NATIONAL CENTER FOR TUMOR DISEASES

NCT HEIDELBERG

Precision Oncology at NCT

The Paradigm Shift: Imaging each Individual Patient‘s CancerAt the Molecular Level

NCT Precision Oncology Program

NCT OMICS

CLINICAL EVALUATION & TRIALS

TARGET EXPLOITATION

TARGETCHARACTERIZATION

TARGET IDENTIFICATION

PATIENT ADMISSION – DOCUMENTATION - BANKING

DATA INTEGRATION

Organized in SAP HANA

STRATIFIED ONCOLOGY

EARLY DIAGNOSIS

RISK STRATIFICATION

PREVENTION

NCT DataThereHouse

INDIVIDUALIZED THERAPY

MOLECULARTUMOR BOARD

DIAGNOSIS &SAMPLING

INDIVIDUALIZEDTHERAPY &TRIALS

NCT OMICS

PATIENT ADMISSIONENROLLMENTCLINICAL DATA

RESPONSE RESISTANCE PREVENTION

BIOINFORMATICSCLINICAL REPORT

NC

T D

ata

Th

ere

Ho

us

e(S

AP

HA

NA

)

NCT MASTER Workflow

National High Throughput Sequencing Core Unit

ICGCINFORM

NCT Molecular Diagnostics Program

2009 2010 2011 2012

Illuminaxten Cluster

ICGC Sequencing

NCT Precision Oncology Program

2015

Mutation

in RNAseq?

Mutation

in RNAseq?

Alternative

Splicing

Alternative

Splicing

fastq QCfastq QC

alignmentalignment

lane

merging

lane

merging

duplicatesduplicates

genotype

matching

genotype

matching

calculate

coverage

calculate

coverage

OneTouchPipeline

PRIMARY ANALYSIS

SNVsSNVsMutation

annotation

Mutation

annotation

INDELsINDELs

Copy number

variants

Copy number

variants

Pathogen

integration

Pathogen

integration

Ploidy

prediction

Ploidy

prediction

Structural

Variants

Structural

Variants

SECONDARYANALYSIS

RNA

sequences

RNA

sequences

DNA

sequences

DNA

sequences

TERTIARY ANALYSIS: „INTERPRETATION“

NCT Applied Bioinformatics

Molecular Tumor Board*

ValidationClinical

EvaluationBioinformatic

AnalysisSequencing

Patient Sample

Asservation

PI3K-AKT-

mTOR

Ba

ske

t Trial w

ith P

ath

wa

y P

rog

ram

s

RAF-MEK-

ERK

Tyrosine

Kinases

Developmental

Pathways

Unbiased Functional

Testing

Focused Functional

Testing

Feed Back Results

Adapt Treatment/

Functional Testing

DDR Signaling

Stefan Fröhling, Christoph Heining, Hanno Glimm, Stefan Gröschel

Claudia Scholl (Functional Genomics)

DKTK – LMU München, Frankfurt, Dresden, Essen/Düsseldorf, Freiburg, Berlin

Other

NCT MASTER – Registry & Interventional Trial

Hypermutated/

ImmunoTherapy

NCT MASTER Current Status

NCT MASTER – Registry & Interventional Trial

INFORM = INdividualized therapy FOrRelapsed Malignancies in childhoodAngelika Eggert, Stefan Pfister, Olaf Witt, Peter Lichter & Study Groups of the GPOH

EXCEL

ALL AML

HGG (incl. DIPG) Medullo/Ependym.

Ewing Sarcoma Neuroblastoma

NHL Osteosarcoma

Phase I/II

Rhabdomyosarcoma Rhabdoid Tumors

Enrollment

Standard of Care: Backbone Chemotherapy

Backbone

TargetedDrug 1

TargetedDrug 2

Feasibility-Registry Study

(Year 1+2)

Clinical Trial

(Year 3-5)

INN

OV

AT

ION

Development of experimental systems for

functional validation

Cancer cell lines

Immortalized non-transformed cell lines

Isogenic cell lines

Introduction/modification of genetic alterations bylentiviral gene or shRNA transferor CRISPR/Cas9 technology

Invitro

Inviv

o

Functional annotation of

molecular lesions

• Viability/proliferation• Apoptosis/cell cycle• Anchorage independence• Invasion/migration• Pathway activation• Others

• Tumorigenicity (mouse, CAM)

1

• Genome-wide or targeted shRNAscreens• Genome-wide or targeted CRISPR/Cas9 screens

Unbiased identification of

functional dependencies2

Invitro

In collaboration with Claudia Scholl, Michael Boutros (NCT

Heidelberg/DKFZ), and Frank Buchholz (NCT Dresden)

Functional Genomics

Genomics of Drug Sensitivity of Primary Cancer Cells

Parallel molecular and functional characterization

Zenz et al.

