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  • Predictive Cancer Models

    Using Patient-Derived

    Xenograft Mice

    Technical Information Services

    April 9, 2020

  • THE JACKSON LABORATORY™

    To discover precise genomic

    solutions for disease and

    empower the global biomedical

    community in our shared quest

    to improve human health

    Our Mission

  • WHAT WE DO AND PROVIDE • Biomedical Research

    Genetics, biology, and mechanism of human diseases

    • Mouse Models and Related Contract Research Services

    Preclinical/Translational: Study-ready mouse models, mouse model generation, breeding, cryopreservation, in vivo preclinical studies– including target identification and confirmation, PK studies, efficacy studies, and more

    Clinical: Specialty clinical services and assays; the JAX™ Clinical Knowledgebase (JAX-CKB)

    • Education & Training

    Courses, conferences, internships, pre- and post-doctoral training, live and on-

    demand webinars, and on-site seminars

  • JAX™ MICE

    • Strains developed from NIH-funding.

    • >11,000 publically available mouse lines

    …and growing.

    >3 million mice shipped annually worldwide

    • Unsurpassed genetic quality and animal

    health.

    • Comprehensive phenotypic descriptions

    and references.

    • Home to common inbred strains (C57BL/6J,

    BALB/cJ, etc.) that support the

    development/collection of specialty strains

    and the JAX biomedical research mission.

    The Gold Standard for Biomedical Research

  • Online Resources to Support and Expedite Your Research

    JAX™ Mice Database

    jax.org/mouse-search

    Mouse Genome Informatics

    informatics.jax.org/

    Mouse Phenome Database

    phenome.jax.org/

    Mouse Tumor Biology Database

    jax.org/mtb

    JAX™ Clinical Knowledgebase

    ckbhome.jax.org

    https://www.jax.org/mouse-search http://www.informatics.jax.org/ https://phenome.jax.org/ https://www.jax.org/mtb https://ckbhome.jax.org/

  • Learning Goals

    6

    Describe how NSG™ are a

    useful platform for human

    disease research

    Demonstrate how PDX models

    are used for predictive and

    preclinical research

    Review Onco-Hu™ models for

    immuno-oncology research

  • Are you currently using patient-

    derived xenograft (PDX) models in

    your research?

    Yes

    No, but I am planning to within the next 6 months

    No, but I want to learn about PDX models

    I do not know

    7

  • The Need for New Preclinical Models

    8

    Kola 2004. Nat Rev Drug Discov. PMID:15286737

    Sharpless 2006 Nat Rev Drug Discov PMID:16915232

    Only 5% of cancer treatments

    entering clinical trials are

    approved

    Major causes of attrition are

    lack of efficacy (30%) and

    safety (30%)

    Use of more predictive animal

    models is needed during

    preclinical testing to diminish

    attrition

    http://www.ncbi.nlm.nih.gov/pubmed/?term=15286737 http://www.ncbi.nlm.nih.gov/pubmed/?term=16915232

  • Vehicle Merodantoin

    Classic Xenograft Model: Nude Mouse

    9

    Gulliya 1994 Cancer PMID:8082074

    MCF-7 breast cancer cell line

    http://www.ncbi.nlm.nih.gov/pubmed/?term=8082074

  • Immune System Components

    10

    Dendritic

    cells

  • NSG™, a Highly Immunodeficient Mouse

    NOD background o Absence of hemolytic complement o Reduced dendritic and NK cell function o Defective macrophages o A more human-like Sirpa allele on macrophages

    11

    Nomenclature

    NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (005557)

    JAX™ Mice |

    http://jaxmice.jax.org/strain/005557.html http://www.jax.org/jaxmice

  • NSG™, a Highly Immunodeficient Mouse

    NOD background o Absence of hemolytic complement o Reduced dendritic and NK cell function o Defective macrophages o A more human-like Sirpa allele on macrophages

    scid mutation o prevents development of mature T and B cells

    12

    Nomenclature

    NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (005557)

    JAX™ Mice |

    http://jaxmice.jax.org/strain/005557.html http://www.jax.org/jaxmice

  • NSG™, a Highly Immunodeficient Mouse

    NOD background o Absence of hemolytic complement o Reduced dendritic and NK cell function o Defective macrophages o A more human-like Sirpa allele on macrophages

    scid mutation o prevents development of mature T and B cells

    gamma chain (Il2rg knockout) o Eliminates signaling from 6 distinct interleukins and blocks NK cell

    development

    13

    Nomenclature

    NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (005557)

