Tumour heterogeneity and
combination strategies
Rajendra Kumari, CSO & GM
CBUK Ltd
Introduction
• Heterogeneity drives cancer progression & treatment failure
• Mutational load influences antitumour immune response
Nature Reviews Cancer 13, 365-376 (May 2013)
• Heterogeneity changes with treatment
• Leveraging mouse models
• Development of Human systems
08/12/2016
2
Mutational heterogeneity in
cancer
•
•
•
Neoantigens: nonsynonymous somatic variations acquired by tumours
Tumours with mutational burden potentially harbour immunogenic antigens
resulting in antigens that trigger an anti-tumour immune response e.g. melanoma
and lung
Carcinogens e.g. tabacco, UV and DNA mismatch repair have high mutations
Lawrence et al; Nature. 2013 July 11; 499(7457):
08/12/2016
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3
Mutation mediated sensitivity to
PD-1 blockade in NSCLC
• Correlation between neoantigens and mutations
• Both high nonsynonymous mutational and neoantigen burdens are associated with
antitumour immune response and clinical response to checkpoint inhibitors
• Genomic landscape shapes the response to anti-PD-1 therapy
Rizvi et al Science 2015, 348: 124-128
08/12/2016
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4
Inducing Immunogenicity
•
Most mutations however occur early on.
Anderson, Nat Genet. 2015 Mar;47(3):196-7).
•
High burden of clonal neoantigens (i.e. present in all tumour cells) is associated with
improved patient survival and durable response to immunotherapy (Clonal neoantigens elicit T cell
(Big Bang and context-driven collapse. Robertson-Tessi &
immunoreactivity and sensitivity to immune checkpoint blockade. McGranahan Science 2016)
•
Treatment of cancer can induce antigen expression (Combining immunotherapy and targeted therapies
in cancer treatment. Vanneman & Dranoff, Nature Rev Cancer 2013, 12:237-251)
•
Induction of immunogenic cell death can increase antigen presentation to T cells
(Immunogenic Cell Death in Cancer Therapy. Kroemer et al Annu. Rev. Immunol. 2013. 31:51–72)
•
Low mutation load, predictive biomarkers, individualised?
08/12/2016
5
Melero et al Nature Review Cancer. 2015 Aug;15(8):457-72
Smart Combinations
TARGETED
AGENTS
• Opportunities for synergy through rational
design
+
STANDARD
OF CARE
• TME, heterogeneity & resistance needs to
be well studied
•
Modulation of the immune
microenvironment
•
Optimisation of dose, sequence and
timing, toxicity
•
Personalised combinations guided by
biomarkers
+
IMMUNOTHERAPY
Here’s my
sequence
Oncology Platforms
OncoExpress
CrystalClear™
Lead Determination
Target expression
Custom reagents
Structural biology
(Fragment
ligand/protein
structures)
Custom cell lines
mAb lead
discovery
Mammalian
expression
08/12/2016
MuBase
HuBase
HuMice™
®
HuTrial™
HuPrime
HuGEMM™
®
HuMark™
HuKemia
HuCELL™
HuSignature™ MiXeno™
XenoBase
ValidatedXeno™ HuScreen™
MuPrime™
MuTrial™
PrimeXeno™
MuScreen™
OncoSphere™
OmniPanel™
XenoSelect™
PrimePanel™
OmniScreen™
Cancer
Biology
2/3D culture
Combinational
Proliferation
Apoptosis
Cell cycle
ADCC/CDC
Gene expression
regulation
Signal
transduction
PK/PD
Analysis
Drug exposure
Target/pathway
Modulation
Translational
Oncology
In Vivo
Pharmacology
Subcutaneous
Orthotopic
Systemic
Angiogenesis
