using pdx models for preclinical trials of oncology...
TRANSCRIPT
Using PDX Models for Preclinical Trials of Oncology
Therapeutics: Immunooncology & beyond
Thomas B. Broudy, PhD
CSO Crown Bioscience, San Diego
9/1/16 Crown Bioscience Inc. │ Confidential – Not For Distribution 2
CrownBio: Global Oncology Focused Partner
Globalcapacity>40,000mice
CBSD History
• 2010: – Molecular Response founded – Establishes PDX CRO business
• 2015: – Crown acquires PDX service business of MRL – Established San Diego site to strengthen US operation
• 2016: – Expands CBSD as US Center of Excellence for Oncology
9/1/16 Crown Bioscience Inc. │ Confidential – Not For Distribution 3
InVitro/ExVivo PDX HuTrial
InVitro Syngeneic MuPrime* huPDX
Oncology Research Platforms
• Crown’s US Center of Excellence in Oncology • A single-site base for a broad range of services
9/1/16 Crown Bioscience Inc. │ Confidential – Not For Distribution 4
1) Chemo & Targeted Therapies
2) Immunooncology
InVitro/ExVivo PDX HuTrial
PDX: Chemo & Targeted Therapies
9/1/16 Crown Bioscience Inc. │ Confidential – Not For Distribution 5
9/1/16 Crown Bioscience Inc. │ Confidential – Not For Distribution 6
• The world’s largest PDX collection (>2,500) • A large cohort of live PDX models • Asian and Caucasian models; pretreated and treatment naïve; primary and
metastatic models
PDX: HuPrime
• A unique collection of patient-derived blood cancer models • 18 ALL, 6 AML, 24 Lymphoma models
HuKemia
• ValidatedXeno: Large CDX collection (>200) including metastatic and bioluminescent models
• Over 20 validated Syngeneic models • PrimeXeno: A unique CDX collection derived from our PDX models
CDX
Oncology Expertise: In Vivo Pharmacology
9/1/16 Crown Bioscience Inc. │ Confidential – Not For Distribution 7
Oncology: In Vivo Pharmacology PDX - HuPrime
CancerType Established
ALL 16
AML 4
Adrenal 2
Bladder 18
BrainTumor 9
Breast 87
Cervical 24
Cholangio-carcinoma 23
Colorectal 319
Esophageal 41
Fallopian 2
Gallbladder 12
CancerType Established
NeuroendocrineTumor 20
Ovarian 84
PancreaTc 146
ParoTdCarcinoma 1
PeritonealCancer 1
Sarcoma 15
SalivaryGlandCarcinoma 4
TesTs 1
Thyroid 6
UnclearPrimarySite 21
UterineCancer 23
Over2,500PDXModels
CancerType Established
Gastric 172
GIST 5
Head&Neck 90
Kidney 16
Liver-HCC 105
Liver-Other 54
Lung-NSCLC 259
Lung-SCLC 72
Lung-Other 45
Lymphoma-HL 2
Lymphoma-NHL 10
Lymphoma-Other 12
Melanoma 26
9/1/16 Crown Bioscience Inc. │ Confidential – Not For Distribution 8
HuPrime Clinically-Relevant PDX for Population Studies
• Model Depth: >2,500 PDX Models and continuing to grow rapidly • Model Diversity:
– Allows selection of PDX population representative of targeted clinical population
– Example: Colon carcinoma, US patients, 2nd line therapy or beyond, met to the liver
Metastatic 41%
Global Population Treatment History Cancer Type
Asia61%
US,Europe39% Drugnaïve
44%Prior
treatment56%
Non-MetastaTc
59%
PDX Models Capture the Clinic
• PDX models recapitulate patient genomics across cohorts
9
Confiden'al*
TCGA%TCGA& PDX%PDX& CCLE%CCLE&
CCLEchip%TCGA&PDX%TCGA& PDXchip%CCLEchip&
Confiden'al*
TCGA%TCGA& PDX%PDX& CCLE%CCLE&
CCLEchip%TCGA&PDX%TCGA& PDXchip%CCLEchip&
PDX TMAs: A Resource for Model Selection
• Screen hundreds of PDX tumors with just a few immunostains – Verify target expression – Select models with variable target expression
