Flu/Bu 10
Fludarabine

Flu/Cy y 9

Flu/Mel 9

TBI-based 12

Busulfan Cyclo phos M l h l Melphalan irradiation other

Busulfan-based regimens look most promising! %

100 90 80 70 60 50 40 30 20 10 0 >1yr TRM >1.5y PFS Regimen Bu Number of studies 10 Number of patients 410 Mel 8 612 TBI 12 1052 Cy 9 172

Can we make SCT available to more patients who do not have a matched sibling? g
Unrelated Cord blood haploidentical

NMDP
1986 U.S. government appropriated funds to establish the National Bone Marrow Donor Registry (Donor Panel) 1988 U.S. Organ Transplant Amendments Act mandated d t d collecting ll ti outcome t data d t (Recipient (R i i t Registry); also collects donor outcomes 150 transplant centers and 90 donor centers ~150 Repository with matched recipient/donor blood samples

Related and unrelated SCT meet less th half than h lf the th need d for f donors d
Percentage g of patients p needing g donors 100% 21,000 no unrelated donor 42% 4,000 unrelated 30% 11,000 related CBT Haplo transplant

Matched Unrelated Donors

6,000,000

60,000

5,335,465 , ,
5,000,000

50,000

4 000 000 4,000,000

adult
30,874

40 000 40,000

3,000,000

30,000

2,000,000

cord

20,000

1,000,000

10,000

1985

YEARS
Year

2006

Cord Blood Transplantation

Laughlin M, NEJM 344:1815, 2001

Laughlin M, NEJM 344:1815, 2001

The CBT learning g curve

Increase stem cell dose by y double (triple?) CBT T depleted haplo sibling plus CBT ex vivo expansion ex-vivo Increase immune effect Salvaged cord lymph expansion pooled Tregs antigen-specific g p T cell expansion p Increase cord banks to provide better matches

Haploidentical transplants
Henslee-Downey Henslee-Downey
n: n: 72 72 Engraftment: Engraftment: 88% 88% Acute A t GVHD: Acute GVHD GVHD: 16% 16% Chronic Chronic GVHD: GVHD: 8% 8% 2 2 year year survival: survival: i l
High risk: risk: 27% High 27% Lo risk: Low risk: risk 55% Low 55%

Aversa Aversa (NEJM (NEJM 1998) 1998)

n: 43 n: 43 Engraftment: Engraftment:100% 100% Acute Acute GVHD: Acute GVHD: 0% 0% Chronic Chronic GVHD: GVHD: 0% 0% TRM: TRM: 40% 40% TRM: 18 mo F/U: F/U: 12/43 12/43 alive alive 18 mo and well well and

Barriers for stem cell transplantation

The 1980s: Extending the indications

The 1990s: Older and debilitated patients Extending the donor pool The last decade: Safer transplants The next decade: More cures

TRANSPLANTS ARE GETTING SAFER

HLA-IDENTICAL HLA IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR LEUKEMIA Registered with the IBMTR, 1975-2002
100

PR ROBABILITY, %

80

1995 (15,126)
60

56%

40

1985-1994 (14,755)

48%

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

20

P = 0.0001
0 0 1 2 3 4 5

YEARS

Why are transplants getting safer?

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

Improved p competence p
Standardized supportive care
IV lines, prophylaxis, transfusions

Stadardized treatments of high high-risk risk complications

VOD, VOD IP, IP CMV, CMV EBV, EBV etc

Education and training widely disseminated and 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 1980s: Extending the indications

The 1990s: Older and debilitated patients Extending the donor pool The last decade: Safer transplants The next decade: More cures

) % (
RELAPS SE PROBA ABILITY, %

TRANSPLANTS ARE NOT MORE CURATIVE

HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS ADVANCED LEUKEMIA* IBMTR, 1975-2002
100

80

60

40

1975-1984 (451) 62% 1985-1994 (2299) 60%

NS

20

1995 (2261) 62%

0 0 1 2 3 4
* Not in remission for AML or ALL Blast phase for CML

YEARS

GVL comes of age!

Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, Rimm AA, Ringdn O, Rozman C, Speck B, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990 Feb 1;75(3):555-62

DLI
Kolb HJ, Mittermller J, Clemm C, Holler E, Ledderose G, Brehm G, Heim M M, Wilmanns W. W Donor leukocyte transfusions for treatment of recurrent chronic y g leukemia in marrow transplant p p patients. myelogenous Blood. 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 no GVHD 90 aGVHD 141 cGVHD 28 a+cGVHD 84 Syngeneic 12 Allogeneic T depleted 84 34 15 41 17 20 Relapse risk % 44

Horowitz et al, Blood 1990,75:555.

NK cells also have a GVL effect

Donor-recipient KIR MHC I KIR-MHC mismatch Alloreacting NK Attacks host DC BLOCKS GVHD

LYSIS

Attacks host leukemia le kemia GVL

Attacks host T cells ENGRAFTMENT

Ruggeri et al Semin Cancer Biol. 2006

Suicide gene therapy

donor

GVHD

GVL
HSZ-Tk gene inserted into proliferating donor PBMC

GVHD modulated

transplanted patient

ganciclovir

Haplo identical SCT for advanced leukemia Haplo-identical 107 CD3+TK+ cells/kg full immune recon broad repertoire p Relapse prevented in 2/3 patients multiple 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 split restimulate IL-2 Select and expand growing clones

10 X 96 well plates

Test select

6-8 6 8 weeks
Give DLI to relapsed CML patient
Pool active and specific CTL lines

Falkenburg et al

NK infusions
Haploidentical p NK cells p proliferate in recipients p and show cytotoxicity
Requirement for lymphodepletion (IL15 driven expansion) 92% of lymphocytes of donor origin and show NK cytotoxicity

Miller et al Blood 2005

GVH

GVL

Selective Depletion
Recipient nonleukemic cells MLR
CD25

Anti-CD25 immunotoxin

Reactive
Donor

Third-party stimulators

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

Recipient p leukemic cells

Sufficient numbers
Recipient
Efficient antigen presentation

Combined GVL strategies for the perfect stem cell allograft

PBSCT
Selective allodepletion CD3 5 x 106 /kg CD34
Boost NK recovery y Block T reg function (Ontacc?)

No immunosuppression !
vaccinate

vaccinate
HLA-matched / Mismatched: TXPT

survival

Select NK alloreactive

Infuse leukemia-specific CTL relapse

0 1 2 YEARS 3 4 5

Anti-leukemia + immunoablation

The future of allogeneic SCT

Small molecules Combination chemotherapy

Early y chemotherapy py

High dose chemotherapy and marrow rescue

Selective immune reconstitution

Thanks !

Our patients

Our mice

Our best friends