GEMM imaging
PDX
MTA
Biomarker
Bioinformatics
Ex vivo capability
Imaging
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ImmunoOncology
CAR-T therapy
HSC-PDX
Humanized
models
GEMM
Murine efficacy/
PD models
Syngeneic
7
Global I/O In vivo Platform
Syngeneic
I/O Platform
Technologies
Humanized
Genetically
altered
December 8, 2016
• MuScreen
• MuPrime
• MiXeno (hPBMC)
• HuMice (HSC)
• HuGEMM
• CAR-T
Crown Bioscience Inc. │ Confidential – Not For Distribution
8
Global I/O Platform
Syngeneic
I/O Platform
Technologies
Humanized
Genetically
altered
December 8, 2016
• MuScreen
• MuPrime
• MiXeno (hPBMC)
• HuMice (HSC)
• HuGEMM
• CAR-T
Crown Bioscience Inc. │ Confidential – Not For Distribution
9
Syngeneic Models: Benchmarking,
Characterization & Immunophenotyping
December 8, 2016
Crown Bioscience Inc. │ Confidential – Not For Distribution
MuScreen™
10
CT26 Benchmarking
Efficacy evaluation of aCTLA-4 (9D9) in
syngeneic models
Antitumor Activity of Test Articles in the Treatment of
Subcutaneous CT26 Murine Colon Carcinoma Model
Isotype control 10 mg/kg BIW x 2weeks i.p.
anti-CTLA4 Ab 10 mg/kg BIW x 2weeks i.p.
4000
3600
3200
2800
2400
2000
1600
1200
800
400
0
Tumor Size(mm3)
anti-PD-1 Ab 10 mg/kg BIW x 2weeks i.p.
anti-CTLA4 Ab 10mg/kg BIW x 2weeks anti-PD-1 Ab
10mg/kg BIW x 2weeks i.p.
7
9
11
13
15
17
19
Days after Tumor Inoculation
December 8, 2016
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11
Base Line Immuno phenotyping
T Cell
35
60
30
CD3+
50
CD3+CD4+
40
Mean %
Treg
30
20
25
CD8+ Teff/Treg
CD3+CD8+
20
15
10
10
5
0
0
December 8, 2016
Teff/Treg
Crown Bioscience Inc. │ Confidential – Not For Distribution
12
Base Line Immuno phenotyping
10
5
December 8, 2016
P388D1
CT26
B16F10
EL-4
4T1
H22
0
RM-1
0
15
Renca
5
20
EMT-6
10
25
L1210
15
30
MC38
20
35
LL2
Mean %
25
MDSC:
CD11b
40
B16BL6
30
45
MBT-2
NK; CD335
Mean %
35
13
OncoExpress
Oncology
Knowledge Databases & App
PDX
Syngeneic
OncoExpressSOC
CDX
GEMM
Data
MuBase
MuPrime
Tissues
• The world’s first commercial database dedicated to mouse
cancer models
• Free online access to search Syngeneics, GEMM, MDX
(MuPrime), HuGEMM™
• Make an informed decision by searching models based on gene
expression, mutational status, gene fusions, etc. across our
unique collection of mouse cancer models
• Wide variety of data compiled including model background,
mouse strain, histopathology, genomic profiling (RNAseq), SoC,
and immuno-profiling (infiltrate immune cells, cytokine profile,
response to checkpoint inhibitors, etc.)
December 8, 2016
News
http://oncoexpress.crownbio.com/ [7/17/16, 2:48:30 PM]
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14
Combination with anti-mCTLA-4 (CT26)
Induction of ICD: Hypofractionated radiotherapy (IGMI) or Oxaliplatin in combination with anti-mCTLA-4
Anti-mCTLA-4 + RT
1750
G1: Vehicle i.p. BIW
G1: Vehicle BIW+ vehicle QW
G2: Radiotherapy 6Gy q.d.x5 ()
G2: 10mg/kg anti-CTLA-4 BIW () + vehicle QW
1500
G3: 10mg/kg anti-mCTLA4 i.p. BIW ()
1000
G4: Radiotherapy 6Gy () + 10mg/kg anti-mCTLA4 ()
G3: Vehicle QW + 6mg/kg Oxaliplatin QW ()
G4: 10mg/kg anti-CTLA-4 BIW () + 6mg/kg Oxaliplatin QW ()
3
Mean tumour volume (mm )
Mean tumour volume (% pre-dose volume)
1250
Anti-mCTLA-4 + Oxaliplatin
750
500
250
1250
1000
750
500
250
0