9/1/16 Crown Bioscience Inc. │ Confidential – Not For Distribution 10
CollecBon Crowncode Catalog# Cancertype SuggestedName#modelsonTMA
#coresonTMA LocaBon
Modeltype
Colorectal
COLTMA TMA-HP-CR-201 Colorectalcancer ColorectalcancerTMA 72 144 SD PDXSET-10 TMA-HP-CR-010 Colorectalcancer ColorectalcancerTMA010 32 93 China PDXSET-12 TMA-HP-CR-012 Clorectalcancer ColorectalcancerTMA012 32 96 China PDXSET-19 TMA-HP-CR-019 Colorectalcancer ColorectalcancerTMA019 32 96 China PDX
Esophageal SET-14 TMA-HP-ES-014 Esophagealcancer EsophagealcancerTMA014 30 90 China PDXGastric SET-9 TMA-HP-GA-009 Gastriccancer GastriccancerTMA009 31 96 China PDXHead&Neck SQHNTMA TMA-HP-HN-202 Head&Neckcancer Head&NeckcancerTMA 18 36 SD PDXLiver SET-13 TMA-HP-LI-013 Livercancer LivercancerTMA013 32 96 China PDX
Lung
SET-15 TMA-HP-LU-015 Lungcancer LungcancerTMA015 32 96 China PDXSET-16 TMA-HP-LU-016 Lungcancer LungcancerTMA016 32 96 China PDXSET-17 TMA-HP-LU-017 Lungcancer LungcancerTMA017 32 96 China PDXNSCLCTMA2 TMA-HP-LU-210 Non-SmallCellLungcancer LungCancerTMA210 32 96 SD PDXSCLCTMA2 TMA-HP-LU-208 SmallCellLungCancer LungCancerTMA208 28 84 SD PDXSCLCTMA3 TMA-HP-LU-209 SmallCellLungCancer LungCancerTMA209 28 84 SD PDX
Ovarian OVATMA TMA-HP-OV-205 Ovariancancer OvariancancerTMA 16 32 SD PDX
PancreaTc SET-11 TMA-HP-PA-011 PancreaTccancer PancreaTccancerTMA011 32 96 China PDXSET-18 TMA-HP-PA-018 PancreaTccancer PancreaTccancerTMA018 32 96 China PDX
Sarcoma SARTMA1 TMA-HP-SA-206 Sarcoma SarcomaTMA206 32 96 SD PDXSARTMA2 TMA-HP-SA-207 Sarcoma SarcomaTMA207 32 96 SD PDX
Melanoma
MELTMA1 TMA-HP-ME-211 Melanoma MelanomaTMA211 32 96 SD PDXMELTMA2 TMA-HP-ME-212 Melanoma MelanomaTMA212 32 96 SD PDXMELTMA3 TMA-HP-ME-213 Melanoma MelanomaTMA213 32 96 SD PDXMELTMA4 TMA-HP-ME-214 Melanoma MelanomaTMA214 32 96 SD PDXMELTMA5 TMA-HP-ME-215 Melanoma MelanomaTMA215 32 96 SD PDXMELTMA6 TMA-HP-ME-216 Melanoma MelanomaTMA216 32 96 SD PDXMELTMA7 TMA-HP-ME-217 Melanoma MelanomaTMA217 32 96 SD PDX
*greendenotesTMAscomrisedofPDXmodelsfromCBSDcollecTon
HuBase: Model Selection Database
• Online searchable database: Rapid review, comparison and selection HuPrime and HuKemia PDX models – Filter for inclusion/exclusion criteria
• Patient information, growth curves and SOC data • Gene expression, copy number, miRNA expression, mutations, or gene fusions
InVitro/ExVivo PDX HuTrial
PDX: HuTrial Population Studies
9/1/16 Crown Bioscience Inc. │ Confidential – Not For Distribution 12
MCT
HuTrial: Mouse PDX Clinical Trials
• Simulate human clinical trials with mouse Patient Derived Xenograft (PDX) patients • Large PDX collection combined with population study designs inform clinical trial design
§ Patient Stratification Criteria, Biomarker/Companion Dx Identification, Combination Therapy Selection, Clinical Candidate Selection, and Drug Resistance Pathway Identification
September 1, 2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 13
HuTrial: Small Cell Lung Cancer Treated with PARP Inhibitor
• Goal: Evaluate SCLC as indication for PARPi in maintenance setting – 31 SCLC PDX Patients – Measured response as %T/C
September 1, 2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 14
Non-responder Responder
Biomarker Analysis
September 1, 2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 15
