Harnessing the Power of the Host Immune System to Fight Cancer Robert Kastelein Immuno-Oncology Discovery Texas FreshAIR Conference 2014 Houston October 23-24
Harnessing the Power of the Host Immune System to Fight Cancer Robert Kastelein Immuno-Oncology Discovery Texas FreshAIR Conference 2014 Houston October.
Dec 21, 2015
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Harnessing the Power of the Host Immune System to Fight Cancer
Robert KasteleinImmuno-Oncology Discovery Texas FreshAIR Conference 2014Houston October 23-24
Immunological Homeostasis
2
Costimulatory Signal
CD28CD40Adhesion moleculesCytokinesGITRTIM1HVEMCD27
CTLA-4PD-1FcRKIRsCytokinesTGFbCD200RTIM3LAG3
Inhibitory Signal
Homeostasis
T cell receptorB cell receptorNCRCD20FcR
Activation Signal
Joe Phillips, Lewis Lanier
Tolerance
Immunity
Role of PD-1 in Chronic Viral Infection
3
PD-1 is Important for Immune Tolerance
• PD-1 interacts with its ligands (PD-L1 and PD-L2) to inhibit activation of T lymphocytes
• Cancers can ‘hijack’ the PD-1 pathway• PD-1 blockade may reactivate anti-tumor immunity
*
MK-3475 Is a Potent Antagonistic Antibody Against PD-1
• First-in-human study of MK-3475 in melanoma (Hamid et al, NEJM 369:134)• Expanded study platform – reported activity in NSCLC, H&N cancer, bladder
and gastric cancer• A signal detection study is exploring activity in 20 different tumor types
selected on the basis of PD-L1 expression• Sep 4, 2014 – U.S approval of Keytruda for treatment of patients with
advanced or unresectable melanoma no longer responding to other treatments
Best Overall Response in Melanoma Patients Treated with Pembrolizumab (RECIST 1.1)
6
ORR 34% by RECIST 1.1; 88% of responses ongoing
Kaplan Meier Estimate of PFS per RECIST 1.1
7
69% OS at 12 months; median OS not reached
Immunotherapy in Oncology: Can we Alter the Survival Curve by Combining Therapies?
Control
Standard or other therapyCheckpoint blockadeCombination with standardof care or other IMRs
Placing Immune Interventions in the Context of Tumor Cell Recognition
Adapted from Chen and Mellman, Immunity 39: 1 (2013)
Cytotoxic agents
Cancer vaccines & adjuvants
Immune checkpoint targets and other
immunomodulators
Chemokines & homing receptor
modulators
Adoptive T cell therapies
Melero I, et al. Clin Cancer Res. 2013;19:997-1008.
Targeting Immunomodulators (IMRs): The Opportunity and the Challenge
©2013 by American Association for Cancer Research.
• By investigating how anti-PD-1 works we will be able to develop meaningful combination strategies
Leveraging Preclinical Data to Inform IMR Selection
11
Human Clinical Response with
MK-3475Mouse Syngeneic Tumor Models
• Responder vs. non-responder signature at baseline
• Post-treatment signatures in responder vs. non-responder
• Flow cytometry of TILs, markers, IMRs
• IHC cell markers, IMRs• Gene expression in tumors
Human Tumor Analysis
Anti-mouse PD1 Surrogate is Efficacious in Multiple, but not all, Syngeneic Tumor Models
12
10 m
g/Kg Is
otype
1 m
g/Kg D
X-400
5 m
g/Kg D
X-400
10 m
g/Kg D
X-400
0
500
1000
1500
2000**
***
Subcutaneous MC38 16 days post single injection of
DX-400
ns
Tu
mo
r V
olu
me
(mm
3)