0
5
10


    
15
Study Day




0
20
25
30
0
5
10



15
Study Day

20
25
30
15
Long term combination effect (CT26)
Flow cytometry
analysis of
subcutaneous tumour
CT26 in vivo outgrowth following A. RT treatment and B. anti-mCTLA-4 + RT
2000
Tumour volume (mm3)
Tumour volume (mm3)
2000
1500
1000
500
 10mg/kg anti-mCTLA-4
1500
1000
0
10
20
30
Study Day
40
50
G4: Radiotherapy 6Gy + 10mg/kg anti-mCTLA4
*+
* p > 0.05 versus G1
30
+
p > 0.05 versus G3
*
20
10
0
1
2
3
4
15
G1: Vehicle i.p. BIW

 
 
0
0
G3: 10mg/kg anti-mCTLA4 i.p. BIW
Group
500

G2: Radiotherapy 6Gy q.d.x5
% viable CD3+/CD8+
 RT 6Gy
G1: Vehicle i.p. BIW
40
0
10
20
30
Study Day
40
50
G2: Radiotherapy 6Gy q.d.x5
G3: 10mg/kg anti-mCTLA4 i.p. BIW
Ratio of CD8+:CD4+/FoxP3+
 RT 6Gy
B
2500
Ratio Teff:Treg
A
2500
% CD3+/CD8+ T-cells
50
G4: Radiotherapy 6Gy + 10mg/kg anti-mCTLA4
10
5
0
1
2
3
4
Group
16
Orthotopic/metastatic breast cancer
syngeneic model (4T1)
Bioluminescent 4T1 MFP model
Ex vivo BLI of metastatic lung
lesions from s.c. tumour growth
In vivo response to combination dosing
of anti-mCTLA-4 + RT
Flow cytometry analysis of
4T1 metastatic lung tumour
% CD3+/CD8+ T-cells
800
G1: Vehicle i.p. q2d x5
0.25
0.20
G4: RT 6Gy q.d. x 5 () + Anti-mCTLA4 10mg/kg q2d x5 ()
400
G1: Vehicle i.p. q2d x5
G2: RT 6Gy q.d. x 5
G3: Anti-mCTLA4 10mg/kg q2d x5
0.04
G4: RT 6Gy q.d. x 5 + Anti-mCTLA4 10mg/kg q2d x5
Ratio of CD8+:CD4+/FoxP3+
G3: Anti-mCTLA4 10mg/kg q2d x5 ()
600
Ratio Teff:Treg
0.05
G1: Vehicle i.p. q2d x5
G2: RT 6Gy q.d. x 5
% viable single lymphocytes
0.15
0.10
0.05
G3: Anti-mCTLA4 10mg/kg q2d x5
G4: RT 6Gy q.d. x 5 + Anti-mCTLA4 10mg/kg q2d x5
0.03
0.02
0.01
0.00
0.00
1
2
3
4
1
2
Group
3
Group
Whole lung total cell isolates
200

0
4
8

 

