Transplant: Past Present and Future

John McCarty M.D.

Medical Director

Bone Marrow Transplantation Program

Massey Cancer Center

VCU Health Systems/MCV Hospitals and Physicians

May 7, 2008

Introduction

• History of stem cell transplantation

• Definition and biology of stem cells by source

• Practical aspects of the transplant process

• Future directions of BMT

Highlights in Stem Cell Transplant

• Studies of atomic bomb victims showed marrow most sensitive to radiation

• Splenic shielding protected mice from radiation• Bone marrow infusion rescued mice from radiation• Murine and canine models developed for transplant• Discovery that immune response controlled by genetic

factors (histocompatibility factors)• Marrow from histocompatible animals rescues from

lethal radiation

Highlights in Stem Cell Transplant

• 1957: marrow safely infused intravenously

• 1958: reports of successful identical twin transplants

• 1969: Cytoxan added to radiation• 1970: bone marrow harvests

perfected to obtain stem cells• 1989: peripheral blood stem cells

harvested• 1990: first successful cord blood

transplant• 1996: first non-ablative transplant

Thomas et al J Clin Invest 1959

What are Stem Cells?• Not characteristics of specific tissues• Divide for the lifetime of the

organism• Can replenish themselves• Stem cells as “seed cells” for the

body• Stem cells may exist in all organs

– Serve in injury repair– “trust fund” to replace cells as they die

off

• Stem cells may circulate from one tissue reserve to another?

Sources of Stem Cells

• Three main types of stem cells– Adult stem cells

• Main reservoir in the bone marrow

– Cord blood stem cells• Circulating stem cells in

umbilical cord blood

– Embryonic stem cells• Derived from fertilized

embryos during early phases of development

Adult Stem Cells

• Replenish cells lost through age or injury

• Largest reservoir in marrow– Stem cells circulate in blood

– “Relocate” to fill empty stem cell slots in other tissues

• Harvested from bone marrow or peripheral blood in stem cell transplants since late 1970’s

• Stem cells isolated from:– Skin, brain, prostate, muscle

Umbilical Cord Blood Stem Cells

• Obtained from blood retained in the umbilical cord and placenta after delivery

• Has been used in stem cell transplants since the late 1980’s– Most often used in children

and small adults– Potential role for double

cord transplants in adults

QuickTime™ and aGIF decompressor

are needed to see this picture.

Indications for Stem Cell Transplants

• Cancer:– Leukemia– Myelodysplasia– Lymphoma– Breast cancer– Testicular cancer– Ovarian cancer– Brain tumors– Pediatric tumors– Multiple myelomas– Sarcomas– Kidney cancers

• Non Cancers:– Autoimmune diseases

• Rheumatoid arthritis– Juvenile and adult

• Multiple Sclerosis

• Scleroderma

• Systemic Lupus

– Immune deficiency

– Sickle cell anemia

– Thalassemia

Annual Numbers Of Blood And Marrow Transplants Worldwide 1970-2002

NU

MB

ER

OF

TR

AN

SP

LA

NT

S

YEAR

1970 1975 1980 1985 1990 1995

Autologous

Allogeneic

20000

5,000

10,000

15,000

20,000

25,000

30,000

35,000

40,000

45,000

Stem Cell Sources By Recipient Age 1997-2004

Bone Marrow (BM)

Peripheral Blood (PB)

Cord Blood (CB)

Age 20 yrs Age 20 yrs

0

20

40

60

80

100

1997-2000 2001-2004 1997-2000 2001-2004

Tran

sp

lan

ts,

%

Bone Marrow (BM)

Peripheral Blood (PB)

Cord Blood (CB)

Practical BMT

• Two main types based on source of stem cells– Autologous: no immunologic conflict

• Stem cell infusion as “rescue” from high dose chemo

– “marrow lethal dose”

– Allogeneic: Minor HLA disparity•Related•Unrelated•Cord blood

– High dose therapy with immunotherapy» “rejection” of the cancer and building better

immunity

Elements of Stem Cell Transplants

• Selection of donor– Based on tissue typing of 6-10 HLA antigens in allogeneic transplantation– Tissue typing unnecessary in autologous transplantation

• Harvest of stem cells from donor– Bone marrow harvest or pheresis of peripheral blood

