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A FUNDAMENTAL CHANGE IN CANCER CARE IN THE ERA OF GENOMICS, PROTEOMICS, AND IMMUNOTHERAPY THE EVOLUTION OF REAL WORLD BIG DATA AND AUGMENTED INTELLIGENCE Presented by: Patrick Soon-Shiong, MD Email: [email protected] A GLOBAL PUBLIC HEALTH CARE CRISIS: The Increasing Global Burden of Cancer 2012 By 2030 New Cancer Cases 14 Million New Cancer Cases 22 Million Cancer Deaths 8.2 Million Per Year Cancer Deaths 13 Million Per Year World Cancer Report 2014, ESMO Information Overload & Big Data in Cancer: A Looming Crisis What molecular subtype? Surgery or Chemotherapy? Has tumor spread? What stage? NY001WT1_3.cdr What dose? What schedule? Pre-operative chemotherapy? In combination with other drugs? 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 Cancer - A Multi-Clonal Disease Burrell RA, et al. Nature. 2013;501(7467):338-345. A 38-year-old man with BRAFmutant 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 BRAFmutant 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 BRAFmutant 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 “…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.” Gerlinger et al. Nature Genetics (2014) “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 Population Patient Tissues Cells DNA Proteins Peptides The Anatomy Cellular & Molecular Biology Current State Molecular 21st Century Precision Medicine An Integrative Omics Approach Population Current State Molecular 21st Century Precision Medicine An Integrative Omics Approach Population Real-time actionable knowledge to provide the highest quality care at the lowest possible cost Lab Data Pharmacy Data Financial Systems and Operational Systems Accessible on Mobile Devices Electronic Patient Record Patient Administration System (PAS) Personal Smart Wearable Sensors Monitoring Medical Devices Current State Genomic Data Imaging Data Molecular 21st Century Precision Medicine Integrated Clinical Operating System – cOS Real-time actionable knowledge to provide the highest quality care at the lowest possible cost Lab Data Pharmacy Data Financial Systems and Operational Systems Accessible on Mobile Devices Electronic Patient Record Patient Administration System (PAS) Personal Smart Wearable Sensors Monitoring Medical Devices Genomic Data Imaging Data 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: Protein Receptor Identifying the target Protein Pathways RNA DNA Which of these 1,000’s of mutations are actionable? 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 Patient results: Pre/Post MET TKI x 6 weeks Baseline PET 7-22-2014 Post-MET TKI 9-10-14 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 Complete Remission 7/3/2007 8/15/2007 Metastatic Pancreatic Cancer is Not Necessarily a Death Sentence Changing The Paradigm Of Cancer Care To A Regimen Of Low Dose Metronomic Combination Therapy Preserving The Immune System Screening 2/27/07 Follow up 4/11/07 Metastatic Pancreatic Cancer is Not Necessarily a Death Sentence Side-chain Theory Hypothesis: Tumors occur at high frequency in humans, but are kept under control by the immune system Paul Ehrlich First Director of the Georg-Speyer-Haus 1906 - 1915 Nobel Prize in Physiology or Medicine 1908 IDENTIFYING EACH PATIENT’S UNIQUE CANCER ANTIGEN BY NEXT GENERATION GENOMIC SEQUENCING IMMUNE EFFECTOR CELL Immune Synapse A DANCE OF PROTEINS CANCER CELL CONFIDENTIAL Immuno Protection System T-CELL • • • Learned (Adaptive) Require switching-on Delayed killing Natural Killer Cell (NK) VS • • • Innate Always switched-on Rapid killing A Living Killing Machine: NK Cell Innate Immune Protector 1 Adhesion & Targeting Receptors Targets and binds to tumor cell & tumor cell matrix, and viral infected cells 7 NATURAL KILLER CELL 2 6 Inhibitory Receptors Turns off cell killing Binds to Antibodies Activates cell death (ADCC) Activation Receptors Triggers release of killing mechanism 3 Release of Chemokines Attracts killer T-Cells 4 Release of Cytokines Induces apoptosis 5 Release of Perforin & Granzyme Direct cell killing & targeted killing A Unique NK Cell: Activated Natural Killer (The aNKTM Cell) 