A FUNDAMENTAL CHANGE IN CANCER CARE IN THE ERA

OF GENOMICS, PROTEOMICS, AND IMMUNOTHERAPY

Presented by:

Patrick Soon-Shiong, MDEmail: Info@NantWorks.com

THE EVOLUTION OF REAL WORLD BIG DATA AND AUGMENTED INTELLIGENCE

A GLOBAL PUBLIC HEALTH CARE CRISIS:The Increasing Global Burden of Cancer

New Cancer Cases

14 Million

Cancer Deaths

8.2 Million Per Year

2012

New Cancer Cases

22 Million

Cancer Deaths

13 Million Per Year

By 2030

World Cancer Report 2014, ESMO

NY001WT1_3.cdr

Has tumor spread?

What molecular subtype?

What dose?

What schedule?

Surgery or Chemotherapy?

What stage?

Pre-operative

chemotherapy?

In combination

with other drugs?

Information Overload & Big Data in Cancer:A Looming Crisis

The Current Paradigm:Costly Trial and Error Treatment

Reactive Medical Care

A 40 year illusion of Clonal Dominance

Burrell RA, et al. Nature. 2013;501(7467):338-345.

A 40 year illusion of Clonal Dominance

Burrell RA, et al. Nature. 2013;501(7467):338-345.

Cancer - A Multi-Clonal Disease

A 38-year-old man with BRAF-

mutant melanoma and

subcutaneous metastatic

deposits. Photographs were

taken (A) before initiation of

PLX4032, (B) after 15 weeks,

and (C) after relapse, after 23

weeks of therapy.

Wagle et al., JCO (2011) 29, 3085-3096

A 38-year-old man with BRAF-

mutant melanoma and

subcutaneous metastatic

deposits. Photographs were

taken (A) before initiation of

PLX4032, (B) after 15 weeks,

and (C) after relapse, after 23

weeks of therapy.

Wagle et al., JCO (2011) 29, 3085-3096

A 38-year-old man with BRAF-

mutant melanoma and

subcutaneous metastatic

deposits. Photographs were

taken (A) before initiation of

PLX4032, (B) after 15 weeks,

and (C) after relapse, after 23

weeks of therapy.

Wagle et al., JCO (2011) 29, 3085-3096

Gerlinger et al. Nature Genetics (2014)

“…an illusion of clonal dominance when assessed by single biopsies. The presence of sub clonal driver events in solid tumours may provide an explanation for the inevitable acquisition of resistance to targeted therapeutics in advanced disease.”

“Resistance is therefore a fait accompli – the

time to recurrence is simply the interval

required for the subclone to repopulate the

lesion.”

- Diaz et al. Nature 486, 537-540 (2012)

Precision Medicine:Crossing the Chasm of Scale

ProteinsCells DNA PeptidesTissuesPopulation

Current State

The Anatomy Cellular & Molecular Biology

Molecular 21st Century Precision Medicine

Patient

An Integrative Omics Approach

Population

Current State Molecular 21st Century Precision Medicine

Lab Data

Pharmacy Data

Financial Systems and

Operational Systems

Electronic Patient Record

Patient Administration System

(PAS)

Genomic Data

Imaging DataPersonal Smart Wearable Sensors

Monitoring Medical Devices

Accessible on

Mobile Devices

Real-time actionable

knowledge to provide the

highest quality care at the

lowest possible cost

An Integrative Omics Approach

Population

Current State Molecular 21st Century Precision Medicine

Integrated Clinical Operating System – cOS

Lab Data

Pharmacy Data

Financial Systems and

Operational Systems

Electronic Patient Record

Patient Administration System

(PAS)

Genomic Data

Imaging DataPersonal Smart Wearable Sensors

Monitoring Medical Devices

Accessible on

Mobile Devices

Real-time actionable knowledge

to provide the highest quality

care at the lowest possible cost

An Integrative Omics Approach

Population

Current State Molecular 21st Century Precision Medicine

Next Generation Sequencing:Identifying the target

Whole Genome:3 Billion base pairs that make up DNA

Whole Exome:20,000 Genes that code for proteins

Which of these 1,000’s of mutations are actionable?

Next Generation Sequencing:Identifying the target

Which of these 1,000’s of mutations are actionable?