• Preparative regimen– Chemo-radiation for ablation and immune suppression

• Stem cell infusion• Post-transplant supportive care

– Autologous 100 days– Allogeneic 180 days or longer for tolerance to develop

Patient Evaluation

• Recipient Age

– Autologous: “0” to 70 years

– Allogeneic:• Matched Related 55-60 years

• Mismatched or Unrelated Donor: 50-55 years» Risk of GVHD significantly increased age >45

• Dose-Adjusted Transplantation for older, or ill patients– Reduced intensity myeloablative

– Non-myeloablative

» Indicated based on extensive pre-transplant evaluation for candidacy

– Patients up to age 70 may be eligible for allogeneic transplant

Preparation for BMT

• Immune suppression and myeloablation required– Bone marrow failure states require more immunosuppression – Immune deficiency without empty marrow leads to rejection.

• Chemotherapy induces aplasia to allow engraftment

• Additional merits of marrow ablation – Provides marrow “space” – Eradicates malignant cells– Reset of the recipient immune system

• Preparative regimens before transplant provide aplasia and immune suppression

HLA and Marrow Transplantation

• Histocompatibility Locus Antigens (HLA) are determinants of immunologic “self” and “not-self”– Immunologic “password”– Allows for effective immune response against infections, cancer

• T cell reaction to foreign HLA molecules (donor) is a major problem of transplantation (alloreactivity)– Need good donor and recipient match for HLA sites– Cause of acute rejection in organ transplant, and of GVHD in

BMT.

HLA Typing in BMT

• Family members typed with patient for HLA A, B and DR– Likelihood of 6/6 or 5/6

match depends on frequency of recipient HLA haplotype

• Likelihood of unrelated donor match related to haplotype frequency in general population– Some HLA combinations

more frequently found among ethnic groups

• Ethnic sequestration phenomenon

Ethnicity and Unrelated Donors

Growth of the Registry has Increased theLikelihood of Matching for All Patients

0%

20%

40%

60%

80%

100%

1988 1990 1992 1994 1996 1998 2000Year

% o

f P

atie

nts

Fin

din

g a

Mat

ch Caucasian 43,780

American Indian/AN, 243

Mult/Oth/Unk/Dec, 7,187

Hispanic, 3,784

Asian/Pacific Islander, 2,328

African American, 4,228

Increasing Donor Pool Essential

• Time from search to unrelated donor: 4 months– Often relapse prevents coming to transplant

• Greater efforts are needed to increase participation and minority representation in the volunteer donor pool (NMDP)– Education regarding safety and need

• Increasing cord blood donation may help some– Everyone has umbilical cord blood they won’t use– No risk to donate– Better reflects the local population demographics

Harvesting Stem Cells

• Adult stem cells obtained by large volume marrow biopsy/aspiration (1-2L)

• Cord blood stem cells obtained at delivery by sterile emptying umbilical cord and placenta into blood donation bag

• Increasingly obtained by processing of peripheral blood of patients and healthy donors– Isolated in “real time” from blood after stimulation with blood

cell growth factors

• Stem cells can be frozen for up to 5-10 years

Practical BMT

• Stem cells infused IV– “Home” to micro-

environment niches in marrow and spleen• Recognition of

arrays of adhesive and growth factors in marrow stroma

• Donor T lymphocytes are essential to engraftment

Hematopoietic Reconstitution• Bone marrow cellularity decreased months post transplant• Immunologic reconstruction over 100 days post transplant

– Graft-vs.-host disease (GVHD) delays immune reconstitution• Immune deficits expected:

– T cell and B cell dysfunction.– Low Ig levels for three months, normal IgG and IgM by one year, IgA by two

year• Predisposes to fungal, viral and bacterial infection

Transplantation Immunology

• In solid organ transplantation, the main relevant immunologic process is graft rejection

• In marrow transplantation, a novel immunologic condition arises due to the immunologic competence of the graft itself.– Rejection is bi-directional

• Graft rejection • Graft-vs.-host disease (GVHD)

– Tolerance develops, immunosuppression not lifelong

Stem Cell Grafts are Complex

GVL,grafting

GVHD

T Lymphocyte functions Stem cell graft components

Stem Cells,progenitors

FacilitatingCells

DendriticCells

NK Cells T and BLymphocytes

Pathophysiology of GVHD

• Essential factors necessary for GVHD to occur:

– Immunologically competent donor graft

– Histo-incompatibility between donor and host

– Immunologically incompetent host

Graft-versus Malignancy Effect

• Lower incidence of leukemic relapse in patients who get acute or chronic GVHD

• Higher relapse rates in syngeneic vs. allogeneic BMT

• High relapse rates in T cell depleted BMT

• Cytogenetic remission induced after post BMT relapse of CML by infusion of donor leukocytes

Nonmyeloablative Stem Cell Transplants as

Immunotherapy• “Mini transplants”: less cytoablative therapy

– host/donor marrow chimerism prominent– early studies effective in CML in patients

up to 75 yrs– low level GVHD

•if chimerism present, malignancy detectable (PCR):

– reduction in immunosuppression– donor lymphocyte infusion– high remission re-induction rate– lower mortality/morbidity

NST: Overview

.