1 Adhesion & Targeting Receptors Targets and binds to tumor cell & tumor cell matrix, and viral infected cells 7 ACTIVATED NATURAL KILLER CELL aNKTM 2 6 Inhibitory Receptors Turns off cell killing Binds to Antibodies Activates cell death (ADCC) Activation Receptors Triggers release of killing mechanism 3 Release of Chemokines Attracts killer T-Cells 4 Release of Cytokines Induces apoptosis 5 Release of Perforin & Granzyme Direct cell killing & targeted killing 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) Cell A Living Drug Delivered in a Blood Bag aNK aNK aNK Tumor Target Tumor Target Tumor Filled With Granzyme STAGE 1 STAGE 2 STAGE 3 Adhesion Activation Apoptosis Synapse Connection Perforin & Granzyme Delivery Cell Death Activated NK Clinically Validated: Phase I Advanced metastatic disease refractory to chemo, biologics, cytokines, radiation, and surgery Nearly half the patients received multiple dosing regimens (up to 6 months) More Than 40 Patients No DLTs; only 1 “grade 4 SAE” (hypoglycemia likely related to tumor lysis) Promising activity against different cancer types, including acute myelogenous leukemia (AML), lymphoma (NHL, HL), melanoma, renal cell cancer (RCC), and lung cancers (SCLC, NSCLC) RUSH UNIVERSITY MEDICAL CENTER Phase I Study Results: Good efficacy against relapsed hematological malignancies • Complete remission in one Hodgkin’s lymphoma patient • Partial response in one diffuse large B cell lymphoma patient Study nearing completion • 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 PATIENT Excellent safety and tolerability • Only two patients have experienced infusion-related events Complete remission 4+ years after receiving aNK treatment. • No significant adverse events reported 38 NK 92: THE Universal Killer Cell NK CELL CANCER CELL Tumor Synapse: Tumor Antigen Targeting taNK: Mechanism of Action Tumor Targeted Killing Known & Unknown Tumor Antigens (Neo-Epitopes) TUMOR CELL 10 16 Antibody Library Tumor Targeted Antibody taNK Tumor Targeted Antibody TM Tumor Targeted Antibody Tumor Targeted Antibody taNK: Mechanism of Action Tumor Targeted Killing Known & Unknown Tumor Antigens (Neo-Epitopes) TUMOR CELL 10 16 10 16 Antibody Library Tumor Targeted Antibody Heavy & Light Chain Antibody Library taNK TM Tumor Targeted Antibody Tumor Targeted Antibody taNK: Mechanism of Action Tumor Targeted Killing Known & Unknown Tumor Antigens (Neo-Epitopes) TUMOR CELL 10 16 Antibody Library taNK 10 16 Tumor Targeted Antibody TM Tumor Targeted Antibody Heavy & Light Chain Antibody Library Tumor Targeted Antibody Tumor Antigen Targeting CD33.taNK in AML Primary AML Memorial Sloan-Kettering Cancer Center CD33.taNK IDENTIFYING EACH PATIENT’S UNIQUE CANCER ANTIGEN BY NEXT GENERATION GENOMIC SEQUENCING IMMUNE EFFECTOR CELL Immune Synapse A DANCE OF PROTEINS CANCER CELL CONFIDENTIAL Delivering Living Drugs in a Blood Bag Targeted and Serial Killing of Her2+ Cancer Cells Schoenfeld et al. Mol Therapy, in press Precision Medicine: Adoptive Immunotherapy retargeted Delivering Targeted Living with Drugs in a BloodNK-92 Bag cells Quality control Expansion Working Cell Bank Tumor Targeted Antibody Master Cell Bank Tumor Targeted Antibody aNK taNK TM Tumor Targeted Antibody Irradiation Tumor Targeted Antibody Transfusion IDENTIFYING EACH PATIENT’S UNIQUE CANCER ANTIGEN BY NEXT GENERATION GENOMIC SEQUENCING IMMUNE EFFECTOR CELL Immune Synapse A DANCE OF PROTEINS CANCER CELL CONFIDENTIAL Super Computing, Machine Learning Cancer Knowledge Action Network The Global Cooperative: Cancer Knowledge Action Network Genomics England 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 Realtime 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. 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. Cancer: The Path To The Cure Analysis Quantitative Real Time Genomic Monitoring Of Cancer is Now a Reality 52 Thank You Patrick Soon-Shiong, MD Email: [email protected] Antibody Killing (ADCC) NK CD-16 Herceptin Tumor Mechanism of Action: haNKTM (ADCC) Antibody Killing TUMOR CELL Her2 Antigen } ADCC Herceptin Antibody High Affinity CD-16 Receptor haNKTM Antibody Killing (ADCC)