anti-dll4 treatment in combination with anti-pd1: from...
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Anti-DLL4 treatment in Combination with anti-PD1: From preclinical to clinical
Angie Inkyung Park, PhDSr. DirectorImmunotherapy & stem cells
Oncomed PharmaceuticalsJanuary 26, 2017
OncoMed 2
RSPO/LGRPathway
RSPO/LGRPathway
WntPathway
WntPathway
NotchPathway
NotchPathway
OncoMed Pharmaceuticals:Targeting Critical Cancer Pathways and TME
• Demcizumab
• Tarextumab
• Brontictuzumab
• Anti-DLL4/VEGF bispecific
• Vantictumab
• Ipafricept
• Small Molecules
• Anti-RSPO3
• Other RSPOs
• Other LGRs
Immuno-oncologyImmuno-oncology
• Anti-TIGIT
• GITRL-Fc
• IO #3 (undisclosed)
Ph2Ph1INDPreclinical
• 7 clinical programs in or achieved to Phase 2
• 14 active clinical trials: evidence of activity
• Data from multiple randomized Phase 2 trials by 2017
OncoMed 3
OncoMed Tumor Bank: Establishment of Patient Derived Xenografts for Studying Cancer Stem Cells
Established > 210 tumors from 18 different cancer types to date
• Focused on major tumor types
- Br, Co, Lu, PN, Ov, Mel, Liv etc.
- Continually expanding
• Extensive genomic characterization
- Gene expression (mRNA-seq)
- Oncogene mutational analysis
- Gene amplifications and deletions
• Models retain tumor cell heterogeneity
- Better predict clinical outcome
- Enable CSC characterization and
biomarker discovery
p1 p2
Immunocompromised
OncoMed 4
Tumor Models
Humanized Mouse Models
SyngeneicMouse Models
Genetically Engineered
(GEMMs)
Using Preclinical Mouse Models to supportdrug discovery
Pros:
• Ability to explore human tumor/immune cell interaction
• Opportunity to utilize valuable PDX tumor models
Cons:• Incomplete immune cell
compliment
• Development of GVHD
• New and not fully characterized
• Cost
Patient derived xenograft (PDX)
Models
Pros:
• Full immune cell compliment
• Used to validate current approved Immune checkpoint inhibitors
Cons:
• Rapid tumor formation• Limited tumor models• Surrogate antibody effects may have
limited human translatability
Pros:• First-in-class Tumor bank,
continually expanding• Extensive genomic
characterization• Tumor cell heterogeneity• Enable CSC characterization
and biomarker discovery
Cons:• Immunocompromised mice• Lack of human stroma
OncologyImmuno-Oncology
OncoMed 5
Signal Transduction by the Notch Pathway: implicated in many cancer types
• The Notch pathway mediates intercellular signaling in stem cell self-renewal, proliferation, and differentiation and immune cell development.
• OncoMed has developed first-in-class Notch pathway mAbs − Anti-DLL4 (demcizumab)− Anti-Notch2/3 (OMP-59R5,
tarextumab)− Anti-Notch1 (OMP-52M51,
brontictuzumab)
Nature Reviews Immunology 13, 427-437 (2013)
OncoMed 6
Anti-DLL4 Inhibits Tumor Growth And ShowsStrong Efficacy With SOC In PDX Models
NSCLC
PN Ca CRC
Days Post Treatment0 7 14 21 28 35 42 49
0
500
1000
1500 Control mAb
Anti-DLL4
Taxol
Anti-DLL4+Taxol
Tu
mo
r V
olu
me,
mm
3
OV
OncoMed 7
Anti-tumor MOA of Anti-DLL4
Anti-DLL4 blocks critical DLL4 role in angiogenesis
AngiogenesisCancer Stem Cells
Anti-DLL4 promotes differentiation and chemo sensitization
Blocking DLL4 function reduces CSCs and disrupt tumor angiogenesis
OncoMed 8
Therapy against Cancers
Time (Years)
Surv
ival
ICI + ???
