history of transplant
DESCRIPTION
Milestones in the History of StemCellTransplantationTRANSCRIPT
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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