Miguel F Sanmamed María Rodriguez Carlos Alfaro Carmen Oñate Inmaculada Rodriguez José L Pérez Gracia Bruno Sangro Salvador Martin -Algarra JM Lopez Picazo Alfonso Gúrpide Javier Rodriguez Jesús San Miguel Jesús Prieto Alberto Benito Ivan Peñuelas Alvaro Gonzalez Mercedes Iñarrairaegui Aizea Morales Arantza Azpilikueta Elixabet Bolaños Inmaculada Rodriguez Sara Labiano Eneko Elizalde Alfonso Rodriguez Angela Aznar Maria Rodriguez-Ruiz Pedro Berraondo Luna Carneiro Ines Guetgeman Juan M Zapata Manuel Rodriguez Valerie Lang Bettina Weigelin Peter Friedl Bristol Myers Squibb Roche/Genentech Pfizer AstraZeneca Boehringer Ingelheim
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Combination opportunities in immunotherapy with ... · Hospital Universitario Reina Sofía, Córdoba Hospital Universitario 12 de Octubre, Madrid Protocol code CT-2007-01 ... humanized
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Miguel F Sanmamed
María Rodriguez
Carlos Alfaro
Carmen Oñate
Inmaculada Rodriguez
José L Pérez Gracia
Bruno Sangro
Salvador Martin -Algarra
JM Lopez Picazo
Alfonso Gúrpide
Javier Rodriguez
Jesús San Miguel
Jesús Prieto
Alberto Benito
Ivan Peñuelas
Alvaro Gonzalez
Mercedes Iñarrairaegui
Aizea Morales
Arantza Azpilikueta
Elixabet Bolaños
Inmaculada Rodriguez
Sara Labiano
Eneko Elizalde
Alfonso Rodriguez
Angela Aznar
Maria Rodriguez-Ruiz
Pedro Berraondo
Luna Carneiro
Ines Guetgeman
Juan M Zapata
Manuel Rodriguez
Valerie Lang
Bettina Weigelin
Peter Friedl
Bristol Myers Squibb
Roche/Genentech
Pfizer
AstraZeneca
Boehringer Ingelheim
IGNORANT T CELL
Insufficient antigen/
lack of co-stimulatory signals
ANERGIC T CELL
Unsuccessful stimulation/
negative regulation
APOPTOTIC T CELL
(DELETED)
Programmed cell death
NAIVE T CELL PRIMED T CELL EFFECTOR T CELL MEMORY
T CELL:
Central memory cell
Effector memory cellCD27
CD28
HVEM
TCR
MHC
-peptide
CD27L
CD80/86
LIGHT
CTLA-4
B7-H4R
CD80/86
B7-H4
PD-1
B7-H4R
B7-H1
BTLA-4
B7-H1
B7-DC
B7-H4
BTLA-4R
CD137
OX40
ICOS
B7-H3R
CD137L
OX40L
B7h
B7-H3
IL-15
IL-7
CD-137
OX-40
others
IL-12
IFN-α
Schematic representation of the concept of immunostimulatory mAbs.
• Nivolumab is a fully human IgG4 anti-PD-1 monoclonal antibody that selectively
blocks the interaction between PD-1 and PD-L1/PD-L2,1 restoring T-cell immune
activity directed against the tumor cell
1. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454
25
And across tumour types, mutation load does not
correlate with clinical activity40%
20%
0%
28%2
0%2
6%1
25%3
0%1
20%5
31%4
0%1
~26%7
~21%8
33%9
29%6
ORR
Alexandrov, et al. Nature 2013
1. Brahmer, et al. N Engl J Med 2012; 2. Lesokhin, et al. ASH 2014; 3. Motzer, et al. N Engl J Med 2015; 4. Muro, et al. ESMO 2014
5. Chow, et al. ESMO 2014; 6. Ott, et al. WCLC 2015; 7. Powles, et al. Nature 2014; 8. Garon, et al. ESMO 2014; 9. Robert, et al. ESMO 2014
27
HCC and Programmed Death-1
(PD-1)
• HCC is typically an inflammation-associated cancer and can be immunogenic1
• Association of hepatitis C and hepatitis B infection with upregulation of PD-12,3
• Upregulation of PD-1 and the PD-1 immune checkpoint ligand, PD-L1, in HCC is
associated with poor outcomes4
• Blockade of PD-1 with monoclonal antibodies combined with immunostimulatory
monoclonal antibodies extended survival in a mouse model of HCC5,6
• Immune checkpoint inhibition (anti-CTLA-4) has shown encouraging activity in an early
clinical trial in HCC7
• PD-1 blockade with nivolumab may boost host immunity against HCC and improve clinical
