The future of HSCT

John Barrett, MD,NHBLI, NIH 

Bethesda MD

Transplants today

Current approaches to improve SCT outcome

Select god risk patients!

YEARS0 1 2 3 4 5

survival

relapseTXPT

Better Supportive care

survival

relapseTXPT

survival

relapseTXPT

Optimize stem cell dose and source

BMT? PBSCT?

survival

relapseTXPT

New conditioning regimens

Controlled regimen intensity

survival

relapseTXPT

Adjusting post transplant I/S to minimize GVHD and preserve GVL

transplant Marrow

recoveryAPC recovery

B cell recoveryT cell recovery

NK recovery

Biological endpoints

GVLcGVHD

aGVHD

Viralreactivation

infection

clinical endpointsRelapse

TRM OSDFSstatistical endpoints

Roadblocks to sucessful outcome

Preventing GVHD

Host APC Donor T cells

CD4

CD8mHA

MHC1MHC2

virus

leukCD8

CD4

Host targetdamage repairengagement Activation/ex

pansion

Remove APCBlock APC

Stop activation

Prevent T‐cell ‐ target contact

Tissue repairblockproliferation

RemoveT‐cells

CSA/TacroSirolimusTregs

MTXCyMMFSteroidsMSC

Steroidshoming

MSCATGCampath

T cell depletionSelective T cell depletion

Conditioning

Bortezomib

PRO

BA

BIL

ITY,

%

100

0

20

40

60

80

YEARS

0 1 2 3 4 5

1995 (9,747) 20%

1985-1994 (8,989) 22%

1975-1984 (1,071) 23%

* 1st CR for AML or ALLChronic phase for CML

NO CHANGE IN RELAPSE AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR EARLY LEUKEMIA*

IBMTR, 1975-2002

* Not in remission for AML or ALLBlast phase for CML

PRO

BA

BIL

ITY,

%

100

0

20

40

60

80

YEARS

0 1 2 3 4 5

1995 (2261) 62%

1985-1994 (2299) 60%

1975-1984 (451) 62%

NO CHANGE IN RELAPSE AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR ADVANCED LEUKEMIA*

IBMTR, 1975-2002

Is BMT at an evolutionary dead end ?

The  challenges ahead

A transplant for every patient that needs one?

Expanding the donor pool

Safer transplants for older patients

Related and unrelated SCT meet less than half the need for donors

21,000 no unrelated donor

4,000 unrelated

11,000 related

30%

42%

100%

Percentage of patients needing donors

CBT

Haplo transplant

SUM-WW11_10.ppt

Allogeneic Transplants for Age 20yrs,Registered with the CIBMTR

1992-2009- by Donor Type and Graft Source -

Slide 10

Num

ber

of T

rans

plan

ts

*

* Data incomplete

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

5,000

1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09

Related BM/PBUnrelated BM/PBUnrelated CB

SUM-WW11_11.ppt

Allogeneic Transplants for Age 20yrs,Registered with the CIBMTR

1992-2009- by Donor Type and Graft Source -

Slide 11

Num

ber

of T

rans

plan

ts

*

* Data incomplete

01,000

2,0003,0004,000

5,0006,0007,0008,000

9,00010,00011,000

12,00013,000

1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09

Related BM/PBUnrelated BMUnrelated PBUnrelated CB

SUM-WW11_11.ppt

Trend: More patients will have a donor

Umbilical cord and URD - Increase in banks

Haploidentical donors – more as the procedure gets safer

Health care delivery- NMDP approach to increasing SCT availability- availability increases with socio-economic status

0

20

40

60

80

100

1989-1995 1996-2002 2003-2009 1989-1995 1996-2002 2003-2009

< 50 years>= 50 years

<60 years>=60 years

SUM11_5.ppt

Trend: Older patients will be increasingly transplanted

(data shown 1989-2009)

* Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma Slide 7

Tran

spla

nts,

%

Allogeneic Transplants Autologous Transplants

RELAPSE

GVHD

INFECTION

REGIMEN RELATED MORTALITY

SUM-WW11_17.ppt

The limits of success today

Cell therapy for HSCT – the Vision

DLI, T cells and NK cells

Virus specific T cells

MSC / Tregs

MSC

>90% survival

GVHD

Relapse

Infection

Organ toxicity

Transplant CD34 cells unmanipulated / T cell depleted

engraftment

Sources: AllogeneicMarrowBloodCord blood

Cell therapy complexity

minimalcell sorting

culture expansion

selectionfeeder cells

gene insertionadjuvants

Level 1

MarrowUCB

G-PBSCTG-Marrow

DLI

minimalmanipulation

Level 2

CD34 selectionCD4 selection

Memory cell selectionT reg selectionNK selection

Level 3

Selective immunodepletionVirus specific T cells

Tumor-specific T cellsTIL, MILNK cells

MSCDC

Level 4

CAR cellsTCR insertionSuicide genes

TGFb resistanceCytokine secreting

Frequency of use

The long winding road to successful T cell therapy

Improved APC generation

Low volumeGMP grade culture systems

multi-virus specific T cells in

the clinic

2000

Improved growth conditions

tumor specific T cells in the clinic

Target antigen identification

1995

Proof of principleVirus specific T cells

Leukemia-specific T cells

Incorporating CD4 and CD8 responder

• 9/40 patients had EBV reactivation• 9/9 patients had decrease in EBV viral load with

corresponding elevation in EBV-specific CTL detected in PB

• No antiviral therapy required

Nat Med. 2006;12(10):1160-1166

Multivirus -specific CTLProtect against EBV after HSCT

Diagnosis of PTLD 2 months later

Adherent PBMCGM-CSFIL-4

PBMC

IL-1bIL-6

TNF-aPGE-2

mDC

LCL LCLLCL

Making LMP1 and LMP2T cells to treat Hodgkins disease

LMP-specificCytotoxic T

Lymphocytes (CTL)

IL-15 IL-2 IL-2

More recentlySubstituting ad

vector for pepmixes

Bollard et al, JIT 2004, Straathof et al, JI 2005

PREPRE

POSTPOST

PREPRE POSTPOST

Clinical Responses post LMP-CTL

Relapsed Disease Arm (n=23)

• No toxicity• 12 CR (1 also given Rituximab)

(includes 1PRCR)• 2 very good partial responses

(up to 36 mths)• 9 progressive disease (2-8 wks)

Median clinical response: 1.5y (range: >6 to >40 mths)

CRPR

n =23

Patients with disease at CTL infusion

Clinical Responses post LMP-CTL

New York Times, December 9, 2012

Progress in the general application of cell therapy 

CommercializationAcceptance

CD34 cell products

Dendritic cells

MSC

CAR‐trans T cells

T regs

NK cells

Clinical trials

Virus‐specific T cells

Tumor specific T cells

Technology

Gene modified T cells

“Black Box” The future for commercial cell therapy?

Apheresis lymphocytes

Add growth factors

Add peptides

Cell product:Virus specific

T cells

Controlled sterile environment

Apheresis monocytes

2043

Transplants in 30 years time ?

Some predictions

PREDICTION: APPROX 5% IMPROVED SURVIVAL / DECADE

(URD myeloablative SCT shown)

PRO

BA

BIL

ITY,

%

100

0

20

40

60

80

YEARS

0 1 2 3 4 5

1995 (7,251) 41%

1984-1994 (2,095) 37%

P = 0.0001

2015

2035

2045

2025

2005

* Not in remission for AML or ALLBlast phase for CML

PRO

BA

BIL

ITY,

%

100

0

20

40

60

80

YEARS

0 1 2 3 4 5

1995 (2261) 62%1985-1994 (2299) 60%

1975-1984 (451) 62%

PREDICTION : IMPROVED CURE RATES

(HLA-ID Sib SCT for advanced disease shown)

2045 – 5%??

Tran

spla

nts

SUM11_41.pptSlide 3

Unpredictables

0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

'80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03'04' '05 '06 '07 '08 '09 '10

AutologousRelated DonorUnrelated Donor

Unpredictables: combinations that work

Surgery radiationchemotherapy

Cell therapy,SCT

New agentscytokines

MonoclonalsSmall molecules

Unpredictables: new treatments change indications for HSCT

another imatinib

cell therapy without HSCT

gene therapy

Small molecules

Cell therapyCytokinesNew drugs

The future evolution of allogeneic SCT

Early chemotherapy

Combinationchemotherapy

High dose chemotherapy and marrow rescue