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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
◆Patients with multiple myeloma will finally evolution into refractory/ relapsed
disease
Background
Blood Cancer J. 2019 Mar 7;9(3):32.
3
◆Novel agents and antibodies developed in recent years
Leukemia (2018) 32, 252–262; doi:10.1038
Background
◆ 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
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
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
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%
CAR-T treatment for MM in China
◆Nanjing Legend Biotech Inc.
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%
CAR-T treatment for MM in China
◆Nanjing Legend Biotech Inc.
BCMA CAR-T treatment for Multiple
myeloma in our center
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Unpublished data
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
◆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
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
Results Prognosis
◆Clinical Efficacy after CAR-T Infusion
Overall response rate 100%, CR or VGPR rate 80.8%
◆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
Extramedullary lesions were eradicated after CAR-T treatment!
Before CAR-T After CAR-T
◆ Extramedullary lesions by PETCT
CAR-T treatment in our center
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
◆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
Results CAR-T cell expansion in vivo
0
10
20
30
40
50
60
70
80
90
100D
1
D2
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D7
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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!
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.
Results CAR-T cell expansion in vivo
◆ CRS grade
◆16 patients received Tocilizumab treatment
◆4 patients received steroid treatment
◆No patient died of CRS
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
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
◆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
◆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
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
Treatment
Treatment
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
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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
Follow-up
The patient still keeps CR 15 months
after CAR-T treatment！
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
Treatment
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
Remain CR for 7 months after CAR-T treatment
Treatment
Negative
Negative
Treatment
Our basic research on BCMA CAR-T cells
Dynamics of T cell subsets during BCMA
CAR-T therapy for R/R Multiple Myeloma
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.
◼ CD4 and CD8 composition of CAR-T
cell populations (by flow cytometry)
◆Dynamics of cytokines and T cell subsets during CAR-T treatment
◆Single cell RNA-seq of CAR-T cells and normal T cells
◼ scRNA-seq was performed on six samples from three time points:
◼ 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)
◼ 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
◼ 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
Our basic research on BCMA CAR-T cells
The microbiome in BCMA CAR-T treatment
for R/R multiple myeloma
◆ 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
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
◆ 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
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！
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
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
Thank You!
New district of First Affiliated Hospital of Zhejiang University School of Medicine
Total Bed: 1200
Bed for HSCT: 46
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