UntreatedStandard or Other Targeted TherapyImmunotherapy (e.g.anti-CTLA4, PD1)Combination with IO agent
OncoMed 9
Role of DLL4 in Immune System
Immune Suppressive Tumor Microenvironment
Immune suppression by MDSC is a significant impediment to cancer immunotherapy
MDSCsTregsM2 macrophageFibroblastEndothelial cellsPericytesExtracellular matrix
Cytotoxic T cellNK cellsDCsNeutrophils
OncoMed 10
Role of DLL4 on MDSC:Immune suppression by MDSC is a significant impediment to cancer immunotherapy
IL-10TGFb
H2O2
TGFb
DC
DLL4
Notch
MDSCi-NOSIL-10Arg1ROSIDO
Tumor
CD4 T
CD8 T
IL-6TGFb
Treg
Th17
Rorgt
IL-17
NK
H2O2-CCL2NO-IL-2Arg, Cys, Trp depletionto CD3 expression
Regulation of T Cell Activation by Notch Ligand, DLL4, Promotes IL-17 Production and Rorc Activation
Mukherjee et al., J Immunol 2009. 182:7381-88
IL-17 Promotes Tumor Development through the Induction of Tumor Promoting Microenvironments at Tumor Sites and Myeloid-Derived Suppressor Cells
He et al., J Immunol 2010. 184:2281-88
Myeloid-Derived Suppressor Cells: Critical Cells Driving Immune Suppression in the Tumor Microenvironment
Parker KH., Beury, DW., and Ostrand-Rosenberg, S. Adv Cancer Res 2015. 128: 95-139
OncoMed 11
MDSCs Inhibit anti-Tumor Immunity
G-MDSC(ROS, Arginase)
CD11b+ Gr1hi
CD11b+Ly6GhiLy6Clo
M-MDSC(iNOS, IL10, Arginase)
CD11b+ Gr1lo
CD11b+Ly6G-/loLy6Clo
T cell ActivationNK cell cytotoxicity
M2 MΦTreg
OncoMed 12
DLL4 Inhibits Murine Tumor Growth in Syngeneic Mice
OncoMed 13
Anti-DLL4 Significantly Reduces Splenic IL17a as Measured by ELISPOT
Control Anti-DLL4
0
50
100
150
200
250
Control Anti-DLL4
IL-1
7a T
OD
(x1
00
0)
*
Control Anti-DLL4
4T1
0
20
40
60
80
100
Control Anti DLL4
IL-1
7a T
OD
(x1
00
0)
*
CT26.WT
OncoMed 14
Anti-DLL4 Reduces Inflammatory Cytokines
contr
ol
Anti-
DLL4
Plasma IL-17
contr
ol
anti-
DLL4
0
20
40
60
80
100
Splenocyte IL-6
contr
ol
Anti-
DLL4
0
50
100
150
Inflammatory Cytokine Reduction Leads to Decreased Neutrophil Counts in Circulation in 4T1 Tumor bearing mice
OncoMed 15
Anti-DLL4 Reduced Neutrophils and Increased Lymphocytes in Blood in 4T1 Bearing Mice
Contr
ol
Anti-
DLL4
% P
op
ula
tio
n
Contr
ol
Anti-
DLL4
% P
op
ula
tio
n
Neutrophils ~ MDSCs
OncoMed 16
Anti-DLL4 Uniquely Decreases Highly Immunosuppressive Monocytic MDSC Cells
FACS analysis of MDSC
Gated on CD11b+ in spleenM-MDSC: CD11b+LY6CintLY6G-
G-MDSC: CD11b+LY6G+LY6Clow
Control
Anti-DLL4Representative
mouse (of 10)
0
4
8
12
16
20
Control Anti-DLL4
% M
-MD
SC
p=0.0008
Spleen M-MDSC
G-MDSC(ROS,
Arginase1)
M-MDSC(iNOS, IL10, Arginase)
T cell ActivationNK cell cytotoxicity
