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He Huang
Bone Marrow Transplant Center
Zhejiang University School of Medicine
Hangzhou, China
5/16/2019
BCMA CAR-T Cellular Therapy
for R/R Multiple Myeloma in China
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◆Patients with multiple myeloma will finally evolution into refractory/ relapsed
disease
Background
Blood Cancer J. 2019 Mar 7;9(3):32.
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3
◆Novel agents and antibodies developed in recent years
Leukemia (2018) 32, 252–262; doi:10.1038
Background
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◆ Zelig Eshhar
Introduction for CAR-T Cells
He first proposed the concept of
chimeric antigen receptor T cell
◆ Carl H. June
His work led to the development and
commercialization of tisagenlecleucel,
the first FDA-approved gene therapy
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https://www.clinicaltrials.gov
World: 744
USA: 292
China: 256
Europe: 111
(up to 5/9/2019)
Immunotherapy becomes a global hot spot!
Summary of CAR-T treatment worldwide
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https://www.clinicaltrials.gov
World: 56
USA: 26
China: 26
Europe: 5
(up to 5/9/2019)
Clinical trial of CAR-T for MM develops rapidly
Summary of CAR-T treatment worldwide in MM
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CAR-T treatment for MM in China
◆Nanjing Legend Biotech Inc.
Zhao WH, et al. J Hematol Oncol. 2018 Dec 20;11(1):141.
Median PFS Median OS
15 months Not reached
N Age ORR CR VGPR PR
57 54(27~72) 88% 68% 5% 14%
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CAR-T treatment for MM in China
◆Nanjing Legend Biotech Inc.
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CAR-T treatment for MM in China
◆Nanjing Legend Biotech Inc.
Xu J, et al. Proc Natl Acad Sci U S A. 2019 Apr 15. [Epub ahead of print]
Disease r/r MM
N 17
Age 56 (35, 73)
ORR 88.2%
CR 76.5%
VGPR 11.8%
1-year PFS 52.9%
1-year OS 82.3%
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CAR-T treatment for MM in China
◆Nanjing Legend Biotech Inc.
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BCMA CAR-T treatment for Multiple
myeloma in our center
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12
◆Patient enrollment
➢ Relapsed or refractory multiple myeloma
➢ Younger than 75 years old
➢ Normal major organ function
➢ BCMA expression rate on MM cells is higher than 50% by flow cytometry or IHC
➢ No active infection complication y eithe
◆CAR construct
BCMA scFv (murine) Transmembrane 4-1BB CD3 ζ
CAR-T treatment in our center
Unpublished data
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Withdraw for severe infection
Screen (n=40)
PBMCs collection and CAR-T
Preparation (n=33)
Excluded ineligiblen=7
n=1
FC-based conditioning regimen and
CAR-T infusion (n=32)
Evaluation for efficacy and toxicity
(n=26)
CAR-T treatment in our center
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◆Patient characteristicsPatient Age Sex Type Cytogenetic
abnormalityAutologousHSCT
ISS/DS No.of Prior Lines of Therapy
CAR -T dose( /Kg)
1 71 M IgG-k None N III/IIIA 4 1.28*10^6
2 61 M IgA-k None N II/III 4 1.05*10^6
3 63 M NSMM None N IA/IIIA 6 2.66*10^6
