Guenther Koehne MD PhD Adult Bone Marrow Transplant Service Division of Hematologic Oncology Department of Medicine Memorial SloanKettering Cancer Center New York New York Autologous SCT ID: 776662
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Slide1
How do transplants fit in the current therapeutic schema?
Guenther Koehne, MD, PhD
Adult
Bone Marrow Transplant Service
Division of Hematologic Oncology
Department of Medicine
Memorial Sloan-Kettering Cancer Center
New York, New York
Slide2Autologous SCT
Who?When?How?Maintenance?
Allogeneic SCT
Who?
When?
How?
Maintenance?
Slide3Multiple Myeloma Treatment Lines in Transplant-Eligible Patients
Induction
Consolidation
Conditioning?
Frontline treatment
Maintenance
Maintenance
Rescue
Relapsed
Bz/Dex
Bz/Dex/Dox
Bz/Thal/Dex
Len/DexRev/Len/DexCRd
SCT
ObservationThalThal/PredRev
Slide4Curr
Opin
Oncol
,
Sept 2012
Slide5Allogeneic Transplantation for Multiple Myeloma
Treatment with curative potential Lack of myeloma cell contamination in graftGraft vs. myeloma effectReserved for fit patientsConventional/Myeloablative studies: TRM >50%Non-myeloablative transplants – BMT CTN #0201No clear survival benefit High rate of acute and chronic GVHD
GVHD, graft versus host disease; TRM, transplant-related mortality.
Slide6Allogeneic Vs. Autologous
US intergroup trial (S9321
)
N =
813
Induction
Therapy
VAD
RANDOMI
ZE
n=261
HD-CTX
collection
N=255
HD-CTX
collection
n=213
HDTMel/TBIautotransplant
n=211SDTVBMCPautotransplant
n=39<55 yearsHLA matched sibling
n= 36Mel/TBIallotransplant
GVHD prophylaxis
x
TRM:53%
HD-CTX, high-dose cyclophosphamide; HDT, high dose therapy; HLA, human leukocyte antigen; MEL,
melphalan
; SDT, standard dose therapy; TBI, total body irradiation; VAD, continuous infusion of vincristine and doxorubicin plus high-dose dexamethasone; VBMCP, vincristine,
carmustine
,
melphalan
, cyclophosphamide, and prednisone.
Barlogie
B,
et al.
J
Clin
Oncol
.
2006; 24:929-936.
Slide7Summary of Recent Studies With Non-Myeloablative Conditioning for Multiple Myeloma
StudyConditioningTransplant (No. Pts) PFS / OS TRM Acute GvHDChronic GVHDBruno, et alN Engl J of Med 2007 TBI 200 cGy8036%@ 3 y80%@ 3 y10%43%Grade II ‒IV63%Extensive – 32%Rosiñol, et alBlood2008Mel 140/FLU25Median not reachedMedian not reached16%32%Grade II‒IV66%Vesole, et alBiol Blood Marrow Transplant2009FC3158%@ 3 y78%@ 3 y8%17%Grade III‒IV57%Extensive – 26%Krishnan, et alLancet Oncol 2011TBI 200 cGySR: 189HR: 3743%40%@ 3 y77%59%@ 3 y11%26%Grade II‒IV54%Björkstrand, et alJ Clin Oncol2011TBI 200 cGy /FLU10835%@ 5 y65%@ 5 y12%20%Grade II‒IV54%Extensive –23%
FC,
fludarabine
plus cyclophosphamide; FLU,
fludarabine
; HR, high risk; OS, overall survival; PFS, progression-free survival; SR, standard risk.
Koehne
G,
Giralt
S.
Curr
Opin
Oncol
.
2012;24:720-726.
Slide8Allogeneic SCT
Who?
Risk stratification based on high-risk factors
When?
Sooner than later
How & Where?
TCD HSCT & MSKCC
Maintenance?
Immunotherapeutic Approaches
Slide9Approaches to Allogeneic SCT for High-Risk Multiple Myeloma
Induction
Consolidation/Conditioning
Maintenance
Relapse# lines of treatmentVDT-PACE2nd salvage auto SCTUpfrontInductionAuto SCT
TCD HSCT
ImmunotherapyDLIAntigen-specific CTLs
1.
2.