Initial tumor volumes at start ~100mm3* Indicates statistical significance
Subcutaneous CT-26single injection of DX-400
PD1 and PDL1 are Upregulated Following Anti-PD1 Treatment
GLIOMA-26
0 5 10 15 200
1000
2000
3000
Isotype (0/5 CR)0.3 mg/Kg muDX400 (0/5 CR)0.6 mg/Kg muDX400 (0/5 CR)1.25 mg/Kg muDX400 (2/5 CR)2.5 mg/Kg muDX400 (4/5 CR)5 mg/Kg muDX400 (4/5 CR)
Days post treatment
Tu
mo
r V
olu
me
(mm
3)
DX400 0.3mpk
DX400 1.25mpk
DX400 5mpk
PDL1 PD1DX400 0.3mpk
DX400 1.25mpk
DX400 5mpk
14
Anti-PD-1 mAb induced Expansion of Mouse Tumor-associated CD3 and CD8b+ T Cells
MC38 mouse syngeneic tumor model4 days post anti-PD-1 mAb treatment (DX400; at 5 mg/kg)tumors were analyzed (pink – antigen; blue – nuclei)
Co
ntr
ol m
Ab
CD3
CD8CD3
CD8
An
ti-P
D-1
mA
b
4 days post anti-PD-1
treatment
Anti-PD-1 Treatment Elicits Genes Associated with Immune Response (preclinical models)
Ln Expression
I 24h pfd
I 24h psd
I 4d
psd
I 4d pfd
Gene Expression in aPD-1 treated miceBlood Expression
I 4d pfd
I 24h pfd
I 24h psd
I 4d
psd
Tumor expression
I 24h pfd
I 4d pfd
I 24h psd
I 4d
psd
Cell Marker
Tumor Biology
Chemokines and Cell Activation/Recruitment
M2 and Immuno Regulatory
Blood LN TUMOR
Cell Marker
Anti-Tumor Immune Response
Chemokines and CellActivation/Recruitment
M2 and Immuno-Regulatory
Profiling Mouse Models: Blood ≠ LN ≠ Tumor
Intra-tumoral Clonal T-Cell Expansion Following Anti-PD-1 Therapy
16
Naïve Day 4 Day 90
2000
4000
6000
8000
Time
# o
f T
ce
lls in
tu
mo
r ti
ss
ue
, tu
mo
r
Naïve Day 4 Day 90.15
0.2
0.25
0.3
0.35
Time
TC
R r
ep
ert
oir
e c
lon
alit
y,
tum
or
Next-generation sequencing and data analyses were performed by Adaptive Biotechnologies.
• MC38-tumor bearing mice were treated with 5 mg/kg anti-PD-1. Tumors were harvested at 4 and 9 days following a single mAb dose.
– Increased intratumoral T cells at 4 and 9 days post-treatment– T cell infiltrate is more clonal by 9 days post-treatment
mDX400
Isotype control
mDX400
Isotype control
Glucocorticoid-Induced TNFR-Related protein (GITR) Biology and Target Rationale
17
18
Day 1
Day 4
Day 1
20
500
1000
1500
2000
2500
TIL Treg
Tre
g /
mg
tu
mo
r
****MC38 isotypeMC38 aGITR
Day 1
Day 4
Day 1
20
2000
4000
6000
2000040000 *
TIL CD8+ T cells
CD
8+ T
cel
l / m
g t
um
or
Day 1
Day 4
Day 1
20
2
4
6
8
10
DLN
CD
8:T
reg
ra
tio
Day 1
Day 4
Day 1
20
20
40
60
80
100
TILs
CD
8:T
reg
ra
tio
****
MC38 isotypeMC38 aGITR
Innoculate MC38
Anti-mGITR or isotype
Analyze TILs and draining LN
0-8 1 4 12
Day
Kinetics of aGITR tx response
Anti-GITR Treatment Specifically Targets ‘Intra-Tumor’ Tregs
Kinetics of Anti-GITR Treatment Response in Tumor Micro-Environment
19
Days post anti-GITR treatment
0 1 4 12
Treg CTL
T c
ell
s /m
g t
um
or
20
Treatment with human GITR Agonist mAb Results in Dose-Dependent Reduction of MLR Induced Regulatory T cells
% C
D4+
/CD
25+
/Fo
xP3+
isoty
pe 20
ug/m
l
GITR 0
.1
g/ml
GITR 1
g/m
GITR 1
0 g
/m
GITR 2
0 g
/ml
10
20
30
40
50
***
*****
Treatment with anti-GITR agonist results in significant reduction of FoxP3 TREGs
TREGs were induced by stimulating human PBMC with allogeneic dendritic cells for 7 days in the presence of indicated concentrations of anti-human GITR.