NST: Graft versus Renal Cell Cancer

60 days post transplant 285 days post transplant

Childs et al NEJM 2000

Tandem Transplantation

• Refers to the deliberate performance of two stem cell transplants within 3-4 months of each other– By intention, rather than by failure to respond

• May consist of autologous-autologous or autologous-allogeneic– The latter allows separation of the high dose component from

the immunotherapy component

• Most often utilized in myeloma, testicular cancer, medulloblastoma, neuroblastoma– Response and risk adaptive approach used in myeloma

Cost of BMT

• Variable due to several factors:– Indication: AML<CML<NHL<AA– Complications: hospital days, blood products most $$– Stem cell source: PBSC<Marrow (faster engraftment)– Preparative regimen: TBI expensive– Unrelated>>Allogeneic>Autologous

• Average ABMT 84k-175k

• Average AuBMT 70k-100k

Cost Effectiveness of BMT

• Welch (NEJM 1989): 41 patients with ALL• 17 w/ matched related donor• 19 w/ no donor; standard consolidation/maintenance

– Costs for survivors (both arms) less than non-survivors

– Incremental cost effectiveness (difference in cost/yrs survival):

– BMT: survivor $166k, nonsurvivor $232k– Chemo: survivor $79k nonsurvivor $157k– More patients surviving after BMT

• ICE of BMT $10k per year of life gained– Rx of moderate HTN $13.5k per year of life gained

Long Term Complications• Infection risk prolonged with GVHD• Infertility (Women>>men, TBI>>HD Cytoxan)• Hypothyroid 15-25%; (TBI)• Cataracts (TBI, steroids)• AVN bone: (steroids)• Autoimmune dysfunction: (GVHD)• Dental: dry mouth, caries (GVHD, TBI)• Malignancy 5-6x increased risk PTLPD

– Non hematologic cancer risks from TBI, Cytoxan

New Directions I Autoimmune diseases heterogenous with variable course

All have a basis in the stem cell

Main intervention is immunosuppression Safety and side effect profile improving for stem cell transplant Transplant considered in patients with severe AID

Life-threatening disease Disease of major morbidity (diffuse Scleroderma) unresponsive to standard therapy (Systemic Lupus) Early in progressive relapse (Multiple Sclerosis)

• Preparative regimens to include BU/CY/ATG avoiding TBI reduces risk of secondary malignancy

New Directions II

• Stem cell transplantation as platform for directed therapies– Dendritic cell/NK cell immune therapy– Vehicle for cancer vaccine delivery– Use of specifically generated cytotoxic T cell

lymphocyte responses• Against malignancy• Against infection

– Enhance autologous Graft versus malignancy effect

Developing Applications I

• Induction of solid organ graft tolerance– In living donor solid organ transplants

• Orthotopic liver• Kidney• Pancreatic islet cell

• Tolerance to solid organ by subsequent NST transplantation– Patient as mixed chimera– Transplanted marrow and lymphocytes tolerate patient and

recognize transplanted organ as “self”

Developing Applications II

• Heart disease– Heart muscle damaged by coronary heart disease or

viral injury– Injection of stem cells into area of dead heart muscle

regenerates viable muscle– Injection of stem cells promotes formation of new

blood vessels in injured heart muscle– Can intracoronary or intravenous purified stem cell

populations be given during cardiac catheterization?

Stem Cells Repair Broken Hearts

Orlic et al PNAS 2001

Conclusions

• Stem cells can be derived from adult, cord blood and eventually embryonic stem cells

• Stem cell transplantation can both support highly intensive chemotherapy and promote highly effective immunotherapy

• Recent advances in stem cell transplantation allow therapy more tailored to disease and patient

• Improved supportive care measures expand transplant to more patients

• Expanded applications capitalizing on stem cell plasticity are feasible