4 60 M IgD-λ t(4;14),1q21,RB1,D13S319,IGH rearrangement
N III/IIIA 2 2.83*10^6
5 55 M IgG- λ 49, XY, +15, +5, +17
N III/IIIA 5 2.64*10^6
6 55 F IgG-k RB1, IGH rearrangement, 1q21, D13S319
Y II/IIIA 4 2.73*10^6
7 58 F IgA- k None N II/IIIA 5 2.48*10^6
8 61 M IgA None N I/IIIA 3 3.06*10^6
9 49 F IgD- λ None N I/IIIA 2 3.55*10^6
10 65 M IgG- λ RB1, 1q21,IGH rearrangement, D13S319
N III/IIIA 4 3.42*10^6
11 65 M IgG-k None N I/I 2 3.77*10^6
12 65 F IgA- k 1q21, D13S319,RB1
N III/IIIA 4 2.05*10^6
13 63 F IgG-k t(4;14), del P53 Y I/II 7 4.91*10^6
14 55 F IgG-k None Y II/III 4 4.80*10^6
15 55 F IgG-k None N I/IIIA 3 5.03*10^6
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Patient Age Sex Type Cytogenetic abnormality
Autologous HSCT
ISS/DS No.of Prior Lines of Therapy
CAR T dose( /Kg)
16 59 M IgA None N I/IIIA 6 4.44*10^6
17 54 M IgG-k None Y I/I 4 4.59*10^6
18 51 F λ light chain
None Y I/IIIA 3 3.93*10^6
19 50 M IgD- λ 1q21 Y III/III 5 4.27*10^6
20 65 M IgA- k None N III/IIIA 5 3.93*10^6
21 67 M λ light chain
1q21 N II/III 4 4.61*10^6
22 64 M IgG-k None N III/IIIA 6 4.40*10^6
23 62 M λ light chain
RB1,TP53 N III/IIIA 5 2.18*10^6
24 65 F IgG-k 1q21,RB1,D13S319,P53,IGH rearrangement
N III/II 4 2.19*10^6
25 71 M IgG-k None N III/IIIB 4 5.35*10^6
26 59 M NSMM TP53 N II/III 3 4.74*10^6
◆Patient characteristics
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Results Prognosis
◆Clinical Efficacy after CAR-T Infusion
Overall response rate 100%, CR or VGPR rate 80.8%
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◆Minimal residual disease in bone marrow by FACSPatient No. 9 Patient No. 17 Patient No. 15Before CAR-T
After CAR-T
All 26 patients achieved MRD negative in BM after CAR-T treatment!
CAR-T treatment in our center
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Extramedullary lesions were eradicated after CAR-T treatment!
Before CAR-T After CAR-T
◆ Extramedullary lesions by PETCT
CAR-T treatment in our center
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Results Prognosis
◆Risk factors associated with CR by multivariate analysis
The efficacy of CAR-T therapy was not associated with cytogenetics, CAR-T cell dose, extramedullary infiltration, age and disease stage.
Covariate P value
Extramedullary infiltration 0.994
Age>60 year-old 0.994
High risk cytogenetics 0.751
ISS staging 0.994
DS staging 0.995R
CAR-T cells>3*10^6/kg 0.994
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◆Clinical Efficacy after CAR-T Infusion
300-day OS 76.4% 300-day PFS 57.7%
Days after CAR-T infusion Days after CAR-T infusion
OS
(%)
PFS
(%
)
Results Prognosis
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Results CAR-T cell expansion in vivo
0
10
20
30
40
50
60
70
80
90
100D
1
D2
D3
D4
D5
D6
D7
D8
D9
D1
0
D1
1
D1
2
D1
3
D1
4
D1
5
D1
6
D1
7
D1
8
D1
9
D2
0
D2
1
D2
2
D2
3
D2
4
D2
5
D2
6
D2
7
D2
8
D2
9
D3
0
D3
1
D3
2
D3
3
D3
4
D3
5
D3
6
D3
7
D3
8
D3
9
D4
0
D4
1
D4
2
D4
3
D4
4
D4
5
D4
6
D4
7
D4
8
D4
9
D5
0
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9
Patient 10 Patient 11 Patient 12 Patient 13 Patient 14 Patient 15 Patient 16 Patient 17Pro
po
rtio
n o
f C
AR
-T c
ell
In C
D3
+ L
ym
ph
oc
yte
(%
)
Days Post CAR-T cell Infusion
High proliferation of CAR-T cells in vivo!