    JAX™ Mice |

    http://jaxmice.jax.org/strain/005557.html http://www.jax.org/jaxmice

  • Immune System Components

    14

    (NSGTM)

    Dendritic cells

  • Applications and Benefits o No scid-associated leakiness

    o Longer life span than NOD-scid (> 16 months)

    o Enhanced primary human tumor and hematopoietic stem cell engraftment (Sirpa allele) – immuno-oncology applications

    15

    Using NSG™ as a Platform for Human

    Disease Research

  • Applications and Benefits o No scid-associated leakiness

    o Longer life span than NOD-scid (> 16 months)

    o Enhanced primary human tumor and hematopoietic stem cell engraftment (Sirpa allele) – immuno-oncology applications

    Considerations o Extremely immunodeficient: require aseptic housing and

    handling

    o scid side effects: radiation sensitivity; genotoxic drugs may have higher toxicity

    16

    Using NSG™ as a Platform for Human

    Disease Research

  • Which mouse strain is more likely

    to engraft primary human cells?

    BALB/c scid

    NOD scid

    17

  • JAX Patient-Derived Xenograft (PDX)

    Program

    18

    Clinical information

    o Tumor type, grade and markers (if known)

    o Treatment history

    Histology

    Gene expression array and CNV array analysis

    o Target cancer panel for mutation analysis

    Archived

    PDX

    tumors

    In Vivo Pharmacology Services |

    http://www.jax.org/jaxservices/invivo.html

  • PDX Development Process

    19In Vivo Pharmacology Services |

    Archived

    PDX

    tumors

    Cohort of miceDonor mice

    Multi-step approach for the development of cohorts of patient derived

    xenograft mouse models

    Study

    http://www.jax.org/jaxservices/invivo.html

  • Established PDX Models

    20

    ~400 clinically relevant PDX tumors

    In Vivo Pharmacology Services |

    http://www.jax.org/jaxservices/invivo.html

  • NSG™

    C.B-17

    scid

    H&E Human cells

    (anti-HLA)

    Mouse blood cells

    (anti-mCd45)

    H&E

    Cancer

    Patient’s Lung

    Tumor

    Fragment

    NSG™ Mice Preserve Patient Tumor

    Characteristics

    21

    Simpson-Abelson 2008 J Immunol PMID:18453623

    http://www.ncbi.nlm.nih.gov/pubmed?term=18453623

  • P a

    ti e

    n t tu

    m o

    r E

    n g

    ra ft

    e d

    tu m

    o r

    H&E Cytokeratin Ki67

    NSG™ Mice Preserve Patient Tumor

    Characteristics

    22

    Simpson-Abelson 2008 J Immunol PMID:18453623

    http://www.ncbi.nlm.nih.gov/pubmed?term=18453623

  • Colon PDX Structure Fidelity

    23In Vivo Pharmacology Services |

    TM00388-P0TM00388-PT

    Colon Adenocarcinoma Metastatic to Lung

    TM00134-PT TM00134-P0 TM00134-P1

    Colon Adenocarcinoma, KRAS G13D

    http://jaxservices.jax.org/invivo/index.html

  • BL0293f563P2 PDX Tumor Volume Response

    to Cisplatin Single Agent Treatment (1500 mm3 tumor endpoint)

    Days (Day 1 = treatment initiation)

    m e

    a n

    t u

    m o

    r v

    o lu

    m e

    ( m

    m 3 ;+

    /- S

    E )

    0 5 10 15 20 25 30 35 40 45 50 55 60 65 0

    250

    500

    750

    1000

    1250

    1500

    Group 1: Saline Control

    Group 2: Cisplatin 2.5 mg/kg

    Bladder PDX Models Standard of Care Treatment Response

    24In Vivo Pharmacology Services |

    TM00016-P2 PDX tumor volume response to Cisplatin Single Agent

    Treatment (1500 mm3 endpoint)

    http://jaxservices.jax.org/invivo/index.html

  • 0 5 10 15 20 25 30 35 40 45 50 55 60 65 0

    500

    1000

    1500

    2000

    2500

    Days (Day 1 = treatment initiation)

    In d

    iv id

    u a

    l T

    u m

    o r

    V o

    lu m

    e (

    m m

    3 )

    Bladder PDX Models Tumor Heterogeneity

    25In Vivo Pharmacology Services |

    TM00016-P2 PDX tumor volume response to Cisplatin

    http://jaxservices.jax.org/invivo/index.html

  • BL0269f404P2 PDX Tumor Volume Response

    to Cisplatin Single Agent Treatment (2000 mm3 tumor

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