And then there’s the immune system
• How do we preclinically model agents acting to modulate:
September 1, 2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 16
InVitro Syngeneic MuPrime* huPDX
Immunooncology
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InVitro Syngeneic MuPrime* huPDX
Immunooncology
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Humanized Immune System PDXs
Rationale: • New I/O targets • Human specific mAbs • Combination strategies • Mutational-load of PDXs • Neoantigen load • Myeloid compartment
September 1, 2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 19
Humanized Mice from JAX Lab
September 1, 2016 Crown Bioscience Inc. │ Non-Confidential 20
Anti-PD-1 Target Engagement in Blood
Control
Keytruda®
Control
Keytruda
PD-1
CD3
Pretreatment
Post-Treatment (48h)
September 1, 2016 Crown Bioscience Inc. │ Non-Confidential 21
Anti-PD-1 Target Engagement in Tumor
Untreated Keytruda-treated
Isotype PD-1
September 1, 2016 Crown Bioscience Inc. │ Non-Confidential 22
• Left shift in PD-1 expression post-Keytruda Rx
Humanization is Required for Efficacy: MDA-MB-231 Model (High PD-L1)
Non-Humanized
September 1, 2016 Crown Bioscience Inc. │ Non-Confidential 23
Humanized
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MDA-MB-231 Rechallenge:
T-cell Memory
Rechallenge
September 1, 2016 Crown Bioscience Inc. │ Non-Confidential 24
• ELISPOT-IFNg• RecalledTCellassay• TCRsequencing
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
September 1, 2016 Crown Bioscience Inc. │ Non-Confidential 25
Low High Intermediate Negative
HuTrial: Humanized PDX studies to support immunooncology
September 1, 2016 Crown Bioscience Inc. │ Non-Confidential 26
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Control
Keytruda
C1
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SCLC#1 SCLC#2 SCLC#3 SCLC#4 SCLC#5 SCLC#6 SCLC#7
• 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
HuTrial: Humanized PDX studies to support immunooncology
• HuTrial response rate is similar to Keytruda clinical response rate (ORR=35%) – Provides translational confidence to PDX study
September 1, 2016 Crown Bioscience Inc. │ Non-Confidential 27
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Control
Keytruda
Responder
Tumor Immuno-Phenotyping
Bcells,DCNK
CD8 CD3 CD4Treg
CD45TCR
Immuno-Phenotype of Keytruda: Responders vs Non-responders
September 1, 2016 Crown Bioscience Inc. │ Non-Confidential 29
• Translational relevance • Increased TILs in responders • Elevated TAMs in non-responders
CD163+FFPE
MacrophagePolarizaTonMarkerAnalysisJablonskiAKetalPLOSONE2015DOI:10.1371
Summary
• Breadth & depth of tumor models – World’s largest & most diverse collection of PDX
• >2,500 established – Broad suite of Immunooncology models
• Mouse systems: Syngeneic, GEMM • Humanized systems: immune system: MiXeno, HuGEMM, huNSG
• Studying a population – Large portfolios of preclinical models enable simulation of clinical
studies • Immune-deficient systems • Immune-competent systems
• Go to clinic with confidence – Patient selection criteria, Biomarker/companionDx, Combination
therapies, Candidate prioritization, Resistance delay
30 Non-ConfidenTal
CrownBio Worldwide Operations
9/1/16 Crown Bioscience Inc. │ Confidential – Not For Distribution 31
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