Advances in Stem Cell Transplantation and Cellular Therapeutics

5/21/2015
Advances in Stem Cell Transplantation
and Cellular Therapeutics
Dr. Joseph McGuirk
Medical Director, Blood and Marrow Transplantation
Interim Director, Division of Hematology/Oncology
1
Disclosures
I do not have any relevant financial relationships with
any commercial interests related to the content of my
presentation.
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5/21/2015
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Blood & Marrow Transplant Volume (FY08-15)
342
350
296
300
# of Transplants
267
250
220
180
160
151
150
161
Total
Auto
Allo
142
146
135
119
106
100
85
77
66
55
50
200
190
200
38
17
74
114
76
107
74
42
0
FY07
FY08
FY09
*FY15 annualized volume as of 4/1/15
FY10
FY11
FY12
FY13
FY14
*FY15
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“One million haemopoietic stem-cell transplants: a
retrospective observational study”
Volume 2, No. 3, e91-e100, March 2015
Prof Alois Gratwohl, MD, Marcelo C Pasquini, MD, Prof Mahmoud Aljurf, MD,
Yoshiko Atsuta, MD, Helen Baldomero, BMS, Lydia Foeken, MD, Michael
Gratwohl, PhD, Prof Luis Fernando Bouzas, MD, Dennis Confer, MD, Karl
Frauendorfer, PhD, Prof Eliane Gluckman, MD, Prof Hildegard Greinix, MD, Prof
Mary Horowitz, MD, Minako Iida, MD, Prof Jeff Lipton, MD, Alejandro Madrigal,
MD, Prof Mohamad Mohty, MD, Luc Noel, MD, Prof Nicolas Novitzky, MD, José
Nunez, MD, Machteld Oudshoorn, PhD, Prof Jakob Passweg, MD, Prof Jon van
Rood, MD, Prof Jeff Szer, MD, Prof Karl Blume, MD, Prof Frederic R Appelbaum,
MD, Prof Yoshihisa Kodera, MD, Prof Dietger Niederwieser, MD,for the
Worldwide Network for Blood and Marrow Transplantation (WBMT)
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Global Development of HSCT, 2010
Gratwohl et al. The Lancet Haemotology, Vol 2, No. 3, e91-e100, March 2015
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Racial/ethnic distribution of potential donors in the National Marrow Donor Program registry
Lee S J Blood. 2013;121:1252-1253
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©2013 by American Society of Hematology
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Adjusted probability of overall survival in 2223
adult AML patients by donor type
HLA-id Sib (N=624)
8/8 MUD (N=1,193)
7/8 MUD (N=406)
Wael Saber et al. Blood. 2012;119:3908-3916
©2012 by American Society of Hematology
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Challenges to Improving Outcomes of
Stem Cell Transplantation
1. Worldwide Access (macroeconomics)
2. Relapse
3. Knowledge regarding SCT indications & timing
4. Graft-vs-Host Disease
5. Lack of Donors
6. Advanced Age/Co-morbidities
7. Regimen-related toxicities
8. Infection
9. Late effects/Long-term Survival
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Causes of Death after Transplants Done in
2011-2012
HLA-identical Sibling
Unrelated Donor
Autologous
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Strategies to improve outcomes in
multiple myeloma
• Post SCT maintenance
• Post SCT consolidation  maintenance
- CTN 0702
• MRD measurement
• Immunotherapeutic strategies for MRD
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Vaccination in Conjunction with HSCT
• Autologous transplant for myeloma offers a
unique opportunity to explore the role of cancer
vaccines
– Patients achieve minimal disease state but reliably
relapse
• Enhanced response to vaccination post-transplant
in animal models
– Depletion of regulatory T cells during the period of posttransplant lymphopoietic reconstitution
– Expansion of tumor reactive clones
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Source: David Avigan, MD; Beth Israel Deaconess Medical Center
Vaccine Characterization
Myeloma Cells CD-38
Dendritic Cells CD86
DC/MM Fusions
CD38/CD86
Rosenblatt et al. Blood. 2011 Jan 13;117(2):393-402
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Cohort 2
Induction
Therapy
Cohort 1 and 2
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Source: David Avigan, MD; Beth Israel Deaconess Medical Center
Background: Vaccination following
Autologous PBSCT for Myeloma
100%
90%
80%
13%
33%
% Participants
70%
25%
60%
50%
38%
40%
30%
54%
20%
29%
10%
0%
100 Day Post-Transplant
CR/nCR
Source: David Avigan, MD; Beth Israel Deaconess Medical Center
Post 100 Day (Best Response)
VGPR
PR
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Myeloma Associated Immune Suppression
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Rabinovich et al. Annual Review of Immunology. 2007;25: 267-96
CD 86
PDL-1 is strongly Expressed on DC/Myeloma Fusions
Avigan, et al. J Immunother. 2011 Jun;34(5):409-18
CD 38
PDL-1
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PD1 blockade enhances immune response to
DC/myeloma fusion vaccine in vitro
PD-1 blockade in conjunction with DC/myeloma fusion stimulation of
T cells in vitro results in:
- increased IFN-gamma secretion
- decreased IL-10 secretion
- decreased expansion of Tregs
- enhanced tumor killing
- increased anti-MUC1 CD8+ CTLs
Avigan, et al. J Immunother. 2011 Jun;34(5):409-18
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PD-1 ligands are overexpressed in Hodgkin’s
Disease through alterations in chromosome 9p 24.1
IFNγ
IFNγR
T-cell
receptor
MHC
Tumor cell
PI3K
NFκB
Other
PD-L1
Shp-2 T
PD-L2
cell
PD-1
PD-1
Nivolumab
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Original Article
PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's
Lymphoma
87% objective response
• N=23
• 78% Auto
• 78% Brentuximab
17% CR
Ansell SM et al. N Engl J Med. 2015;372:311-319.