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Results CAR-T cell expansion in vivo
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12
Patient 13 Patient 14 Patient 15 Patient 16 Patient 17
Pro
po
tio
no
f C
D4
+C
AR
-T C
ell
(%)
Days Post CAR-T Infusion
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12
Patient 13 Patient 14 Patient 15 Patient 16 Patient 17
Pro
po
tio
no
f C
D8
+C
AR
-T C
ell
(%)
Days Post CAR-T Infusion
◆Change of CAR-T cell subsets in vivo
For the first 3-5 days after CAR-T infusion, most CAR-T cells are CD4+, then CAR-T cells change to CD8+ T cells implying that CD8+ CAR-T cells eradicate myeloma cells rapidly.
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Results CAR-T cell expansion in vivo
◆ CRS grade
◆16 patients received Tocilizumab treatment
◆4 patients received steroid treatment
◆No patient died of CRS
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Results Adverse Effect
◆Adverse Effect
0
2
4
6
8
10
12
14
16
18
Feve
r
Hyp
oxi
a
Pan
cyto
pn
ea
Ch
ills
Co
ugh
Nau
sea
He
art
Dys
fun
ctio
n
Fati
gue
Vo
mit
tin
g
Edm
a
Acu
te k
idn
ey
inju
ry
Ras
h
Po
or
app
eti
te
Atr
ial f
ibri
llati
on
Dia
rrh
ea
Sto
ma
chd
istr
ess
He
adac
he
Nu
mb
ne
ss
He
rpe
s
Ple
ura
l eff
usi
on
Blo
od
y sp
utu
m
Hyp
ote
nsi
on
De
rmat
orr
hag
ia
Aci
d r
efl
ux
Pre
cord
ial d
istr
ess
Ne
uro
toxi
ty
Pu
lmo
nar
y in
fect
ion
Pe
rica
rdia
l eff
usi
on
Gin
giva
l ble
ed
ing
Ep
ista
xis
Arr
hyt
hm
ia
Sho
ck
Aci
do
sis
Nig
ht
swe
at
Ora
lulc
er
Adverse Effect
Cas
eC
ou
nt
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Results Adverse Effect
◆Renal Function and Tumor Lysis
0
100
200
300
400
500
600
0 10 20 30 40 50
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12Patient 13 Patient 14 Patient 15 Patient 16 Patient 17
crea
tin
ine(μmol/
L)
Days Post CAR-T Infusion
0
100
200
300
400
500
600
700
800
0 10 20 30 40 50
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12
Patient 13 Patient 14 Patient 15 Patient 16 Patient 17
uri
c ac
id(μmol/
L)
Days Post CAR-T Infusion
0
2000
4000
6000
8000
10000
12000
0 10 20 30 40 50
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12Patient 13 Patient 14 Patient 15 Patient 16 Patient 17
LDH
(U/L
)
Days Post CAR-T Infusion
0
5000
10000
15000
20000
25000
30000
35000
40000
0 10 20 30 40 50
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12
Patient 13 Patient 14 Patient 15 Patient 16 Patient 17
Ferr
itin
(ng/
ml)
Days Post CAR-T Infusion
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◆Renal Function
Before CAR-T During CAR-T
P=0.007
81.72±28.95 67.23±36.79
Cre
atin
ine
(μmol/
L)eG
FR(m
l/m
in)
78.38±41.28 133.23±123.60
P=0.010
Before CAR-T During CAR-T
BU
N (
mm
ol/
L)
Before CAR-T During CAR-T
5.78±2.39 10.80±8.84
P=0.003
Before CAR-T During CAR-T
Uri
c A
cid
(μmol/
L)
328.29±135.88 329.46±163.06
P=0.960
Only one patient needed hemodialysis support
Results Adverse Effect
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◆Coagulation Dysfunction
0
5
10
15
20
25
30
35
40
0 10 20 30 40 50
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12Patient 13 Patient 14 Patient 15 Patient 16 Patient 17
PT
(s)
Days Post CAR-T Infusion
0
20
40
60
80
100
120
0 10 20 30 40 50
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12Patient 13 Patient 14 Patient 15 Patient 16 Patient 17
Days Post CAR-T Infusion
AP
TT(s
)
0
1
2
3
4
5
6
7
0 10 20 30 40 50
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12Patient 13 Patient 14 Patient 15 Patient 16 Patient 17
Days Post CAR-T Infusion
Fib
rin
oge
n(g
/L)
0
10000
20000
30000
40000
50000
60000
70000
80000
90000
0 10 20 30 40 50