outcomes
1. Hato T, et al. Hepatol. 2014;60:1776-1782
2. Xu P, et al. Gut Liver. 2014;8:186-195
3. Barathan M, et al. Apoptosis. 2015;20:466-480
4. Zeng Z, et al. PLoS One. 2011;6:e23621
5. Chen Y, et al. Hepatology. 2015;61:1591-1602
6. Morales-Kastresana A, et al. Clin Cancer Res.
2013;19:6151-6162
7. Sangro B, et al. J Hepatol. 2013;59:81-88
Phase 1/2 Safety and Antitumor Activity
of Nivolumab in Patients With Advanced
Hepatocellular Carcinoma (HCC): CA209-
040
Anthony B. El-Khoueiry,1 Ignacio Melero,2 Todd S. Crocenzi,3
Theodore H. Welling III,4 Thomas Yau,5 Winnie Yeo,5 Akhil Chopra,6
Joseph F. Grosso,7 Lixin Lang,7 Jeffrey Anderson,7 Christine de la Cruz,7 Bruno
Sangro2
1University of Southern California Norris Comprehensive Cancer Center, Los Angeles,
CA, USA; 2Clinica Universidad de Navarra and CIBERehd, Pamplona, Spain; 3Providence Cancer Center, Portland, OR, USA; 4University of Michigan, Ann Arbor,
MI, USA; 5University of Hong Kong, China; 6Johns Hopkins Singapore International
Medical Centre, Singapore; 7Bristol-Myers Squibb, Princeton, NJ, USA
Abstract LBA 101
29
Study Design
• Patients received nivolumab Q2W for up to 2 years (maximum of 48 doses), depending on response
– Imaging for disease assessment performed every 6 weeks
• A 3+3 design was used in the phase 1 dose escalation phase
• Here, we report interim results from the ongoing dose escalation phase and part of the expansion phase
*5 patients not evaluable: first disease assessment not yet performed in 4 patients, 1 patient died from clinical
progression before disease assessment†Patient with resolved HCV infection
Investigator-Assessed Best Overall
Response
32
Maximal Change in Target Lesions
From Baseline120
100
80
60
40
20
0
-20
-40
-60
-80
-100
Patients (N = 40)†
Ch
an
ge
in
Ta
rge
t L
es
ion
Fro
m B
as
eli
ne
, %
Uninfected
HCV
HBV
Confirmed response
*
* *
* ** *
* *
†2 uninfected patients not shown: 1 had disease progression before the first assessment; 1 had a maximal change of +23%‡Patient with resolved HCV infection
Confined tracks, concentrated Dwell timehigh dwell time per tumour cell
Ctrl
0h 1h
0
50
100
150
200
CT
L :
tu
mo
ur
ce
llco
nta
ctd
ura
tio
n(m
in)
0
Tumour: F10 F10/OVA
2
4
8
6
10
12
Sp
ee
d(µ
m/m
in)
OT1OT1 + αCD137
OT1OT1 + αCD137
OT1OT1 + αCD137
0 20 40 60 80
dt (min)
0
1000
2000
3000
Weigelin, et al. PNAS in press
Tumor
Proliferation
Blood
vessel
Activation of
endothelial cells
Enhanced CTL effector
functions
Costimulation
Killing
A B
C
00:00 h 00:40 h 01:06 h
CTL mitosis00:00 h 00:14 h 00:32 h
Tumor cell apoptosis
OT1 CD8 T cells Blood vessels
B16F10/OVA melanoma cell nuclei
CD8 T cells B16F10/OVA melanoma cells
Autofluorescent tissue
Hot spots for extravasationOverview tumor lesion
500 µm
CTL migration tracks
Enrichment of potent
effector cells
Costimulation during
activation
Chimeric receptors
containing CD137cyt
Ligand binding
Transmembrane
Costimulatory
Signaling
CD137 -derived
Dendritic cell Migration track
CD8 T cellTumor cellα-CD137 mAb
TILAPC
Proliferation
Effector function
Cell culture flaskDomains:
Imm
uno
-magnetic
cell
sort
ing
Undesired cells
TIL
CD137 and adoptive T cell transfer. A perfect marriage?