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2727
Moskowitz CH, et al. Lancet Oncol. 2015; 16:284-292
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Survival of Patients with AML Relapsing post AlloSCT
Bejanyan et al. Biology of Blood and Marrow Transplant. 2015 21, 454-459
Copyright © 2015 American Society for Blood and Marrow Transplantation
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Timing Matters
• Patients transplanted earlier in their disease have better
outcomes than patients with advanced disease,
regardless of the degree of match
Lee SJ et al. Blood. 2007;Vol 110:4576-4583.
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Underutilization of Stem Cell Transplantation
Adult Unmet Need for Allogeneic SCT in 2012
Adapted from Besse et al. Journal of Oncology Practice. (2015) Vol 11, Issue 2
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Effect of T-Cell Depletion and GVHD on
Probability of Relapse in Leukemia
Probability of Relapse
1.0
0.8
Twins
0.6
T-cell depletion
0.4
No GVHD
Acute GVHD only
Chronic GVHD only
Acute+Chronic GVHD
0.2
0.0
0
12
24
36
Months
48
60
72
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Adapted from: Horowitz M et al. Blood. 1990; 75; 55-62.
Marrow aplasia
• DLI
GVHD
Poor efficacy
• TIL + IL2– e.g. melanoma
• TCR – modification
HLA-restricted
Mis-pairing α and β chain
Doesn’t recognize glycolipids
or carbohydrates
• CAR T Cells (not HLA restricted)
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T Cells on the Attack
J Couzin-Frankel. Science. 20 Dec 2013. Vol. 342 no. 6165 pp. 1432-1433
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Optimizing the CAR Signaling Domain to Treat
Hematologic Malignancies
(Signal 2)
(Signal 1)
S. R. Riddell et al. Biol Blood Marrow Transplant. 19 (2013) S2-S5
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Copyright © 2013 American Society for Blood and Marrow Transplantation
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Schematic of the Treatment of a Patient with Chimeric
Antigen Receptor (CAR) T Cells
Jacobson C A and Ritz J Blood 2011;118:4761-4762
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©2011 by American Society of Hematology
CD19: An Ideal Tumor Target in B-Cell Malignancies
• CD19 expression is generally restricted to B cells and B cell
precursors1
– CD19 is not expressed on hematopoietic stem cells1
• CD19 is expressed by most B-cell malignancies1
– CLL, B-ALL, DLBCL, FL, MCL1
• Antibodies against CD19 inhibit tumor cell growth
B cell lymphomas and
leukemias
preB-ALL
Hematopoietic
stem cell
Pro-B
Pre-B
Immature
(IgM)
Mature
(IgM, IgD)
CD19 expression
Activated
B cell
1. Scheuermann RH, et al. Leuk Lymphoma. 1995;18:385-397
Image adapted from Janeway CA, Travers P, Walport M, et al. Immunobiology. 5th ed. New York, NY: Garland Science; 2001:221-293; Scheuermann
RH, et al. Leuk Lymphoma. 1995;18:385-397; and Feldman M, Marini JC. Cell cooperation in the antibody response. In: Roitt I, Brostoff J, Male D,
eds. Immunology. 6th ed. Maryland Heights, Missouri: Mosby;2001:131-146.