12


16


Lung
metastasis

20
24
Study Day
Bioluminescent models in development
• Pancreatic, breast, prostate, liver, bladder
• Lung metastasis, Bone metastasis
December 8, 2016
Crown Bioscience Inc. │ Confidential – Not For Distribution
750
G1: Vehicle i.p. q2d x5
Total cell isolates (normalised to controls)
Tumour volume (% of pre-dose volume)
G2: RT 6Gy q.d. x 5 ()
G2: RT 6Gy q.d. x 5
G3: Anti-mCTLA4 10mg/kg q2d x5
G4: RT 6Gy q.d. x 5 + Anti-mCTLA4 10mg/kg q2d x5
500
250
0
1
2
3
4
Group
17
4
Global I/O Platform
Syngeneic
I/O Platform
Technologies
Humanized
Genetically
altered
December 8, 2016
• MuScreen
• MuPrime
• MiXeno (hPBMC)
• HuMice (HSC)
• HuGEMM
• CAR-T
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18
Global I/O Platform
Syngeneic
I/O Platform
Technologies
Humanized
Genetically
altered
December 8, 2016
• MuScreen
• MuPrime
• MiXeno (hPBMC)
• HuMice (HSC)
• HuGEMM
• CAR-T
Crown Bioscience Inc. │ Confidential – Not For Distribution
19
MiXeno Concept
A fast and economic way to evaluate I/O therapies alone or in combination
Immune Function
Involved
T cell function
08/12/2016
NK cell function
Test Substance
CrownBio Experience
BiTE type of Ab
CD19/HER2/EGFR/EpCAM-CD3
Immune checkpoint
inhibitors/agonists
PD-1, PD-L1 inhibitors
CAR-T
CD19
ADCC
Cetuximab
Crown NK
Bioscience
Inc. │ Confidential
modulating
agents – Not For DistributionN/A
20
OncoExpress
Oncology
Knowledge Databases
PDX
Syngeneic
XenoBase
OncoExpress
December 8, 2016
CDX
GEMM
MuPrime
Tissues
SOC
Data
• Free online database for curated CDX models
• Over 2,000 cell lines available
• Combining public profiling data (gene expression,
copy number and mutation) and proprietary in
vivo pharmacology data
• Make an informed decision by searching based on
gene mutation, amplification and expression, tumor
growth in vivo and response to SoC treatments
News
http://oncoexpress.crownbio.com/ [7/17/16, 2:48:30 PM]
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21
HCC-827 NSCLC model
•
•
•
•
Somatic mutations in EGFR gene in NSCLC
HCC-827 NSCLC adenocarcinoma cell line
Harbours an activating EGFR mutation (del E746-A750)
HCC-827 erlotinib resistant models generated with cmet amplification
• High PD-L1 expression (Xenobase & FACS)
Somatic Mutations in the EGFR Gene
HCC-827 WT model shows exquisite
sensitivity to Erlotinib whereas as the
resistant model shows c-met
amplification and sensitivity to Crizotinib
PD-L1 expression
Transl Lung Cancer Res. 2015 Feb;4(1):67-81.
08/12/2016
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22
MiXeno HCC827 Model
Responds to Anti-PD-1 Antibody
• Pembrolizumab demonstrates significant antitumor activity
 NCG mice;
 PBMC implanted via i.v. 3 days before tumor cell inoculation;
 HCC827 inoculated subcutaneously on day 0.
08/12/2016
Crown Bioscience Inc. │ Confidential – Not For Distribution
23
Global I/O Platform
Syngeneic
I/O Platform
Technologies
Humanized
Genetically
altered
December 8, 2016
• MuScreen
• MuPrime
• MiXeno (hPBMC)
• HuMice (HSC)
• HuGEMM
• CAR-T
Crown Bioscience Inc. │ Confidential – Not For Distribution