M1 to M2 MΦTreg
0
1
2
3
4
5
Control Anti-DLL4
% M
-MD
SC
Tumor M-MDSC
OncoMed 17
Anti-DLL4 Results in Less Suppressive MDSCs
15.5%
17%31%
29%
CD4
CD8
Control Anti-DLL4
OncoMed 18
Anti-DLL4 inhibits Th17 Response Leading to anti-Tumor Immune Response
DC
DLL4
Notch
MDSCi-NOSIL-10Arg1ROSIDO
Tumor
CD4 T
CD8 T
IL-6TGFb
Treg
IL-10TGFb
Th17
Rorgt
IL-17
NK
H2O2
TGFb
H2O2-CCL2NO-IL-2Arg, Cys, Trp depletionto CD3 expression
OncoMed 19
Anti-DLL4 Treatment Significantly Reduces PD-1 Levels in CT26WT Tumors
Western Blot
PD-1
*
*p<0.03
Contr
ol
Anti-
DLL4
15
20
25
30
35
CD45
% P
op
ula
tio
n
**
Increased Immune Infiltration Decreased PD1 Expression
OncoMed 20
Anti-DLL4 combined with anti-PD1 significantly inhibits mouse CT26WT tumor growth while enhancing IFN-g and IL2 but decreasing IL17 cytokines
Tumor Growth ELISPOT
Tum
or
Vo
lum
e (
mm
3)
Tum
or
Vo
lum
e (m
m3)
Tum
or
Vo
lum
e (m
m3)
OncoMed 21
Anti-DLL4 reduces IL17 and M-MDSCs in Tumor
0
50
100
150
200
250
300
350
Control 21R50 PD1 Combo
IL17a T
OD
(x1000)
Tumor IL17a ELISPOT
*
*
0
1
2
3
4
5
6
Control DLL4 PD1 ComboC
d11b
+G
r1lo
w
Tumor M-MDSC
**
OncoMed 22
Mice Previously Treated with Anti-DLL4 and Anti-PD1 are Resistant to Tumor Re-challenge
Control
0 10 20 30 40 50-500
0
500
1000
1500
2000
2500
Days
Anti-DLL4
0 10 20 30 40 50-500
0
500
1000
1500
2000
2500
Days
Tu
mo
r V
olu
me (
mm
3)
Anti-PD1
0 20 40 60-500
0
500
1000
1500
2000
2500
Days
11/20
Anti-DLL4+PD1
0 20 40 60-500
0
500
1000
1500
2000
2500
Days
14/20
(45%) (79%)
Second Re-challenge
% Protection
Naive 0 (0/10)
Anti-PD1 40% (2/5)
Anti-PD1/DLL4 100% (11/11)
OncoMed 23
Anti-DLL4 inhibits Th17 Response Leading to anti-Tumor Immune Response
DC
DLL4
Notch
MDSCi-NOSIL-10Arg1ROSIDO
Tumor
CD4 T
CD8 T
IL-6TGFb
Treg
IL-10TGFb
Th17
Rorgt
IL-17
NK
H2O2
TGFb
H2O2-CCL2NO-IL-2Arg, Cys, Trp depletionto CD3 expression
Immune Memory
Checkpoint Inhibitors
OncoMed 24
Anti-DLL4 Use in Humanized SGM3 Models
OncoMed 25
Establishing Humanized Mice (JAX)
•• Three week old NSG/SGM3 mice are engrafted through the tail vein with purified human CD34+ HSCs.
• Twelve weeks later the circulating human CD45+ cell population is quantitated and confirmed to be at least 25% of the cell population.
• Selected human PDX tumors are then engrafted subcutaneously into the mice.
• Major human immune cell types: T cells, B cells, and myeloid cell lineages (limited NK and DCs).
• Tumors have been shown to grow regardless of HLA match/mismatch.
• Great opportunity to test PDX tumor models with human-specific humanized antibody biologics.