Memory
B cell
(IgG, IgA)
Plasma
cell
(IgG)
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Outcomes for Adults with 1st Relapse ALL
Male vs Female
Fielding A K et al. Blood . 2007;109:944-950. ECOG 2993
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Outcomes for Adults with Relapsed ALL
after Allogeneic SCT
Poon, et al. BBMT 2013;19, 1064
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Original Article
Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Response
N=30
%
Complete Response
27/30
90%
No response
3/30
10%
Not evaluable
extramedullary dz (1)
and short f/u (2)
3/30
10%
Maude SL et al. N Engl J Med. 2014;371:1507-1517.
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ALL: Overall Response to CTL019
Maude SL et al. N Engl J Med. 2014;371:1507-1517.
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Toxicity: CTL019
• No significant acute infusional toxicity
• Tumor lysis syndrome (3 grade 3-4)
– Reversible and manageable
• B cell aplasia and hypogammaglobulinemia in responding
patients (toxicity or efficacy?)
– Supported with intravenous immunoglobulin (IVIG)
– No excessive or frequent infections
• Cytokine Release Syndrome (CRS)
• Neurotoxicity
Maude SL et al. N Engl J Med. 2014;371:1507-1517.
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Targeting AML:
CD33 and CD34 as differentiation antigens
• CD33 antigen expressed on ~88% of AML1
• Not expressed by multipotent hematopoietic progenitor cells 2
• Minimal expression on non-hematopoietic normal cells
1 A Ehninger et al. Blood Cancer J. 2014 Jun 4, e218
2 Roland B. Walter et al. Blood. 2012;119:6198-6208
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DLBCL
MCL
• CAR T – other CD19+ targets
Follicular
Multiple myeloma
– other Hem. Targets (e.g. CD33)
EBV
Adenovirus
• CAR T
BK
RSV
CMV
• CAR T – multivalent
• CAR T – solid tumors
Virus
Tumor
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On Target
Off Tumor
Toxicity
M.H. Kershaw et al. Clin Transl Immunology. 2014 May; 3(5): e16
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Mechanism of Action of Different Suicide Gene Technologies
Jones BS, et al. Front Pharmacol. 2014; 5:254.
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Generation of Transgene and Function of Activated iCasp9
Di Stasi A et al. N Engl J Med. 2011;365:1673-1683.
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Characteristics of Patients & Clinical Outcomes
P t#
Ge nd e r
(ag e in
yrs)
Diag no sis
Dise ase
status at
SC T
1
M (3)
Secondary
AML
2
F (17)
B-ALL
CR2
3
M (8)
T-ALL
PIF-CR1
4
F (4)
T-ALL
Active
disease
CR2
5
M (6)
B-ALL
CR2
(7q31 del)
6
F (17)
Biphenotypic
leukemia
CR2
7
F (7)
T-cell
lymphoblastic
lymphoma
CR2
8
M (14)
T-ALCL
CR1
9
F (9)
MDS
No excess
monosomy 7
blasts
10
F (8)
Biphenotypic
leukemia
CR1
C o nd itio ning /
Inte nsity*
Bu-FluCampath/MAC
Bu-CyCampath/MAC
AraC-CyCampathTBI/MAC
Bu-CyCampath/MAC
AraC-CyCampathTBI/MAC
Flu-MelCampath/RIC
HDAC-CyCampathTBI/cranial
XRT/MAC
AraC-CyCampath/MAC
Infuse d
C D34/kg
Infuse d
C D3/kg
Days fro m SC T
to T-ce ll
infusio n
Infuse d
T
ce lls/kg
aGVHD
cGVHD
Ad ministratio n
o f AP 1903
Grade I/II
None
Yes
Alive, CR (D+1440)
Grade I
None
Yes
Relapse of ALL (D+552),
death D+591
C urre nt status
(d ay afte r SC T†)
1.2 × 10
8.2 × 10
66
1 × 10
1.0 × 107
3.8 × 104
80 and 111
1 × 10 6
1.3 × 107
1.7 × 105
93
3 × 10 6
None
None
None
Alive, CR (D+1388)
1.6 × 107
5.5 × 104
30
3 × 10 6
Grade I
None
Yes
Relapse of ALL (D+57),
death D+158
1.5 × 107
0.4 × 104
42
1 × 10 7
Grade I
None
Yes
Relapse of ALL (D+158),
death D+164
0.8 × 107
0.3 × 104
87
1 × 10 6
None
None
None
Alive, CR (D+1016)
1.3 × 107
0.9 × 104
75 and 368
1 × 10 7
None
None
None
Alive, CR (D+954)
7
None
None
None
Alive, CR (D+835)
None
None
None
Relapse (D+312) alive,
CR (D+475) (second alloHSCT)
None
None
None
Death from respiratory
failure secondary to
refractory AIHA (D+ 615)
7
4
1.2 × 10
0.3 × 10
40
Flu-CampathTBI/RIC
2.2 × 107
0.5 × 104
90 and 271
AraC-CyTBI/MAC
1.5 × 107
0.6 × 104
124 and 248
7
4
1 × 10
6
1 × 10 7
1 × 10 6
1 × 107 5 ×
106