Cross-regulation of PD-1 and GITR in vivo
Upregulation of GITR mRNA in tumor after anti-PD-1 treatment
Anti-PD-1 single dose
GITR
Diff
eren
tial r
espo
nse
Tumor
d1 d4 d1 d4
anti-PD-1isotype
Upregulation of PD-1 and PD-L1 mRNA in tumor after anti-GITR treatment
Bar Chart
tissue, day, Treatment
Min
(nor
m v
alue
)
ctrl
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1 ctrl
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1 ctrl
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1 ctrl
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1
d1 d4 d8 d12 d1 d4 d8 d1
2 d1 d4 d8 d12 d1 d4 d8 d1
2
Blo
od
Tum
or LN Live
r
PD-1
130
120
110
100
90
80
70
60
50
40
30
20
10
0
PD-1Bar Chart
tissue, day, Treatment
Min
(nor
m v
alue
)
ctrl
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1 ctrl
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1 ctrl
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1 ctrl
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1
Iso
type
DTA
-1
d1 d4 d8 d12 d1 d4 d8 d1
2 d1 d4 d8 d12 d1 d4 d8 d1
2
Blo
od
Tum
or LN Live
r
PD-1
Min
(nor
mal
ized
val
ues)
Tumor
d1 d4 d8 d12
Bar C
hart
tissue, day, Treatment
Min(norm value)
Anti-GITRisotype control
PD-L1Bar Chart
tissue, day, Treatment
Min
(nor
m v
alue
)
ctrl
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1 ctrl
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1 ctrl
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1 ctrl
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1
d1 d4 d8 d12 d1 d4 d8 d1
2 d1 d4 d8 d12 d1 d4 d8 d1
2
Blo
od
Tum
or LN Live
r
Pdcd1 (PD-L1)
Bar Chart
tissue, day, Treatment
Min
(nor
m v
alue
)
ctrl
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1 ctrl
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1 ctrl
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1 ctrl
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1
Isot
ype
DTA
-1
d1 d4 d8 d12 d1 d4 d8 d1
2 d1 d4 d8 d12 d1 d4 d8 d1
2
Blo
od
Tum
or LN Live
r
Pdcd1 (PD-L1)
700
650
600
550
500
450
400
350
300
250
200
150
100
50
0
Tumor
d1 d4 d8 d12
Anti-GITR single dose
Anti-PD-1 + Anti-GITR Combination Efficacy
● Large established MC38 tumors used● Synergistic combination anti-tumor efficacy observed● Combination efficacy observed in additional models● All mAbs dosed at 5mg/kg
22
Large MC38 tumors(300mm3 starting volume)
Day post anti-GITR and/or anti-PD1All doses 5 mg/kg
Mea
n T
um
or
Vo
lum
(m
m3)
0 7 14 21 280
1000
2000
3000Isotype ctrl d0,7,14
(anti-GITR+anti-PD1) d0,7
anti-GITR d0,7,14,21anti-PD1 d0,7,14,21
10/10 CR
2/10 CR
2/10 CR
0/10 CR
Exploiting the Patient’s Immune System for Optimal Anti-Tumor Activity
Pushing the accelerator
• cancer ‘vaccines’• adjuvants (e.g. BCG, TLRs)• tumor-specific antigens• adoptive immunotherapy• cytokines (IL-2, IL-12, IFNa)• cellular immunotherapy• agonists to immunostim.
IMRs – anti-GITR
Releasing the brakes
• anti-CTLA-4 • anti-PD-1• antagonists to additional
inhibitory IMRs
Are both approaches needed for optimal efficacy?
23
Acknowledgements
• MK-3475 team and Anti-GITR team
• Discovery Team (Palo Alto & Boston) especially:– Amy Beebe– Smita Mauze– Renu Jain– Ashley Mahne – Terri Mcclanahan– Svetlana Sadekova– Doug Wilson– Debbie Law
24
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