Richard Champlin, M.D., Chair, Dept. of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center - Newest Modalities in Bone Marrow Transplantation Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

1. New Modalities in Stem
Cell Transplantation
Richard Champlin, M.D.

2. Major Innovations SCT-CT
• Nonmyeloablative Conditioning
• Alternative Donors
– Cord Blood
– Haploidentical Transplants
• Cell Therapy
– T-cells
– Chimeric Antigen Receptors
– NK Cells

3. Hematopoietic Stem Cell Transplantation
Preparative D D
Regimen D D
HSCT
D
R
R D
R D
RL D
RL D
Allogeneic hematopoietic is an effective, but toxic treatment for
hematologic malignancies, associated with a high risk of morbidity
and mortality (10->50%), restricting its use to young patients without
comorbidities

4. Goal of Conditioning Regimen
• Provide immune suppression to prevent
rejection and create “space” for
engraftment
• Eradicate the malignancy
– Most effective drugs/radiation treatments
for hematologic malignancies also kill
normal myeloid and lymphoid cells
– Kill malignant stem cells

5. Allogeneic BMT for CML
Importance of GVL
High Dose
Chemoradiotherapy
Donor Lymphocyte
Infusion
Remission
T-cell
depletion
Identical twin
Unmodified Limit of
Detection
BMT Time

7. Graft-vs-Malignancy
Allogeneic SCT
• High dose therapy and allogeneic SCT is an
effective treatment for hematologic malignancies
• Much of the benefit of alloSCT is due to immune
GVL effect; therefore maximally ablative therapy
may not be needed.
• Lower dose nonmyeloablative preparative
regimens are sufficient to prevent rejection.
• We hypothesized that a reduced intensity,
nonmyeloablative allogeneic transplant could
reduce toxicity and allow successful treatment of
older patients and those with major comorbidities.

9. Nonablative and Reduced
Intensity Regimens
Nonablative Reduced Intensity Ablative
TBI/CyT
F-TBI
2Gy BuF BuCy
MF
FCR
Myelosuppression
Champlin et al 2000

10. Nonmyeloablative Transplant
PreparativeDsc DT DT
Regimen D DT DT DT
HSCT +DLI
Dsc DT DB
R
R DNK Dsc
R DT DNK
RL R D
RL RL D
Recipient Donor Mixed Chimera Complete Chimera

11. Busulfan AUC Relative to Toxicity and aGVHD
0.8
Probability of Mucositis ≥ 3 Probability of GI Toxicity ≥ 3
0.8
0.6
0.6
Probability
Probability
0.4
0.4
0.2
0.2
0.0
0.0
800 1000 1200 1400 1600 1800 800 1000 1200 1400 1600 1800
AUC AUC
Probability of Hepatic Toxicity ≥ 2 Probability of GVHD ≥ 2
1.0
0.8
0.8
0.6
0.6
Probability
Probability
0.4
0.4
0.2
0.2
0.0
0.0
800 1000 1200 1400 1600 1800 800 1000 1200 1400 1600 1800
AUC AUC
Andersson et al 2002

12. Pathophysiology of
Acute GVHD
APC=antigen-presenting cell; CTL=cytotoxic T lymphocyte; IFN=interferon;
IL=interleukin; LPS=lipopolysaccharide; Mac=macrophage; NK=natural killer cell;
TH=T-helper cell; TNF-α=tumor necrosis factor-alpha.

13. Grade 2-4 Acute GVHD
1.00
A
C 0.75
U HR 3.1 (CI= 1.3-7.2)
T
E
0.50
G BUCY/FM
V
H
D 0.25
0.00 NMA
0 50 100
Days

14. Nonablative BMT
• Reduced toxicity
• Reduced GVHD
• Similar infections occur, but generally
respond to therapy
• Lower treatment related mortality
• Can extend the use of HSCT to patients
up to 75 years of age

15. Comparisons Albative vs. RIC SCT
• Lack of randomized controlled trials
• Non-randomized comparisons always
confounded by different patient populations
– Ablative- young, fit patients
– RIC- Older patients with comorbidities
• Conclusions
– RIC higher relapse, lower NRM, survival not
significantly different.
• Can one develop effective anti-tumor
preparative regimens, with acceptable (less)
toxicity?

16. IV Bu-Flu Overall Survival
and Event Free Survival
1.0
1.0
0.8
0.8
Event-free probability
Survival Probability
0.6
0.6
0.4
0.4
In remission, PB.blast=0
Active Disease, PB.blast=0
Active Disease, PB.blast>0
0.2
In remission, PB.blast=0 0.2
Active Disease, PB.blast=0 p<0.0001
Active Disease, PB.blast>0 p<0.0001
0.0
0.0
0 20 40 60 80 100 120 0 20 40 60 80 100 120
Time(weeks) Time(weeks)

17. Nonablative AlloSCT vs Chemo for
Elderly AML

18. Opportunities for Cure in CML
Preparative Regimen
CML Cell Mass
Donor Lymphocyte
Imatinib
Infusion
Time

19. Survival

20. Ablative Allo-BMT in
Indolent Lymphoma
100
Survival
DFS
Probability, %
80 Treatment-related mortality
Relapse
60
40
20
0
0 1 2 3 4 5 6
van Besien et al. Blood. 1998;92:1832-1836. Years

21. NON-MYELOABLATIVE ALLOGENEIC SCT
Conditioning Regimen
Rituximab Fludarabine 30 mg/m2 Rituximab
375 mg/m2 Cyclophosphamide 750 mg/m2 1000
mg/m2
ASCT
Days
-13 -6 -5 -4 -3 0 +1 +8
•ATG 15 mg/kg daily, was given days –5 to –3 for mismatched or unrelated SCT
•Tacrolimus and methotrexate were used for GVHD prophylaxis

22. FCR allo SCT for Low Grade
Lymphoma
Khouri et al Blood 2008

23. Rituximab: Mechanism of Action
Antibody-Dependent Cell-Mediated
Cytotoxicity (ADCC)
Macrophage,
Monocyte,
or Natural Killer
Cell
CD20
FcγRI, FcγRII, or
FcγRIII
CELL
LYSIS
Anderson DR, et al. Biochem Soc Trans. 1997;25:705-708,
Clynes RA, et al. Nat Med. 2000;6:443-446.