24
HuPrime - largest collection
•
•
Explore CrownBio models through our online databases
One stop search for PDX, cell line derived xenografts,
syngeneics with OncoExpress™ at oncoexpress.crownbio.com
OncoExpress
PDX Oncology
Knowledge Databases
PDX
CDX
Syngeneic
OncoExpress
SOC
GEMM
Data
HuBase
MuPrime
Tissues
• Free online database to access our curated >2500
PDX models
• Complete genomic annotation (gene expression, copy
number and mutation), clinical and pharmacology data
• Select models that match your criteria using: clinical
information, diagnosis and pathology, whole genome
gene expression profiling and copy number variation,
Hotspot sequence mutation, key biomarker IHC
information, tumor growth and SoC response curve
December 8, 2016
News
http://oncoexpress.crownbio.com/ [7/17/16, 2:48:30 PM]
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HuTrial Concept
08/12/2016
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27
Humanized Immune System
PDXs
Rationale:
•
•
•
•
•
•
December 8, 2016
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New I/O targets
Human specific mAbs
Combination strategies
Mutational-load of PDXs
Neoantigen load
Myeloid compartment
28
Humanized Mice from JAX Lab
• Validation with MDA-MB231 & Keytruda
• HuTrial with SCLC
December 8, 2016
Crown Bioscience Inc. │ Non-Confidential
29
JAX Humanized Mice:
Donor Phenotype Analysis
C o h o rt 1
C o h o rt 2
CD45
40
20
80
60
40
20
CD45
CD3
CD45
CD19
C o h o rt 4
CD3
20
CD3
CD19
CD19
100
P e rc e n ta g e %
P e rc e n ta g e %
40
20
CD3
CD19
60
40
CD45
CD3
80
60
CD45
CD19
C o h o rt 5
CD45
100
80
0
0
0
CD19
100
P e rc e n ta g e %
60
CD3
CD19
100
P e rc e n ta g e %
P e rc e n ta g e %
80
CD45
CD3
CD19
100
C o h o rt 3
CD45
CD3
CD45: ~20-90%
T-cells: ~10-55%
B-cells: ~50-80%
80
60
40
20
0
0
CD45
CD3
December 8, 2016
CD19
CD45
CD3
CD19
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30
Selection of High PD-L1 SCLC PDX Tumors
• 30 SCLC PDX models screened for PD-L1 expression
• Selected 7 PD-L1 high models for pharmacology studies
Negative
December 8, 2016
Low
Intermediate
Crown Bioscience Inc. │ Non-Confidential
High
31
Study Design
• 7 SCLC models (PD-L1 positive)
• n=1 checkerboard assay using humanized mice from 5 HSC
donors
• Treatment initiated when tumor volume reached 50-70mm3
• Each model is run with 2 mice:
• Vehicle: 1 animal; i.p., q.5.d.
• Keytruda: 1 animal; 10mg/kg, i.p., q.5.d.
• Readouts:
•
•
•
•
TGI
TIL analysis
Histology
FFPE - CD163+ qRT-PCR for M1/M2 polarization
December 8, 2016
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32
HuTrial: Humanized PDX studies
to support immunooncology
•
Goal: Evaluate SCLC as indication for PD1 checkpoint inhibition
– 35 SCLC PDX Patients (in human immune-reconstituted mice)
•
7 SCLC PDX x 5 Immune Donors
– Measured Keytruda response as TGI
0
20
40
60
20
30
40
50
0
20
40
60
20
40
60
Tumor volume mm3
Tumor volume mm3
0
0
20
40
400
200
0
60
0
5
10
Date
C2
C2
C2
20
40
60
0
10
20
30
40
50
0
0
20
40
60
80
0
0
10
20
30
40
50
1000
0
0
20
40
1000
0
60
3000
2000
0
20
40