Slide10Cytogenetics and Disease
High-risk cytogenetics: 25% of patientsDeletion 17p: del(17p)10% of newly diagnosed patientsAssociated with aggressive disease and shorter overall survival No conclusive evidence that any currently available treatments are effective for patients with del17pTranslocation of the immunoglobulin heavy chain (IgH) locus on chromosome 14t(4;14); t(14;16)Deletion 13q: del13qRelated to association with t(4;14) and del17pHypodiploidy
High risk disease affects outcome and
should therefore affect treatment
Slide11Current Study at MSKCC: TCD HSCT for Multiple Myeloma – IRB #10-051
Phase II study of TCD Allogeneic Transplantation for High-Risk Multiple MyelomaPrinciple Investigator: Guenther Koehne MD, PhDEligibility Criteria:Relapsed multiple myeloma following ASCT High risk cytogenetics or relapse ≤ 15 months postASCT At least PR to salvage therapyConditioning: Bu/Mel/Flu (+ ATG)TCD: CliniMacs device: CD34+ cells positively selected
ASCT, allogeneic hematopoietic stem cell transplantation; ATC,
antithymocyte
globulin; Bu:
busulfan
; FISH, fluorescent in situ hybridization; IRB, internal review board; MSKCC, Memorial Sloan-Kettering Cancer Center; TCD, T-cell depleted, VGPR, very good partial response.
Slide12Design of Study: TCD (CD34+ selection) HSCT for Multiple Myeloma
DLI (5x10
5 CD3+/Kg) at earliest 5-6 months post SCTDLI (5x105 CD3+/Kg) at earliest 8-9 months post SCTDLI (1x106 CD3+/Kg) at earliest 12-13months post SCT
DLI (1x10
5 CD3+/Kg) at earliest 5-6 months post SCTDLI (5x105 CD3+/Kg) at earliest 1-3months post SCT, following the first infusionDLI (1x106 CD3+/Kg) at earliest 3-4months post SCT, following the second infusion
Prophylactically in recipients of HLA-matched allografts
Preemptively in recipients of HLA-mismatched allografts
DLI, donor lymphocyte infusion.
Courtesy of Koehne G, et al. MSKCC.
Busulfan
:
0.8
mg/kg x 10 doses
Melphalan
:
70
mg/m
2
x 2 doses
Fludarabine
:
25mg/m
2
x 5
d
ATG:
2.5
mg/kg x 2
d
Slide13UPN
MM
Cytogenetics
Prior Lines of TX
(Detail)
Prior Lines of TX
Age
of BMT
BMT
Match
Donor
1
IgG
Kappa
Normal
Thal/
D
ex
, tandem auto, RVD
3
42
11/28/2007
9/10
Unrelated
2
IgA Lambda
t(4;14), del 13q
Vel/Dex x 6, auto SCT, Len/Dex, Vel/Dex
4
38
6/18/2008
10/10
Related
3
IgG Kappa
del13q
Thal/Dex, auto SCT, Vel/Thal/Dex
3
32
8/20/2008
10/10
Related
4
IgG Lambda
del 17p, del 13q
Thal/Dex, Vel/VP-16/Cy, auto SCT, VAD, VP-16/Cy
5
57
3/4/2009
10/10
Unrelated
5
IgG Kappa
t(4;14)
RVD, auto SCT, RVD
3
69
4/30/2009
10/10
Related
6
IgG Kappa
t(4;14)
RVD, tandem auto SCT, DCEP
3
54
9/3/2009
10/10
Unrelated
7
IgA Kappa
t(4;14), del 13q
Thal/Dex, Vel/Dex, auto
SCT #1,
RVD, DCEP,
auto
SCT #2
6
54
10/23/2009
10/10
Related
8
IgG Lambda
t(4;14), del 13q
Rev/Dex
, tandem auto SCT, BD, DCEP, RVD
5
49
11/20/2009
10/10
Unrelated
9
IgG Lambda
del 17p, t(4;14)
VDD, tandem auto SCT, RVD