DNA

RNA

Protein Pathways

Protein Receptor

Next Generation Sequencing:Identifying the target

Next Generation Sequencing:Identifying the target

From DNA to RNA

From DNA to RNA to Protein to Drug

By combining

proteomics with

genomic interpretation,

we can give a holistic

understanding of the

progression of disease

and universe of options

for individualized care

Molecular Diagnostic Case Studies

Gastric/Gastroesophogeal junction case study

Baseline PET

7-22-2014

Post-MET TKI

9-10-14

Patient results: Pre/Post MET TKI x 6 weeks

Collaboration with D. Catenacci

“Resistance is therefore a fait accompli – the

time to recurrence is simply the interval

required for the subclone to repopulate the

lesion.”- Diaz et al. Nature 486, 537-540 (2012)

Introducing Quantum Oncotherapeutics

Changing The Paradigm Of Cancer Care To A Regimen Of

Low Dose Metronomic Combination Therapy

Preserving The Immune System

Wide Spread Pancreatic Cancer

7/3/2007

Complete Remission

8/15/2007

Metastatic Pancreatic Cancer is Not Necessarily a Death Sentence

Screening 2/27/07 Follow up 4/11/07

Changing The Paradigm Of Cancer Care To A Regimen Of Low Dose Metronomic Combination Therapy

Preserving The Immune System

Metastatic Pancreatic Cancer is Not Necessarily a Death Sentence

Side-chain Theory

Paul EhrlichFirst Director of the Georg-Speyer-Haus

1906 - 1915

Nobel Prize in Physiology or Medicine1908

Hypothesis:

Tumors occur at high frequency in

humans, but are kept under control

by the immune system

CONFIDENTIAL

IDENTIFYING EACH PATIENT’S UNIQUE CANCER ANTIGEN BY NEXT GENERATION GENOMIC SEQUENCING

Immune SynapseA DANCE OF PROTEINS

IMMUNE

EFFECTOR

CELL

CANCERCELL

• Learned (Adaptive)• Require switching-on• Delayed killing

• Innate• Always switched-on• Rapid killing

Immuno Protection System

VSNatural Killer

Cell (NK)T-CELL

A Living Killing Machine: NK Cell Innate Immune Protector

NATURAL

KILLER CELL

Adhesion & Targeting Receptors

Targets and binds to tumor cell

& tumor cell matrix, and viral

infected cells

1

Activation Receptors

Triggers release of killing

mechanism2

Release of Chemokines

Attracts killer T-Cells3

Release of Cytokines

Induces apoptosis 4

Release of Perforin & Granzyme

Direct cell killing & targeted killing5

Binds to Antibodies

Activates cell death (ADCC)6

Inhibitory Receptors

Turns off cell killing7

Adhesion & Targeting Receptors

Targets and binds to tumor cell

& tumor cell matrix, and viral

infected cells

1

Activation Receptors

Triggers release of killing

mechanism2

Release of Chemokines

Attracts killer T-Cells3

Release of Cytokines

Induces apoptosis 4

Release of Perforin & Granzyme

Direct cell killing & targeted killing5

Binds to Antibodies

Activates cell death (ADCC)6

Inhibitory Receptors

Turns off cell killing7

ACTIVATED NATURAL

KILLER CELL

aNKTM

A Unique NK Cell: Activated Natural Killer (The aNKTM Cell)

MOA: Broad range of killing attributed to lack of KIR and persistence of the activated state of aNK

NK cells from blood express KIR which - upon interaction with HLA on target cells -

inhibit NK cell activation. NK-92 does not express this inhibitory receptor

A Unique NK Cell: Activated Natural Killer (aNK) CellA Living Drug Delivered in a Blood Bag

STAGE 1 STAGE 2 STAGE 3

Adhesion

Synapse

Connection

Activation

Perforin &

Granzyme

Delivery

Apoptosis

Cell Death

aNK aNKaNK

Tumor

Target

Tumor

Target

Tumor

Filled With

Granzyme

Activated NK Clinically Validated: Phase I

More Than 40 Patients

Advanced metastatic disease refractory to chemo,

biologics, cytokines, radiation, and surgery

Nearly half the patients received multiple dosing

regimens (up to 6 months)

Promising activity against different cancer types,

including acute myelogenous leukemia (AML),

lymphoma (NHL, HL), melanoma, renal cell

cancer (RCC), and lung cancers (SCLC, NSCLC)No DLTs; only 1 “grade 4 SAE”

(hypoglycemia likely related to

tumor lysis)

RUSHUNIVERSITYMEDICAL CENTER

Phase I Study Results:

38

Good efficacy against relapsed hematological malignancies

• Complete remission in one Hodgkin’s lymphoma patient

• Partial response in one diffuse large B cell lymphoma

patient

• Stable disease in one Hodgkin’s lymphoma patient and one

CLL patient

• Activity seen in Hodgkin’s, Diffuse Large B-Cell Lymphoma,

CLL w/Richter’s transformation, and Myeloma

Excellent safety and tolerability

• Only two patients have experienced infusion-related events

• No significant adverse events reported

Study nearing completion

PATIENTComplete remission

4+ years after receiving aNK

treatment.