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12Patient 13 Patient 14 Patient 15 Patient 16 Patient 17
D-dim
er(μg/L)
Days Post CAR-T Infusion
Results Adverse Effect
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Case 1
◆ male,71y,Multiple Myeloma for 3 years(IgG, kappa,IIIA)
2 cycles of PCD(Velcade + DXM + CTX)
Because of peripheral neurotoxicity (Grade 3), PCD discontinued
5 cycles of RCD(Lenalidomide + DXM + CTX)
6/12/2017:DECP,PD
Bendamustine + Lenalidomide + DXM
PD
Enrolled for clinical trial of BCMA CAR-T cell therapy
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Treatment
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Treatment
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Days after CART infusion
◆ CRP ◆ Cytokine
◆ IgG ◆ CAR-T proliferation
0
1000
2000
3000
4000
5000
6000
7000
8000
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
IL-6
IL-10
IFNγ
0
10
20
30
40
50
60
70
80
90
D1
D2
D3
D4
D5
D6
D7
D8
D9
D1
0
D1
1
D1
2
D1
3
D1
4
D1
5
D1
6
D1
7
D1
8
D1
9
D2
0
D2
1
D2
2
D2
3
D2
4
D2
5
D2
6
Days Post CAR-T Infusion
CAR-T cell infusion
CAR-T cell infusion
Treatment
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Follow-up
The patient still keeps CR 15 months
after CAR-T treatment!
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Case 2
◆ 63 year-old woman with history of multiple myeloma for 6 years,
Monoclonal IgG and Kappa, t(4;14)
Vertebral internal fixation + 8 course of radiotherapy
2012-08-05 1st ASCT with MEL200
2015-11 Relapse, t(4;14), del P53, radiotherapy and 4 courses of RVd
2016-02-22 2nd ASCT with MEL200
2017-5 Relapse, Pomalidomide + Daratumumab and Dexamethasone
2018-6 Relapse
Enrolled for clinical trial of BCMA CAR-T cell therapy
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Treatment
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0
2000
4000
6000
8000
10000
12000
14000
16000
1 3 5 7 9 11131517192123252729313335373941434547495153
Tali IL-6
Tali IL-10
Tali IFN-γ
Days after CART infusion
◆ CRP ◆ Cytokine
◆ IgG ◆ Κ chain
Treatment
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Remain CR for 7 months after CAR-T treatment
Treatment
Negative
Negative
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Treatment
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Our basic research on BCMA CAR-T cells
Dynamics of T cell subsets during BCMA
CAR-T therapy for R/R Multiple Myeloma
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Case Primary Plasma Cell Leukemia
◆ Patient 17: Primary plasma cell leukemia, refractory
Before CAR-T Day 2 CAR-T Day 3 CAR-T Day 4 CAR-T Day 5 CAR-T Day 6 CAR-T Day 7 CAR-T
CAR-T cells expanded
rapidly and eradicated
plasma cell leukemia
within 7 days.
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◼ CD4 and CD8 composition of CAR-T
cell populations (by flow cytometry)
◆Dynamics of cytokines and T cell subsets during CAR-T treatment
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◆Single cell RNA-seq of CAR-T cells and normal T cells
◼ scRNA-seq was performed on six samples from three time points:
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◼ T cell subsets in different time point samples
Day 0 (before CAR-T infusion) Day 8 (peak CRS) Day 15 (after CRS)
CAR-T cells
Normal T cells
T-SNE plot of T cells for each sample based on the expression of highly variable genes:
Total 24 clusters
Total 29 clusters
◆Single cell RNA-seq of CAR-T cells and normal T cells
Day 8 (peak CRS) Day 15 (after CRS)
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◼ T cell subsets in total samples
⚫ CAR-T cells before CAR-T infusion(Day 0) mostly are CD4+CD25+ cells.