3
48
12/17/2009
10/10
Related
10
IgG Kappa
MLL, del 13q
BDD, auto SCT,
Vel/Dex/Cy
, RVD
4
57
12/24/2009
9/10
Unrelated
11
IgA Kappa
del 13q, del 14q32
Thal/Dex, auto
SCT #1,
Vel/Thal/Dex,
auto
SCT #2
4
46
1/15/2010
10/10
Related
12
IgA Kappa
del 13q, 1q23
Thal/Dex, auto
SCT #1,
DT-PACE, auto
SCT #2
4
68
1/21/2010
10/10
Related
13
IgG Kappa
t(4;14), del 13q
VDD, auto SCT, RVD
3
56
3/5/2010
10/10
Related
14
IgG Kappa
Normal
XRT; VDx5;
Auto SCT
,
RVDx3
,
DVT-PACE x2
4
65
8/13/2010
10/10
Related
15
IgG Kappa
Normal
BDDx3 /TDx2;
auto
SCT; XRT; RDx5;
BVDx2
;
auto SCT #2;
XRT
7
63
8/19/2010
9/10
Unrelated
16
IgG Kappa
Normal
VDD x 5: VDD/Rev; Tandem auto; Thal maintenance; RVD x6; DT-PACE x2
5
58
8/25/2010
9/10
Unrelated
17
IgA Lambda
extra1q, del(13q), t(4:14)
Thal; BDD x3;
auto#1
; Thal; RDx4;
VDD x2;
DVT-Pace x4;
auto
#2
8
59
9/8/2010
9/10
Unrelated
Slide14UPN
MM
Cytogenetics
Prior Lines of TX
(Detail)
Prior Lines of TX
Age
of BMT
BMT
Match
Donor
18
IgG
Kappa
del(13q), der(1)
Thal/Dex
x5, tandem auto, Thal/Dex, XRT, Vel/Dox; RVD; RD;
DCEP x5
8
61
11/10/2010
9/10
Unrelated
19
IgG Lambda
Normal
Cy/Dex x2; VD x2; Auto #1; VD; RD/Mel;
Auto #2
6
57
12/2/2010
10/10
Related
20
IgG Kappa
Normal
Thal/Dex x4;
RVD x5,
Auto
#1; RVD
4
54
12/10/2010
10/10
Unrelated
21
IgG Kappa
p53, tri 17, 5p, 11, 15,
BiRD
x5
; Auto SCT #1; RVD; maintenance
Rev
; VD-
Cy
x5; VDT-PACE
x2;
Auto #2
6
37
3/2/2011
10/10
Unrelated
22
IgG Kappa
Normal
BDDx3 /TDx2, Auto #1; maintenance
Rev
; Auto #2; maintenance
Rev
;
VDT-PACE x2
; RVD-Cyx3
5
49
4/14/2011
10/10
Unrelated
23
Nonsecretory
del(20q), del(13q), del(17p), p53
BDDx4; BDx5 Auto#1; VD; RD;
Auto #2;
BiRD
7
63
4/20/2011
10/10
Related
24
IgG Kappa
MLL, del(13q),
IgH
, p53
BBD x2; Thal/Dex x2; tandem auto SCT; maintenance thal; XRT;RVD x 10
5
45
5/26/2011
10/10
Unrelated
25
IgG Lambda
extra 1q23 and 19p13, IgH, MLL, del p53, extra of 1q, 1p, del(13) and del(17p), extra 4,11, and 14
Thal/Dex x 3 ; VD x3;
RD,
VD-PACEx1; VD-PACE x3;Auto #1;
Bortez
maintenance
6
60
6/3/2011
10/10
Unrelated
26
IgG Lambda
extra 1q25, mono 13, Der3, I5p, I5q, trans IgH locus, del(17p)
Thal/Dex x1;
RD x4
; Auto #1 XRT/Dex followed by
RD x6
; Auto #2; maintenance Rev; VD-Cy x5
7
62
8/31/2011
10/10
Unrelated
27
IgG Lambda
Dup(1q), del(4p), 1q25, tri(9), mono (13), tri 15, mono 16, loss p53 gene, MLL
RVD x 4, Auto #1 ; RVD; DCEPx3 with RVD between cycles; VD-Bendamustine;
VDT-PACE x1
;
Auto #2
8
56
9/21/2011
9/10
Unrelated
28
IgG Kappa
del(1)(p13p22), +3,+5+9,+11,del(13), (q12q14), del(14)(q24), der(16), t(11;16), (p13.1;q24
RVD x9; XRT; Auto #1; VD x 4; VDT-PACE
x3
;
Auto #2
6
61
10/21/2011
9/10
Unrelated
29
Lambda LC
Normal
Thal/Dex,auto SCT, Len main., RevDex, RVDx1 -->BDx6
4
56
12/29/2011
10/10
Unrelated
30
IgG Lambda
Normal
RVDx6, Cytoxan --> Mel + auto
SCT #1,
PomCLARx5, Carfilzomib x3, VDT-PACE, salvage MEL +
