The future of early molecular cancer diagnostics and preventive …309f6ea9-b5d1-42db-a2d6... ·...

CONFIDENTIALNOT FOR DISTRIBUTION

11CONFIDENTIALNOT FOR DISTRIBUTION

The future of early molecular cancer

diagnostics and preventive immunotherapy

Kenneth J Bloom, MD, FCAP

President, HLI

Head of Oncology and Immunotherapy


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CANCER IS A COMPLEX DISEASE

PREDISPOSITIONEARLY

ADENOMA

LATE

ADENOMACARCINOMA

INVASIVE

CARCINOMA

Loss of APCtumor

suppressor

KRAS oncogene

Loss of DCC tumor

suppressor

Loss of p53 tumorsuppressor

Insensitivity to antigrowth signals, promotion

of survival signals

Tissue invasion and metastasis

Limitless potential for replication

Vascular recruitment

and endothelial cell growth

Evading apoptosis

Cellular proliferation through independent

growth signaling

APC=adenomatous polyposis coli; DCC=deleted in colon cancer.

Adapted from Weinberg. Sci Am. 1996;275:62-70.

A colorectal cancer model


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PREDISPOSITION HYPERPLASIA DYSPLASIA CARCINOMAINVASIVE

CARCINOMA

CANCERS ACQUIRE GENETIC CHANGES THAT ENABLE ADVANTAGEOUS TRAITS

Insensitivity to antigrowth signals,

promotion of survival signals

Limitless potential for replication

Evading apoptosis

Cellular proliferation through independent

growth signaling

Vascular recruitment

and endothelial cell growth Tissue invasion

and metastasis

Acquired functional

capabilities ofcancer cells

3


4

Linear Model of Cancer Progression

Esserman L, Lancet Oncol 2014; 15: e234–42

Normal Cell

Atypical Cell

Carcinoma in-

situ

Stage I

Cancer

Stage II-III

Cancer

Detectable

Metastasis

Cancer

Death

Detection at

this stage

results in

marked

decrease in the

incidence of

cancer


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Trends in Age-adjusted Cancer Death Rates* by Site, Females, US, 1930-2012


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Normal Cell

Atypical Cell

Carcinoma in-

situ

Stage I

Cancer

Stage II-III

Cancer

Detectable

Metastasis

Cancer

Death

Early detection will

reduce mortality


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Incidence of Metastatic Breast Cancer Has Stayed Flat Over Last 35 Years

DOI: 10.1056/NEJMoa1600249


8

National Lung Screening Trial

Primary Results

• 20% relative reduction in lung

cancer mortality with Low Dose

CT

• 6.7% reduction in all-cause

mortality with Low Dose CT

NLST (2011) NEJM, 365, 395-409.


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Three Strikes to Cancer

Vogelstein B, Kinzler K, New Engl J Med 2015; 373: 1895

Phase Key event

Breakthrough A single cell acquires a driver-gene

mutation and begins to divide

abnormally

Expansion A cell acquires a second driver-gene

mutation and becomes a benign tumor.

Invasive A cell acquires a second driver-gene

mutation in at least one of the key

pathways that allow it to invade the

surrounding tissue.


10Nat Med. 2008 September ; 14(9): 985–990. doi:10.1038/nm.1789

• DNA rapidly

cleared by the

liver

• ½ life is

approximately

2 hours.


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Finding Circulating DNA

DOI: 10.1200/JCO.2012.45.2011

Technique Sensitivity

Sanger Sequencing > 10%

Pyrosequencing 10%

NGS 2%

Quantitative PCR 1%

ARMS 0.10%

Digital PCR <0.01%


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Mutations Do Not Always Behave the Same

Vogelstein B, Kinzler K, New Engl J Med 2015; 373: 1895

Phase Melanoma Pancreatic

Carcinoma

Cervical

Carcinoma

Colo-Rectal

Carcinoma

Breakthrough BRAF KRAS TP53

RB

APC

Expansion TERT CDK2NA PIK3CA KRAS

Invasive CDK2NA

TP53

PIK3CA

SMAD4

TP53

MAPK1

STK11

FBXW7

SMAD4

TP53

PIK3CA

FBXW7


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ctDNA Correlates with Recurrence

Nat Med. 2008 September ; 14(9): 985–990. doi:10.1038/nm.1789


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Atypical

Cell/CIS

Stage I

Cancer

Normal Cell

Atypical

Cell/CIS

Stage I

Cancer

Normal Cell

Stage I-III

Cancer

Detectable

Metastasis

Normal Cell

Stage II-III

Cancer

Detectable

Metastasis

Indolent Slowly

Progressive

Rapidly

Progressive

Early detection unlikely

to affect mortality

Early detection can

reduce mortality

Systemic therapy key

to reduce mortality


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Pathologists Classify Disease

15

© Farside

Not everything that

looks the same,

behaves the same.Gene

Chromosome

Nucleosome

DNA

SKY

CGH

Protein

Bisulfite PCR

Methylation arrays

ELISA

FACS

IHC

Proteomics

FISH

PCR

DNA sequencing

Microarrays

qRT-

PCR

mRNA


16

Personalized Medicine is not a New Concept

If it were not for the great

variability among individuals,

medicine might as well be a

science and not an art.

The good physician treats the

disease; the great physician

treats the patients who has the

disease.