24. Rituximab
Antigen Presentation and Cross-Priming
Tumor Cell
T Cells
FcR Tumor Antigen
Dendritic Cell

25. Efficacy of Nonablative HSCT
Highly Effective Dose Intensity
(better than ablative) Important
LGL, CLL CML
Mantle cell lymphoma AML /MDS
Myeloma (tandem)? LCL, Hodgkin’s disease
Renal Cell, Ovarian ALL
Breast CA-Promising

26. ATG with RIC SCT
CIBMTR-Soiffer Blood 2011
• Compare T-replete transplants with no
ATG, ATG, Alemtuzumab
• ATG- assoc with decreased cGVHD,
increased relapse, worse PFS and
survival
• Alemtuzumab- assoc with decreased
acute and cGVHD, increased relapse,
no change in survival

27. Best Available Donor

28. MD Anderson Cord Blood Bank
Elizabeth J. Shpall MD

29. Cord Blood Transplantation
• Rich source of stem cells
• ~50,000 units banked, immediately available
for transplantation
• Immunologically immature- less prone to
produce GVHD
• Less risk of transmitting infection
• Can successfully transplant across HLA
mismatch
• Major concern- low stem cell dose, longer
time to engraftment- may be overcome by ex
vivo expansion
• Results comparable to MUD BMTs

30. Mesenchymal Stem Cells (MSC)
• MSC are a stromal component
of the hematopoietic
microenvironment.
• They provide cellular and
extracellular components of the
stem cell “niche”.
• When isolated and used in vitro
in combination with cytokines,
MSC markedly increase the
expansion of CB hematopoietic
progenitors.

31. Co-culture with MSC significantly enhances
ex vivo expansion of CB cells
Fold increase x13 x25 x7 x14 x200 x44
Day 14 hematopoietic output from liquid culture of CD133+ (solid bar) vs.
co-culture of non-selected CB cells with MSC (striped bar)
Robinson et al. Bone Marrow Transplantati

32. MSC-CB Expansion Trial Engraftment Data
Median time to engraftment (range)
Neutrophil (>500/µl) 15 days (range 9-42)
Platelet (>20,000/µl) 40 days (range 13-62)
Cumulative Incidence of Engraftment
Neutrophil (>500/µl) 97% (n=31)
Platelet (>20,000/µl) 81% (n=26)
- One patient died before engraftment
de Lima et al. Blood (ASH Annual Meeting Abstracts), 2010; 116: 362

33. Post Transplant Cyclophosphamide
for Haploidentical Transplantation

34. NST for Haploidentical
Transplantation
Luznick et al 2008

35. Cell Therapy +/- HSCT

36. T-cell Immune Response
T-Cell Activation
and Proliferation
36

37. Chimeric antigen receptors (CARs)
TCR-complex
Antibody
α β
γε εδ
ζ ζ
vL
Fab
vH CL
CH1
vH vL
Chimeric antigen receptor
(Eshhar et al; PNAS 1993)

38. Chimeric Antigen Receptors
Cooper et al

39. Allo NK-based conditioning:
Ablation of recipient targets
Kill recipient APCs =
protection from GvHD
Donor DC
alloreactive
DC
NK cells
DC
NK
Lysis
NK
NK Lysis
leukemia
Lysis
Kill leukemia =
T TT T GvL effect
Kill recipient T cells =
improved engraftment
Ruggeri et al. Science 2002

40. Addition of NK cells to HSCT
Phase I/II study to determine toxicity and efficacy of addition of
alloreactive NK cells to high dose chemotherapy and allogeneic
stem cell transplantation for myeloid leukemias
Haploidentical
Allo reactive Allo match
Busulfan NK Cells PBPC
ATG
Fludarabine
Champlin et al

41. Hematopoiesis
T-lymphocytes
Stem Cells
B-lymphocytes
Granulocytes
Monocytes
Eosinophils
Basophils
Erythrocytes
Megakaryocytes
Platelets

42. Glands
GI tract, islet cells
Immune System
Blood
Heart
Stem Cell
Mesenchymal
Blood vessels
Fibrous tissue
Nervous System
Liver and other organs

44. Approach to Abrogate GVHD

45. Suicide Switch- Prevention of GVHD
45

46. Modified Caspace 9- Self
Destruct Switch
46

47. If We Can Prevent GVHD
• Dramatically expand use of allogeneic
SCT
• Bone marrow failure/immune deficiency/metabolic
diseases of hematopoietic cells
• Non malignant hematologic/metabolic/immune
mediated diseases
– Thalassemia, Hemoglobinapathies
– Autoimmune diseases
» Arthritis, Diabetes, Rheumatologic diseases, ……
• Tolerance for Organ Transplants
• Malignant Diseases
– Eliminates major toxicity of highly effective treatment

48. Ideal Nonablative Hematopoietic Transplant
Preparative D D D D D
Regimen D D Vaccine or
Immune
HSCT
Effector cells
R R R D D
D
R D D
R D D
RL R D
RL RL D
Recipient Donor Tolerant Complete Chimera
Mixed Chimera
No GVHD, Immune Reconstitution, GVL for malignancy