auto SCT
#2
7
50
2/1/2012
10/10
Related
31
IgG Kappa
extra 1q25, trisomy 5,9,15; del12p1q
RXT, BDx2, BDDx2, CTX; MEL + auto SCT, main. Len, CyBorDx4,
VDT-PACE x3
5
59
4/20/2012
9/10
Unrelated
32
Nonsecretory
mono 13, t(11;14)
Thal/Dex x3
,
Bortez
+ Thal/Dex x2,, tandem auto SCT,
RevDex,lorvotuzumab
/mertansine x 9,
BD x4
4
52
8/1/2012
10/10
Unrelated
33
Kappa LC
Normal
RVD x 4, auto SCT, Bortez/Rev main., Cytoxan/Velcade x2
3
48
9/5/2012
10/10
Unrelated
34
IgG
Lambda
del13q, del20q, extra 1q25, del 4,12,16
RVD x4,
auto
SCT
#1,
CyBorD
x4
,
Bortez
/Mel
,
Auto SCT #2
5
44
12/28/2012
10/10
Unrelated
Slide15Acute GVHD (grade II – IV) at 12 months (N = 34)
Transplant-related Mortality (at 12 months) (N = 34)
Courtesy of Koehne G, et al. MSKCC.
0.09 (0.02-0.23)
0.06 (0.01-0.17)
Slide16Chronic GVHD
Graft failure or rejection
Courtesy of Koehne G, et al. MSKCC.
None observed
Slide17OS + PFS of pts with multiply relapsed MM following allo TCD HSCT(N=34)
Courtesy of
Koehne G, et al. MSKCC.
Among survivors, median f/u is 44 mos (range: 18-79)
07/2014
1-y OS
66%
95% CI, 0.51-0.85
1-y PFS
49%
95% CI,
0.34-0.69
2-y OS
52%
95% CI,
0.36-0.73
2-y PFS
27%
95% CI,
0.14-0.49
Slide18OS (a) + PFS (b) of pts with multiply relapsed MM by previous lines of therapy prior to allo TCD HSCT
a.
b.
p = 0.02
p = 0.05
Courtesy of Koehne G, et al. MSKCC.
Slide19OS (a) and PFS (b) of pts with multiply relapsed MM with < 6 previous lines of therapy prior to allo TCD HSCT based on donor selection(related vs. unrelated)
Courtesy of Koehne G, et al. MSKCC.
b.
At 2yrs
Related:
0.30 (0.12-0.77)
Unrelated:
0.36 (0.17-0.76)
At 2yrs
Related:
0.60 (0.36-0.99)
Unrelated:
0.72 (0.51-0.99
)
a.
Slide20OS (a) + PFS (b) of pts with multiply relapsed MM by previous lines of therapy prior to allo TCD HSCT
G. Koehne et al. MSKCC.
Slide21Clinical responses induced by Bu/Mel/Flu conditioning chemotherapy
Slide22Clinical responses induced by Bu/Mel/Flu conditioning chemotherapy
Slide23Clinical responses after initial DLIs (when receiving at least 2 doses) given for relapsed or residual MM
Slide24Single Patient Response
DLI 5x10e5/kg 06/09
July -1, 2014
65 months
in
CR
72 months post allo BMT
39-year-old
male dx stage III IgA lambda,
multiple myeloma (MM) high-risk
cytogenetics
(del 13; t(4;14).
Bortezomib /Dexamethasone (Dex) x 6, autoSCT 9/07 with relapse disease 12/07, Lenalidomide/Dex x1, Bort/Dex x2, alloHSCT from matched related donor (10/10) in 06/08, in complete remission (CR) since 5/09.
Slide25DLI and Disease Course
55-year-old male dx stage III IgG lambda, MM high-risk cytogenetics (del 17p by FISH, del 13q by karyo). Thalidomide/Dex x 4 months with PD + ARF, Bort–MI–CAGB with EF 35%, VP-16 + cyclophosphamide (CY) with PR, auto SCT 08/07 with relapse disease 08/08, VAD with PD, VP-16 + CY x 3, allo HSCT from matched unrelated donor (10/10) in 03/09.