60
80
2000
1000
0
0
20
40
Date
Date
Date
Date
Date
Date
Date
C3
C3
C3
C3
C3
C3
C3
20
30
40
50
0
20
40
60
80
1000
0
10
20
0
0
0
10
20
30
40
50
40
50
1000
0
20
40
20
40
60
80
80
10
20
1000
0
100
0
20
30
40
50
1000
0
40
60
0
20
40
60
200
0
5
10
80
Keytruda
1000
0
0
10
20
30
40
50
Date
C4
C4
1000
0
20
40
60
80
1200
2000
1000
0
0
20
40
1000
800
600
400
200
0
60
0
5
10
Date
Date
Date
Date
Date
Date
Date
Date
C5
C5
C5
C5
C5
C5
C5
C5
20
40
Date
December 8, 2016
60
0
0
10
20
30
Date
40
50
0
0
20
40
Date
60
80
1000
0
0
10
20
30
Date
40
50
2000
1000
0
0
20
40
Date
60
4000
2000
1000
0
0
Crown Bioscience Inc. │ Non-Confidential
10
20
Date
30
3000
2000
1000
0
15
20
25
15
20
25
1200
Tumor volume mm3
1000
2000
3000
Tumor volume mm3
1000
2000
3000
Tumor volume mm3
1000
2000
3000
Tumor volume mm3
2000
3000
Tumor volume mm3
3000
Tumor volume mm3
3000
25
400
Date
3000
2000
0
20
600
Control
C4
3000
2000
15
800
2000
Date
C4
1000
0
2000
Date
3000
2000
0
60
Tumor volume mm3
Tumor volume mm3
0
C4
2000
0
30
Date
3000
Tumor volume mm3
2000
0
60
C4
3000
Tumor volume mm3
1000
40
Date
C4
2000
20
0
Date
1000
25
1000
0
60
Tumor volume mm3
10
3000
2000
20
3000
Tumor volume mm3
0
1000
3000
Tumor volume mm3
60
1000
2000
Tumor volume mm3
40
2000
3000
Tumor volume mm3
1000
3000
Tumor volume mm3
Tumor volume mm3
2000
0
20
3000
15
1200
Tumor volume mm3
1000
3000
2000
Tumor volume mm3
1000
3000
2000
Tumor volume mm3
2000
Tumor volume mm3
1000
3000
Tumor volume mm3
Tumor volume mm3
3000
2000
0
Tumor volume mm3
Tumor volume mm3
10
600
C2
C4
Tumor volume mm3
0
0
800
C2
Date
0
80
1000
C2
1000
0
60
0
2000
C2
2000
0
40
1000
C2
3000
0
20
0
2000
Date
3000
0
0
1000
1000
Date
0
C5
50
0
2000
1200
Date
1000
0
40
1000
C1
3000
Date
3000
C4
30
2000
C1
3000
Date
Tumor volume mm3
Tumor volume mm3
Tumor volume mm3
20
0
3000
Date
3000
C3
10
1000
SCLC#7
C1
Date
2000
0
0
2000
Tumor volume mm3
0
3000
C2
1000
Tumor volume mm3
0
2000
SCLC#6
C1
3000
Tumor volume mm3
1000
3000
SCLC#5
C1
3000
Tumor volume mm3
2000
SCLC#4
C1
4000
Tumor volume mm3
Tumor volume mm3
3000
C1
SCLC#3
C1
Tumor volume mm3
SCLC#2
C1
Tumor volume mm3
SCLC#1
0
20
40
Date
60
1000
800
600
400
200
0
0
5
10
Date
33
HuTrial: Humanized PDX studies
to support immunooncology
• HuTrial response rate is similar to Keytruda clinical response
rate (ORR=35%)
0
0
20
40
50
0
20
40
60
80
0
0
10
20
30
Date
Date
Date
C3
C3
C3
Tumor volume mm3
20
30
40
50
1000
0
20
40
60
80
Date
50
0
20
40
Date
2000
1000
0
0
10
20
30
40
50
3000
1000
60
40
20
Date
0
0
40
0
C4
80
20
1000
0
10
20
30
Date
40
50
0
1000
20
0
Date
4010
Date
60
20
2000
1000
0
40
60
20
40
30 80
1000
40
0
10
Date
C4
60
20
0
0
40
0
Date
10
1000
0
20
0
50
60
20
Da
3000
2000
1000
0
0
40
2000
1000
10
50
0 20
0
Da
C
3000
1000
0
0
40 0
2000
Date
2000
20
60
1000
80
30
3000
1000
2000
3000
C3
2000
C
3000
C
C2
2000
20 0
60
Da
Date
3000
2000
0
0
20 0
60
3000
0
100
40
3000
1000
1000
3000
C3
2000
0
2000
Date
3000
2000
1000
3000
C3
C2
60
Date
20
3000
Date
1000
20
0
C1
4000
2000
0
60
40
2000
Crown 0Bioscience Inc. │ Non-Confidential
0
80
20
0
3000
C4
2000
0
0
0
Date
Tumor volume mm3