Sir William Osler


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Stratifying Disease Identifies which Therapies are Beneficial and Enhances Patient Outcomes

• Slide courtesy of Mara Aspinall


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All cancers are not the same

Kras

EGFR

ALK

PIK3CA

Her2

BRAF

Akt

MET

Unknown

Adapted from Crystal AS et al, Clin Adv Hematol Oncol. 2011; 9:207


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PRECISION DRUGS REQUIRE PRECISION ASSAYS

Same Diagnosis

Same Prescription

Drug is

toxic but

beneficial

Drug is

toxic and

NOT

beneficial

Drug is NOT

toxic but also

NOT beneficial

Drug is NOT

toxic and

beneficial

Right Drug

Right Patient

Right Time

Right Dose


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Targeted Therapy Provides Benefit Only When Target is Present

Mok TS, et al. N Engl J Med 2009


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Targeted Therapies Work Rapidly but Demonstrate Little Overall Survival Benefit

Solomon BJ, et al. N Engl J Med 2014;371:2167

Shaw AT, et al. N Engl J Med 2014;370:1189


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The Cancer-immunity Cycle

Modified from Chen and Mellman. Immunity 2013

Accessingthe tumor

Active T cell

TUMOUR MICROENVIRONMENT

3 Priming and activation

2 Cancer antigenpresentation

1 Release of cancer cell antigens

7 Killing of cancer cells

6 Recognition of cancer cells by T cells

5 Infiltration of T cells into tumors

4 Trafficking of T cells to tumors

Apoptotic tumor cell

Cancer-cell recognitionand initiation of cytotoxicity

Antigens

Initiating and propagating anti-cancer immunity

Dendritic cell

Active T cell

Tumor cell


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From theory to practice

Pardoll. Nat Rev Cancer 2012

Lymph node Tumor microenvironment

MHC

T cell

Tumour

cell

Antigen presenting cell

TCR

B7.1/

B7.2CTLA-4

T cell

TCR MHC

PD-1

PD-L1/

PD-L2

CTLA-4 pathway PD-1 pathway


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Broad pan-tumor potential with anti-PDL1/PD1 inhibitors: ~ORR in all-comers with monotherapy

Modified from Chen. BioScience Forum 2015


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Key Differences Between Targeted Therapy and Immunotherapy

Targeted Therapy Immunotherapy

Tends to be organ specific Pan tumor potential

Patients negative for

biomarker get no benefit

Patients negative for biomarker

still get benefit

Benefits seen early Benefit not always

seen early

Duration of benefit limited Extended duration of benefit

Impact on survival limited Impact on overall survival

Biomarker in tumor cells Tumor cells + TME


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Baseline

Post C2 (Week 6)

Baseline

23 months

Baseline

Day 90

CD8

CD8

Immunotherapies targeting PD-L1 and PD-1 are having a dramatic impact in the clinic

1. Chaft et al. WCLC 2015; 2. McDermott et al. J Clin Oncol 2015; 3.

Hamid et al. N Engl J Med 2013

Patient with NSCLC treated with atezolizumab (FIR study)1

Patient with RCC treated with nivolumab (NCT00730639)2

Patient with melanoma treated with pembrolizumab (KEYNOTE-001)3


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The Tumor Microenvironment (TME) Shapes Tumor Evolution

•The immune

system

naturally

identifies and

eliminates

cancerous

cells

Normal

fibroblastsAg recognition

Type I cytokines

Ag

NK cells


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Tumors Exploit Different Pathways to Evade the Immune System

Influence by TAMS

MMPs

Cathepsins

Type II cytokines

Influence by CAFs

TGF-β, MCP1, PDGF,

FGF, proteases

Angiogenesis

Inhibition of B- and

T-cell responses

Tumor-associated Ag

presentation inhibited

M1 phenotype

blocked

Inhibition of cytolytic

granule release

Immune suppression

VEGF

Hypoxia

VEGF


29

PD-L1 is not good enough

Non-sq.=non-squamous; sq.=squamous

1. Weber et al. Lancet 2015; 2. Robert et al. Lancet 2015; 3. Larkin et al. N Engl J Med 2015; 4. Borghaei et al. N Engl J Med 2015

5. Brahmer et al. N Engl J Med 2015; 6. Antonia et al. ASCO 2015; 7. Motzer et al. J Clin Oncol 2015; 8. Le et al. ASCO GI 2016

9. Kefford et al. ASCO 2014; 10. Garon et al. N Engl J Med 2015; 11. Plimack et al. ASCO 2015; 12. Vansteenkiste et al. ECC 2015

13. Rosenberg et al. Lancet 2016; 14. McDermott et al. J Clin Oncol 2015; 15. Rizvi et al. ASCO 2015; 16. Segal et al. ASCO 2015

17. Gulley et al. ASCO 2015; 18. Apolo et al. ASCO GU 2016; 19. Dirix et al. SABCS 2015; 20. Chung et al. ASCO GI 2016

0

20

40

60

80ITT

PD-L1+

PD-L1-

Nivolumab Pembrolizumab Durvalumab AvelumabAtezolizumab

OR

R (

%)

~50%

~20%

~30%


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CD8 Cell

Tumor Mutations Create Neoantigen T-Cell Targets

Endoplasmic

Reticulum

Protein

Proteasome

Mutations

Peptides

TAP

MHC1

Neoantigen

TCR

The proteasome degrades

intracellular proteins into short

peptides that will be transported to

the ER via TAP transport. Most

peptides won’t bind to MHC class

1 molecules but if a peptide binds

with high affinity, the stable

complex will be transported to the

membrane surface.


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Identifying Possible Neoantigens

• Sequence the tumor to identify mutations

• Perform RNAseq to ensure mutation is being expressed

• Prediction algorithms based of MHC expression


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Predicting Neoantigens


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No Need to Guess


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Sample ELISPOT readout


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Part of Our Comprehensive Cancer Program


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WES/WGS will be the cornerstone of cancer therapy

• Early detection

• ctDNA

• Germline DNA

• Target therapy

• Recurrence Monitoring

• Immunotherapy


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Thank YouFOR MORE INFORMATION ABOUT

HUMAN LONGEVITY, INC.

Phone: 858.864.1155

Email: [email protected]


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