Allo BMT
DLI 5x10e5/kg
DLI 5x10e5/kg
DLI 1x10e6/kg
Slide26WT1-Specific T-Cell Responses in Patients
with Multiple Myeloma
A2-RMG, HLA-A2 restricted peptide; CMB, cytomegalovirus; MHC, major histocompatibility complex; WT1,
Wilms tumor gene product 1. Tyler EM, et al. Blood. 2013;121:308-317.
WT1-specific T cells by MHC tetramer
A24-CMV
A2-RMF
4/2/09
04/09 Blood 01/11 Bone Marrow 01/11
3.5%
1.0 %
2.9 %
A2-RMF
CD8+
CD8+
Slide27WT1—A Potential Target for Multiple Myeloma?
WT1: zinc finger transcription factorRoles in cell proliferation, differentiation, apoptosis and organ developmentPreferentially expressed during embryogenesis, but also at low levels in kidney, ovary, endometrium, testis and spleen of adultsFrequently overexpressed in a number of solid and hematologic malignanciesExpression correlates with disease progression in MDS, ALL, & CMLMolecular marker for risk assessmentEmergence of WT1-specific T cells correlates with better relapse-free survival post allogeneic transplant in leukemia1MM cells are efficiently lysed by WT1-specific cytotoxic T lymphocytes2 WT1 expression in the BM of myeloma patients correlates with disease stage3
ALL, acute lymphocytic leukemia; CML, chronic myeloid leukemia; MDS,
myelodysplastic
syndrome.
1.
Rezvani
K, et al.
Blood.
2007;110:1924-1932; 2. Azuma T, et al.
Clin
Cancer Res.
2004;10:7402-7412; 3.
Hatta
Y, et al.
J
Exp
Clin
Cancer Res.
2005;24:595-599.
Slide28WT1-Specific T Cells and Disease Course
Slide29WT1-Specific T Cells and Disease Course
55-year-old male dx stage III IgG lambda, MM high risk cytogenetics (del 17p by FISH, del 13q by karyo). Thal/Dex x 4 months with PD + ARF, Bort – MI – CAGB with EF 35%, VP-16 + CY with PR, auto SCT 08/07 with relapse disease 08/08, VAD with PD, VP-16 + CY x 3, allo HSCT from MUD (10/10) in 03/09.
Allo BMT
DLI 5x10e5/kg
DLI 5x10e5/kg
DLI 1x10e6/kg
Slide30WT1-Specific T Cell Frequencies Increase in All Patients Following DLI
Max response to DLI: 47 WT1-specific T cells/
μL
blood 6.6-fold increase over pre-DLI frequenciesResults from the selective expansion of WT1-specific T cells rather than general immune reconstitution
Figure 1. WT1-specific T-cell numbers and function increase following transplant and DLI.
Tyler EM, et al.
Blood.
2013;121:308-317.
Slide31IHC With WT1 mAb 6F-H2
CD138 (brown)/ WT1 (red) co-staining of BM biopsy
WT1 (red) co-staining
of kidney
biopsy
CD138 (brown) staining of BM biopsy
BM, bone marrow; IHC, immunohistochemistry.
Tyler EM, et al.
Blood.
2013;121:308-317.
Slide32IHC Analyses of WT1 Expression in the BM of MM pts
++++
+++
CD138 (MI15; DAB) = brown; WT1 (6F-H2,
nFu
) = red
++
Focal
Negative
Grading
Neg
0
Focal < 5%+ < 25%++ 25 – 50%+++ 50 – 75%++++ > 75%
90% PC’s by biopsy
50 -60 % PC’s by biopsy
45% PC’s by biopsy
5% PC’s by biopsy
No PC’s by biopsy
DAB 3,3-diaminobenzidine;
nFU
, nFu1 antibody; PC, plasma cell.
Tyler
EM, et al.
Blood.
2013;121:308-317.