Xiaoou Zhou et al. Blood. 2014;123:3895-3905
©2014 by American Society of Hematology
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Rapid Reversal of GVHD after Treatment with AP1903
Di Stasi A et al. N Engl J Med 2011;365:1673-1683
Di Stasi A et al. N Engl J Med. 2011;365:1673-1683
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Dual Antigen
Targeting
CAR T
Signal 1
Signal 2
Anti-MUC1
Anti-Erb-B2
MUC1
Erb-B2
Cancer
Cell
Erb-B2
Somatic
Cell
MUC1
Somatic
Cell
Adapted by Wilkie S, et al. J Clin Immunol. 2012
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Causes of Mortality related to Allogeneic BMT
(2011-2012)
HLA-identical Sibling
Unrelated Donor
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Kaplan-Meier estimates
Shernan G. Holtan et al. Blood. 2015;125:1333-1338
©2015 by American Society of Hematology
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Prevention Strategies
1. T Cell depletion in vivo / ex vivo
2. Drugs: CNI, anti-metabolites, steroids, M-TOR
3. T Cell homing-Interference
4. Post-Transplant Cytoxan
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Overall Survival in Steroid-responsive
and refractory aGVHD
J Westin et al. Adv Hematol. 2011; 2011: 601953.
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Mechanisms of MSC suppression
Inhibition:
Direct contact dependent
• B7-H1
Indirect Cytokine-mediated
• PGE2
• Cox 1 & 2
• HGF
• TGF-B
• IL-10
• HLA G & E
• LIF
• IDO
Rasmusson I, Exp Cell Ther. 2006 – Modified by Weiss M.
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MSCs for GVHD – Summary
• 20 studies used MSCs for GVHD grade 2-4
• MSCs have a positive effect (varies between studies)
• Conditioning varied from myeloablative, nonmyeloablative,
RIC, DLI, etc.
– No apparent difference in response
• MSCs from HLA identical, haploidentical and unrelated,
unmatched have been used
– No apparent differences in response
• MSCs from fresh or frozen/thawed
Source: Mark Weiss
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Worldwide HUMAN stem cell trials 2015
MSCs from three sources compose 89% of trials
**
Source: Mark Weiss
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Wharton’s Jelly Cells – the MSCs of the Umbilical Cord
No risk to donor, painlessly collected
Easy isolation, low risk of failure
Superior source to bone marrow:
More CFU-F, faster expansion
Longer lived in culture
Available autologous to cord blood
Source: Mark Weiss
Umbilical cord is not biohazardous waste.
It is a gold mine!
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Wharton’s Jelly Cells
Tissue
engineering
GvHD
Treatment
Source: Mark Weiss
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Source: Helen Heslop
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Takeaways
• Greater understanding of patient eligibility
and timing of the transplant
– During stable disease
– During appropriate time in disease process
– NMDP/ASBMT guidelines for consultation timing
• Partnering for comprehensive treatment plan
– Ensures treatments given do not preclude transplant
– Allows patient to move quickly to transplant, if needed, before
disease progresses or complications develop
– Allows adequate time for unrelated donor/cord blood search, if
needed
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Advances: Timing & Planning
• Long-term Survival after SCT
- CIBMTR study of 10,632 alloSCT recipients surviving ≥ 2 years in
remission (median follow-up 9 years)
Overall Survival
Non-relapse Mortality
J Wingard et al, JCO 2011;29:2230
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HSCT Guidelines Summary
• Recommendations include:
– Adult and pediatric populations
– Autologous and allogeneic
recipients
• Timing recommendations
– 6-month post-HCT check-up
– 1-year check-up
– Annually thereafter
• Post-HCT vaccination schedule
• At risk ‘special populations’ testing
recommendations:
– Chronic GVHD, corticosteroid
exposure, TBI, pediatrics
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Thank You!
Questions?
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