⚫ CAR-T cells in CAR-T peak level (Day 8) are mainly CD8+LAG3+ cells.
⚫ Normal T cells grouped into a series of subsets during CAR-T
therapy.(LAG3+,TIM3+, CCR7+,CD62L+)
◆Single cell RNA-seq of CAR-T cells and normal T cells
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◼ CAR-T cell proliferation at different time point
Day 0 (before CAR-T infusion)
Day 8 (peak CRS) Day 15 (after CRS)
⚫ The proliferative capacity of CAR-T cells are highest in peak CRS (Day8).
⚫ The ability of CAR-T cell proliferation decreases as the tumor cells decrease.
◆Single cell RNA-seq of CAR-T cells and normal T cells
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Our basic research on BCMA CAR-T cells
The microbiome in BCMA CAR-T treatment
for R/R multiple myeloma
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◆ FC0: before FC chemotherapy
◆ FC2: after FC chemotherapy and before CAR-T cell infusion
◆ CRS0: no CRS after CAR-T cell infusion
◆ CRS1: one day after CRS
◆ CRS2: CRS restoration
◆Flora samples taken at different time point:
Our basic research on BCMA CAR-T cells
◆Methods for Stool sample detection:
◆ 16S RNA
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Our basic research on BCMA CAR-T cells
Shannon index
FC0 FC2 CRS0 CRS1FC2 NA NA NACRS0 NA NACRS1 * NACRS2 * **
Simpson index
FC0 FC2 CRS0 CRS1FC2 NA NA NACRS0 NA NACRS1 * ** NACRS2 * ** *
Chao index
FC0 FC2 CRS0 CRS1FC2 NA NA NA CRS0 NA NA CRS1 NA CRS2
NA: not available; *P<0.05 **P<0.01
◆Beta diversity
Beta diversityCRS0 CRS1 FC0 CRS2 FC2
CRS0 1 * **CRS1 * 1 **FC0 1 **CRS2 ** ** 1 **FC2 ** ** 1
*P<0.05 **P<0.01
◆Alpha diversity
Flora microbiome diversity
decreased in CRS stage
Flora microbiome structure
changed after CAR-T treatment
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◆ Chao index of alpha diversity is significant
difference between CR and nonCR group
in CRS1 stage.
◆ Microbiome diversity is higher in CR group
than in nonCR group.
Higher diversity of microbiome might
be associated with treatment efficacy.
Our basic research on BCMA CAR-T cells
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Our basic research on BCMA CAR-T cells
The dominant microbiome is different between CRS less than grade 3 group
and grade 3 CRS group.
A: CRS less than grade 3; B: Grade 3 CRS
The dominant microbiome might be associated with CRS grade!
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Summary
◆ BCMA CAR-T cells for R/R MM have very good efficacy
◆ BCMA CAR-T cells for R/R MM are safe
◆ Single cell RNA sequence may provide tools to study
mechanisms of CAR-T cytotoxicity
◆ Flora microbiome might be associated with therapeutic efficacy
and CRS grade
◆ More patients enrollment and expanded follow-up time will be
needed
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Acknowledgement
◆Clinical Team
➢ Yongxian Hu
➢ Jian Yu
➢ Yi Luo
➢ Jimin Shi
➢ Guoqing Wei
➢ Wenjun Wu
➢ Jie Sun
◆Hcblab LAB
➢ Huijun Xu
➢ Hao Zhang
➢ Zuyu Liang
➢ Xiujian Wang
➢ Lijuan Ding
➢ Wanmao Ni
◆Cellular
Therapeutic Lab
➢ Hongseng Zhang
➢ Lei Xiao
➢ Zhao Wu
➢ Yanlei Zhang
➢ Jinping Wang
➢ Xin Wu
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Thank You!
New district of First Affiliated Hospital of Zhejiang University School of Medicine
Total Bed: 1200
Bed for HSCT: 46