Slide33Phase I Trial #IRB 12-175:TCD (CD34+ selection) Allo SCT Followed by WT1-Specific T-Cell Infusions for Patients With Relapsed/Refractory Multiple Myeloma or Plasma Cell Leukemia
Busulfan
:0.8 mg/kg x 10 dosesMelphalan:70 mg/m2 x 2 dosesFludarabine:25mg/m2 x 5 dATG: 2.5 mg/kg x 2 d
WTW
WT1-specific CTLs
WT1 CTLs - Dose levels 1, 3 and 5 x10e6/ kg; -3 doses/recipient of HLA-matched and HLA-mismatched allografts. First dose at 6-10 weeks post transplant. The second dose will be given 4-8 weeks following the first infusion and a third dose will be administered 4-8 weeks following the second infusion. The second and third dose will only be administered in the absence of grade III-IV toxicity and grade II-IV acute GvHD following the preceding T-cell dose.
CTL, cytotoxic T lymphocytes.
Courtesy
of
Koehne
G,
et al. MSKCC.
Slide34Plasma Cell Leukemia
Overall Survival
(OS) in pPCL and sPCL, showing superior survival of pPCL vs sPCL from the time of leukemia diagnosis.
pPCL
, primary plasma cell
leukemia;
sPCL
, secondary plasma cell leukemia
.
Albarracin
F, Fonseca R. Blood Rev. 2011;25:107-112.
Slide35Case―61-Year-Old AA Female With Secondary Plasma Cell LeukemiaUndergoing TCD HSCT Followed by WT1 CTLs Residual Disease Post VDT-PACE, but HLA-Matched Brother
TCD HSCT
02/13/12
WT1 #1 1x10e6/kg
04/18/12
WT1 #2 1x10e6/kg
05/16/12
WT1 #3 1x10e6/kg
06/13/12
Slide36Immune Reconstitution Post-WT1-CTL Infusions
TCD HSCT
02/13/12
WT1 #1
1x10e6/kg
04/18/12
WT1 #2
1x10e6/kg
05/16/12
WT1 #3
1x10e6/kg
06/13/12
IFN-γ
CD8
CD4
IFN-γ
TCD HSCT
02/13/12
WT1 #1
1x10e6/kg
04/18/12
WT1 #2
1x10e6/kg
05/16/12
WT1 #3
1x10e6/kg
06/13/12
WT1 all pools
6/13/12
Slide37WT1 CTLs + Disease Course
WT1 #3
1x10e6/kg
06/13/12
WT1 #2
1x10e6/kg
05/16/12
WT1 #1
1x10e6/kg
04/18/12
WT1
#4
5
x10e6/kg
09/26/12
WT1
#5 5x10e6/kg11/02/12
WT1 #6 5x10e6/kg12/05/12
TCD HSCT
02/13/12
WT1 #1
1x10e6/kg
04/18/12
WT1 #2
1x10e6/kg
05/16/12
WT1 #3
1x10e6/kg06/13/12
WT1
#4
5
x10e6/kg
09/26/12
WT1 #5 5x10e6/kg11/02/12
WT1 #6 5x10e6/kg12/05/12
M-Spike Gamma
Kappa: Lambda Ratio
Feb 2014
Feb 2014
#
#
Slide38Slide39IHC With CD138 + WT1 mAb 6F-H2
Relapse
11/11
Post
allo
BMT + WT1 CTL #1
05/16/12
Slide40WT1 CTLs + Disease Course
Slide41Future Approaches to Treatment for High-Risk Multiple Myeloma
Induction
Conditioning
Maintenance
RelapseUpfront
TCD HSCT
Suicide-gene modified DLIWT1-specific CTLs
1.
2.
Do we need an auto SCT? CRD x 6 cycles TCD HSCT WT1 CTLs ?
3.
Do we need an allo SCT? Induction auto SCT MM-specific CARS?
Slide42Acknowledgement
Research Team Eleanor Tyler, PhD, Cornell Weill College Achim Jungbluth, MD, Pathology, MSKCC Denise Frosina, Senior Research Technician Sean Devlin, PhD, Biostatistics, MSKCC Evelyn Orlando, RSA Eric Smith, MD, PhD Satya Kosuri, MD
Adoptive Immune Cell Therapy Facility (AICT lab)Ekaterina Doubrovina MD PhDRichard O’Reilly, MD
Myeloma ServiceHeather Landau MD Hani Hassoun MD Alex Lesokhin MD Nikoletta Lendvai MD PhDDavid Chung MD, PhD Sergio Giralt MDOla Landgren, MD
Otsuka Pharmaceutical Co, Ltd – for generous research support