NCT Immunotherapy Program

Medical OncologyJägerNeurooncologyPlatten/WickImmunogeneticsKrammer Mol. Oncology of Gastrointestinal TumorsRienk OffringaTranslational ImmunologyBeckhoveApplied Tumor ImmunityHalama/JägerRecombinant Therapeutic AntibodiesKrauss/Arndt Immunology of Malignant MelanomaEnk / HasselCellular ImmunologyRodewaldInnate ImmunityCerwenka

Beckhove J Clin Invest 2009 & 2010Krammer Blood 2006Hämmerling Nature 2008Cerwenka Blood 2008Jäger PNAS 2010

MISSION• Use the patients immune system for treating the tumor• Reinduce immunosurveillance

FOCUS• Shape host-tumor-interactions at different levels:

- Checkpoint blockade- Modulation of local environment- Antibody based therapy- T cell-based therapy (vaccine/adoptive transfer)- Genetically modified T cell therapy (TCRs/CARs)- Develop novel reagents/strategies into clinicalapplication

NETWORK• Cancer Immunotherapy Consortium CRI/Ludwig New

York• CIMT/CRI/AACR• DKTK• Spitzencluster für individualisierte Immunintervention

CI3• Alliances Roche/Genentech, Bayer

NCT Radiation Oncology Program

Heidelberg Ion Therapy (HIT)

3 Clinical Rooms, 1 Experimental RoomSynchrotron 400 MeV/u, Active Scanning, Ion Gantry (600 t)Particles: Clinical: H, C-12 Experimental: O-14, He-4

Radiation Oncology

Debus

Translational Radio-

Oncology

Abdollahi

Medical Physics in

Radiation Therapy

Jäckel

Medical Physics in

Radiology

Ladd

Radiology

Schlemmer (Delorme),

Kauczor

NuclearMedicine

Haberkorn

Radiopharmacy

Kopka

Mol. Radiation Oncology

Huber

ParticleTherapy

Herfarth

NCT Cancer Prevention, Early Detection and Outcomes Program

DepartmentsPreventive Oncology

Brenner (temporary)

Division of Clinical Epidemiology

and Aging Research.

Brenner

Molecular Genetic Epidemiology

Hemminki

Cancer Epidemiology

Kaaks

Epigenomics and Cancer Risk

Plass

Cancer Early Detection

Von Knebel-Doeberitz

Tobacco Control

Pötschke-Langer

Psychooncology

Herzog

MISSIONTo reduce the burden of cancer through • Reduction of risk factors (primary prevention)• Early detection and screening (secondary prevention) • Improving outcomes and quality of life of cancer patients

(tertiary prevention)

FOCUS• Identification of genetic, behavioral and environmental

risk factors and avenues for prevention with novel methods and technologies

• Population-wide and risk-adapted (personalized) early detection and screening programs

• Cancer outcomes research• Clinical trials: early detection, behavioral interventions

NETWORKS• Leadership in national & international consortia:

e.g. IMPACT Consortium, DKTK, National Cohort

Selected Publications

Lancet 2014

BMJ 2014

Science 2013

JCO 2011,2012,2014

JAMA 2010

Display Data from Various Sources for a Comprehensive Overview of Information Relevant for Personalized Treatment

NCT NCT DataThereHouse

INDIVIDUALIZED TREATMENT PLAN

SEQUENCING DATA

ARRAY DATA

CLINICAL PATHWAYS

UNSTRUCTURED DATA

DOCOTOR’S LETTER

STRUCTURED DATA

PHYSICIAN

SCIENTIST

TUMOR BOARD

CASE MANAGER

STUDY NURSE

DOCUMENTALIST

ARZT FORSCHERCASE MANAGER

REPORTER

DOKUMENTAR

PHYSICIAN

SCIENTIST

=

NEUE STUDIE

EINSCHLUSS & AUSSCHLUSS KRITERIEN

BOARD

SPRECHSTUNDE/AMBULANZ

SOP*

BEGLEITENDE DIENSTE

KIS, PACS, REGISTER

KIS, PUBMED, UPTODATE, BIOBANK, INTRANET, REGISTER

PATIENT

HYPOTHESE

STUDIEN PROTOKOLL

AUFKLÄRUN/SCREENING

STUDY NURSE

REPORT

EINBINDUNG

THERAPIEAM NCT ODER EXTERN

LOI*

THERAPIE

POP*

ARZTBRIEF

PATIENTENAKTE

ABLAUF

DATENFLUSS

PATIENTENPFAD

DATENBANK

ARTEFAKTE

KONFERENZ

BEGLEITENDE DIENSTE

Current Scenario

NCT NCT DataThereHouse

NCT Clinical Development Strategy

PATIENT

THERAPIEAM NCT

KLINISCHE STUDIEN

DIAGNOSE

KLINISCHESKREBSREGISTER

NCT

IS-H, PUBMED, UPTODATE, BIOBANK, INTRANET, IS-H, PACS

MONITORING

DOKUMENTAR

ARZT FORSCHER

PUBLIKATION

IS-H, PUBMED, UPTODATE, BIOBANK, INTRANET, IS-H, PACS

FORSCHER

ARZT

DOKUMENTAR

Organized in SAP HANA

DOKUMENTAR DOKUMENTAR

NCT DataThereHouse

NCT CANCERREGISTRY

NCT Partnerships

Academic Collaboration

DKTK

EMBL DKFZ-ZMBH

ALLIANCE

Joint Industry-Academia Collaboration

Cancer Core Europe Consortium Centers

Strengthen NCT Partnerships

German Consortium for Translational Cancer Research (DKTK)

Fusing

High-Throughput Technologies

with

Hypothesis-driven,

Stratification & Intervention

towards

Personalized Medicine

NATIONAL CENTER FOR TUMOR DISEASES

NCT HEIDELBERG