NK 92: THE Universal Killer Cell

CANCER CELLNK CELL

Tumor Synapse:

Tumor Antigen Targeting

taNK: Mechanism of ActionTumor Targeted Killing

taNK

Tumor Targeted

Antibody

Tumor Targeted

Antibody

Tumor Targeted

Antibody

Tumor Targeted

Antibody

TM

TUMOR

CELL

Known & Unknown

Tumor Antigens

(Neo-Epitopes)

1016 Antibody

Library

taNK

Tumor Targeted

Antibody

Tumor Targeted

Antibody

Tumor Targeted

Antibody

TM

TUMOR

CELL

1016 Heavy & Light Chain

Antibody Library

Known & Unknown

Tumor Antigens

(Neo-Epitopes)

taNK: Mechanism of ActionTumor Targeted Killing

1016 Antibody

Library

taNK

Tumor Targeted

Antibody

Tumor Targeted

Antibody

Tumor Targeted

Antibody

TM

TUMOR

CELL

Known & Unknown

Tumor Antigens

(Neo-Epitopes)

taNK: Mechanism of ActionTumor Targeted Killing

1016 Heavy & Light Chain

Antibody Library

1016 Antibody

Library

Tumor Antigen Targeting CD33.taNK in AML

Primary AML CD33.taNK

Memorial Sloan-Kettering

Cancer Center

CONFIDENTIAL

IDENTIFYING EACH PATIENT’S UNIQUE CANCER ANTIGEN BY NEXT GENERATION GENOMIC SEQUENCING

Immune SynapseA DANCE OF PROTEINS

IMMUNE

EFFECTOR

CELL

CANCERCELL

Delivering Living Drugs in a Blood BagTargeted and Serial Killing of Her2+ Cancer Cells

Schoenfeld et al. Mol Therapy, in press

Transfusion

Adoptive Immunotherapy with retargeted NK-92

cells

Precision Medicine:Delivering Targeted Living Drugs in a Blood Bag

Expansion

Quality control

Irradiation

Working Cell Bank

taNK

Tumor Targeted

Antibody

Tumor Targeted

Antibody

Tumor Targeted

Antibody

Tumor Targeted

Antibody

TM

Master Cell Bank

aNK

CONFIDENTIAL

IDENTIFYING EACH PATIENT’S UNIQUE CANCER ANTIGEN BY NEXT GENERATION GENOMIC SEQUENCING

Immune SynapseA DANCE OF PROTEINS

IMMUNE

EFFECTOR

CELL

CANCERCELL

Super Computing, Machine Learning

Cancer Knowledge Action Network

The Global Cooperative:

Cancer Knowledge Action Network

Genomics England

UNIVERSITY HOSPITAL

SOUTHAMPTON NHS

FOUNDATION TRUST (UHS) AND

NANTHEALTH PARTNER TO

DELIVER PRECISION MEDICINE

FOR CANCER PATIENTS

NantHealth and UHS to jointly deliver genomic and

transcriptomic sequencing platform and analytics

capabilities, incorporating NantHealth’s intelligent

clinical operating system (cOS) to transform

cancer care coordination

London AND Southampton, UK 3 JUNE, 2015 –

University Hospital Southampton NHS Foundation

Trust (UHS) and NantHealth today announced a

strategic partnership with the aim of delivering and

transforming cancer services using the most advanced

molecular genomic and proteomic diagnostics,

treatment decision support and unique IT integration

capabilities for better informed precision treatment

selection and care coordination.

NANTHEALTH APPOINTED BY

GENOMICS ENGLAND TO

DELIVER CLINICAL GENOMIC

INTERPRETATION AND

REPORTING CAPABILITIES TO

SUPPORT 100K GENOMES

PROJECT

Secure, Sophisticated NantHealth and

NantOmics UK Based Technology Empowers

Clinical Genomic Research to Happen in Real-

time

London, UK – 3 June, 2015 - NantHealth, a high

speed secure cloud-based information technology

provider combining science and big data to

transform healthcare, today announces its

appointment by Genomics England to deliver

the clinical interpretation and reporting of sequenced

genomes for the much anticipated and

coveted 100K Genomes Project.

52

Analysis

Quantitative Real Time Genomic Monitoring Of Cancer is Now a Reality

Cancer: The Path To The Cure

Thank You

Patrick Soon-Shiong, MDEmail: Info@NantWorks.com

NK

CD-16

Tumor

Herceptin

Antibody Killing (ADCC)

High Affinity

CD-16 Receptor

haNKTM

Herceptin Antibody

Her2 Antigen

}ADCC

Mechanism of Action: haNKTM (ADCC)

Antibody KillingTUMOR CELL

Antibody Killing (ADCC)