PROFESSIONALCROSSPRIMING DENDRITIC CELLS
0 2 0 4 0 6 0
0
1 0 0
2 0 0
3 0 0
4 0 0
0 / 2 8
0 2 0 4 0 6 0
4 / 2 3
0 2 0 4 0 6 0
1 6 /2 3
0 2 0 4 0 6 0
8 / 9
0 2 0 4 0 6 0
0 / 1 6
0 2 0 4 0 6 0
0
1 0 0
2 0 0
3 0 0
4 0 0
0 / 2 4
0 2 0 4 0 6 0
0 / 1 6
0 2 0 4 0 6 0
0 / 9
Untreated αCD137 αPD-1 αCD137 + αPD-1
WT
Batf3-/-
Days post-inoculation
Tu
mo
r si
ze (
mm
2)
0 2 0 4 0 6 0 8 0
0
2 0
4 0
6 0
8 0
1 0 0 8/9
16/23
4 /23
W T C D 1 3 7 + P D - 1
W T C D 1 3 7
W T P D - 1
W T c o n tro l
***
0 2 0 4 0 6 0 8 0
0
2 0
4 0
6 0
8 0
1 0 0
B a t f3- / -
C D 1 3 7 + P D - 1
B a t f3- / -
C D 1 3 7
B a t f3- / -
P D - 1
B a t f3- / -
c o n t r o l
**
WT Batf3-/-
Per
cent su
rviv
al
Days post-inoculation Days post-inoculation
Crosspriming DC absolutely needed!
0 10 20 300
50
100
150
200
Control mAb
13%
CD137
Avera
ge t
um
or
siz
e (
mm
2)
0 10 20 300
50
100
150
200
250
Batf3-/-
Days post-inoculation
Avera
ge t
um
or
siz
e (
mm
2)
0 10 20 300
50
100
150
200
Batf3-/-
Days post-inoculation
Avera
ge t
um
or
siz
e (
mm
2)
0 10 20 300
50
100
150
200
33%
FLT3L+PolyIC FLT3L+PolyIC + mAb
-PD-1
Avera
ge t
um
or
siz
e (
mm
2)
IMMUNOAVATAR
MICE PROJECTS
0
50
100
150
hPBMCs
hIgG4hCD137
hPD-1
4 7 21Time (Days) 4 7 21 4 7 21 4 7 21
+ + ++ + + + + ++ + +- - -- + +- + +
- - -- - -- + +
- - -- + +- - -
- - -- - -
- + +
h-I
FNg
(pg
/mL
)
Xenografted syngenic gastric cancer with autologous PBMCs experiments
Sacrifice(day 50)
5·105
PBMCs(i.p.)
7mmx7mmTUMOR
TRANSPLANT
0 5 6 12 19 26 33 40 48
200g Urelumab 200g Nivolumab (iv)TUMOR:
-FACS ANALYSES
-IHQ
Immunostimulatory monoclonal antibodies anti-hCD137 (urelumab) and anti-hPD-1 (nivolumab) alone or in combination show antitumoractivity against a xenografted human colon cancer mediated by transferred allogenic human PBMC.
Xenografted syngenic gastric cancer with autologous PBMCs experiments
Co
mb
oα
-hC
D1
37
α-h
PD
-1C
on
tro
l
CD3/CD8/CD20/CK/DAPI
CD3/CD8/CD20/CK/DAPI
CD3/CD8/CD20/CK/DAPI
CD3/CD8/CD20/CK/DAPI
IgG4
-hCD13
7
-h
PD-1
Com
bo0.00
0.01
0.02
0.03
0.04
Tumor compartment
*
rati
o h
CD
3/t
ota
l p
are
cn
ch
ima c
ells
IgG4
-hCD13
7
-h
PD-1
Com
bo0.0
0.2
0.4
0.6
0.8Stromal compartment
rati
o h
CD
3/ to
tal str
om
a c
ells
Multiplexed immunofluorescence microphotographs showing the architecture of tumor xenografts