December
8, 2016
0
0
10
20
30
40
1000
C4
Tumor volume mm3
1000
1000
C3
2000
0
0
2000
3000
Date
3000
2000
50
3000
2000
0
40
1000
0
60
Responder
3000
Tumor volume mm3
TGI≥48%: N=8/22; 36%
0
2000
40
C2
3000
Tumor volume mm3
1000
Tumor volume mm3
Tumor volume mm3
1000
2000
20
C1
Tumor volume mm3
40
2000
3000
0
Date
Tumor volume mm3
30
3000
60
Tumor volume mm3
0
1000
Tumor volume mm3
50
Tumor volume mm3
Tumor volume mm3
40
Tumor volume mm3
20
1000
10
30
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3000
0
20
Tumor volume mm3
10
10
C2
3000
0
0
C2
3000
Tumor volume mm3
80
C2
C4
60
60
Date
Date
0
40
2000
80
30
3000
2000
1000
34
0
0
40
Tumor volume mm3
20
Date
Tumor volume mm3
Tumor volume mm3
Tumor volume mm3
0
0
Date
2000
0
0
Tumor volume mm3
50
1000
Tumor volume mm3
40
1000
2000
Tumor volume mm3
30
1000
Date
1000
60
2000
C
3000
Tumor volume mm3
20
1000
Tumor volume mm3
10
3000
0
2000
Tumor volume mm3
0
2000
0
2000
C1
3000
Tumor volume mm3
Non-responder
60
Tumor volume mm3
1000
3000
0
C1
3000
– Provides translational confidence to PDX study
2000
Tumor volume mm3
60
Tumor volume mm3
Tumor volume mm3
3000
0
40
C1
3000
Tumor volume mm3
C1
3000
Tumor volume mm3
C1
4000
50
2000
1000
20
0
0
Da
Keytruda Clinical Trial in SCLC
Merck
Presented By Patrick Ott at 2015
ASCO Annual Meeting
Merck: ORR from trials
TNBC: 15%
NSCLC: 41%
SCLC: 35% (prelim data)
Melanoma: 24%
Ovarian: 11.5% (prelim data)
December 8, 2016
Crown Bioscience Inc. │ Confidential – Not For Distribution
35
Immuno-Phenotype of Keytruda:
Responders vs Non-responders
CD38
15
R e s p o n d e rs
R e la t iv e E x p r e s s io n
N o n - R e s p o n d e rs
10
M1
5
N
o
n
-R
R
e
e
s
s
p
p
CD163+
FFPE
o
o
n
n
d
d
e
e
rs
rs
0
PTG S1
R e s p o n d e rs
5
N o n - R e s p o n d e rs
R e la t iv e E x p r e s s io n
4
M2
2
1
0
o
o
p
p
s
s
e
e
-R
n
o
N
Crown Bioscience Inc. │ Confidential – Not For Distribution
R
December 8, 2016
n
n
d
d
e
e
rs
rs
Macrophage Polarization Marker Analysis:
Jablonski AK et al PLOS ONE 2015 DOI: 10.1371
3
36
Summary
• Tumour heterogeneity drives cancer progression & treatment failure
• Modelling the human TME is a challenge
• Broad suite of PDX & Immuno-oncology models
– Study population diversity
– Mouse systems: Syngeneic, MuPrime
– Humanized systems: HuGEMM, MiXeno, HuMice™
• Syngeneics/MuScreen™ provides a large scale immuno-phenotyping
and efficacy testing platform for evaluating novel therapeutics and I/O
combinations
• Checkerboard 1x1 HuMice™ clinical trial (HSC-engrafted mice) is a
powerful translation approach for clinical confidence
December 8, 2016
Crown Bioscience Inc. │ Confidential – Not For Distribution
37
Thank you & acknowledgments
CBSD
Tommy Broudy*
Jayant Thatte
CBUK
Rajendra Kumari*
Andrew McKenzie
Nektaria Papadopoulou
CBBJ
Henry Li*
Jie Cai
Sheng Guo
Annie An
CBTC
Qian Shi*
Juan Zhang
Davy Ouyang
Jinying Ning
Global capacity
>40,000 mice
08/12/2016
38
*Crown Scientific leaders
CrownBio Worldwide Operations
USA
CHINA
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•
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