OncoMed 26
Effects of Human Anti-DLL4 + Anti-PD1 on OMP-M9 Melanoma PDX in hSGM3 mice
Tu
mo
r vo
lum
e (
mm
3)
PD1 (Keytruda)
0 10 20 300
1000
2000
3000
Days Post Treatment
Tu
mo
r vo
lum
e (
mm
3)
DLL4
0 5 10 15 20 25 300
1000
2000
3000
Days Post Treatment
Tu
mo
r vo
lum
e (
mm
3)
*
**
Tu
mo
r vo
lum
e (
mm
3)
DLL4 + PD1
0 10 20 300
500
1000
1500
2000
2500 Control
DLL4
PD1 (Keytruda)
DLL4 + PD1
Days Post Treatment
OncoMed 27
Effects of Human Anti-DLL4 + Anti-PD1 on OMP-LU121 (AdC) in hSGM3 mice
Control
0 5 10 15 200
500
1000
1500
2000
2500
Treatment (Days)
PD1 (Keytruda)
0 5 10 15 200
500
1000
1500
2000
2500
Treatment (Days)
DLL4
0 5 10 15 200
500
1000
1500
2000
2500
Treatment (Days)
***
***
DLL4 + PD1
0 5 10 15 200
500
1000
1500
2000
2500
Treatment (Days)
Tu
mo
r V
olu
me (
mm
3)
***
*****
Tu
mo
r V
olu
me (
mm
3)
OncoMed 28
Anti-DLL4 and Anti-PD1 (Keytruda) Combination Increases T Cells and Decreases MDSCs in the Tumor
Hu CD45+
Contr
ol
DLL4PD
1
DLL4
+ PD
10
10
20
30
40
***
Contr
ol
DLL4
PD1
DLL4
+ PD
1
Contr
ol
DLL4
PD1
DLL4
+ PD
1
OncoMed 29
Anti-DLL4 and Anti-PD1 (Keytruda) Combination Decreases PD1 Expression in Splenic CD4+ and CD8+ T Cells
CD4+ (Non Treg)
Control
DLL4
PD1
DLL4 +
PD10
20
40
60
80
100
%C
D4 in
CD
45
* *
CD8+
Control
DLL4
PD1
DLL4 +
PD10
20
40
60
%C
D8 in
CD
45
Contr
ol
DLL4PD1
DLL4
+ PD1
%P
D1+
in
CD
4+
T
CD8+PD1+
Control
DLL4
PD1
DLL4
+ PD1
0
20
40
60
80
*
OncoMed 30
Dual Blockade of DLL4 and PD1 Increases T Cell to MDSC Ratio
CD3T/MDSC
Contr
ol
DLL4
PD1
DLL4
+ PD1
0
5
10
15
* **
CD4T/MDSC
Contr
ol
DLL4
PD1
DLL4
+ PD
1
0
5
10
15
***
**CD8T/MDSC
Contr
ol
DLL4
PD1
DLL4
+ PD1
0
2
4
6
8
10
* **
OncoMed 31
Anti-DLL4 Summary
A phase 1b study with Anti-DLL4 in combination with anti-PD1 is on going.
DLL4 Inhibition
SyngeneicMice
Humanizedmice
IL-17 TBD
MDSC
TIL
PD1
OncoMed 32
Multiple Mechanisms of Anti-DLL4
Anti-DLL4 blocks critical DLL4 role in angiogenesis
AngiogenesisCancer Stem Cells
Anti-DLL4 promotes differentiation and chemo sensitization
Blocking DLL4 reduces CSCs, disrupt tumor angiogenesis, and inhibits MDSCs
MDSCs
Anti-DLL4 reduces and inhibits MDSCs
OncoMed 33
Acknowledgements
Tumor ImmunologyMinu SrivastavaHyun-Bae Jie
Rui YuErin Mayes
ARFKellie Pickell
Xiaomei SongRoger Lopez
Trans MedAnn Kapoun
Belinda CancillaFiore CattaruzzaErwan LeScolan
Jennifer CainPete YeungMin Wang
Chun ZhangAlayne Brunner
Akbar Currimbhoy
Process DevPeter StathisJohn BurkyJoy Chen
Esohe IdusogieJim Burrell
Ruby Casareno
James Keck and The Jackson Labs
Molecular BiologyAustin GurneyFumiko AxelrodJorge MonteonCecile Chartier
May JiAndrew Lam
Caner BiologyTim Hoey
Chris MurrielJean Yen
Marcus Fischer
John Lewicki (CSO)Paul Hastings (Chairman, CEO)