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Towards a World Without Patients

Stephen Albert JohnstonCenter for Innovations in Medicine

Biodesign Institute

Center for Innovations in Medicine

Stephen.johnston@asu.edu

TRILOGY STEMS Group February 3, 2012

DISCLOSURERelevant Financial Relationship(s)

HealthTell, IncCalviri, LLC

Traditional Approach

Scientist’s area of expertise drives the research focus

Research addresses highly specific component of a problem– may later be stitched to other components. Applications—if pursued—emerge from the findings

CIM Approach

Societal needs drive the research focus—then the needed experts are tapped

A team addresses the identified need in an orchestrated manner, linking the components (project management) The area of application is clear throughout project; may be adapted by the findings.

An Alternative Approach to Academic Science

Big Problem orChallenge inBiomedicine

DisruptiveInnovationor Invention

Chemistry

ImmunologyComputation

Biology

Solution?

CIM’s APPROACH to SCIENCE

CIM: Focus on TRANSFORMATIVE Technologies

Blue Ocean Strategy by W. Chan Kim and Renee Mauborgne, 2005

Apollo Projects in Healthcare

• 1. Universal, Preventative Cancer Vaccine

• 2. Inexpensive, Comprehensive Health Monitoring System for Early Diagnosis of Any Disease.

• 3. Synbodies: Solution to Antibiotic Problem

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Forbes Magazine, 1/19/2012

U.S. Healthcare Hits $3 Trillion

 National Healthcare Expenditure – or NHE. … NHE for 2012 is probably closer to $2.7 trillion but there’s this nagging bookkeeping accrual of about $300 billion where we (narrowly) avoided those darn pesky SGR cuts to Medicare.  …  That puts the real NHE at about $3 trillion for 2012 (+ about 4% for each year forward – as far as the

eye can see).  As one economist said – we don’t have a debt problem in this country – we have a healthcare problem.

http://www.forbes.com/sites/danmunro/2012/01/19/u-s-healthcare-hits-3-trillion/

$3 trillion is ~19% of the GDP for the US

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Healthcare:Systems management vs. crisis management

A process engineer at a chemical manufacturing plant would not wait until this happened before intervening. Why do we?

We need both different tools and different thinking to apply process control principles to medicine.

How to Frighten a 20-year Old

Me

You

http://flatrock.org.nz/topics/money_politics_law/boom_moves_along.htm

Post-Symptomatic MedicineTo Pre-Symptomatic Health

2009 GNP $14.7T 2009 Health Care Costs $2.5T

Graphs from “Trends in Health Care Costs and Spening, Kaiser Family Foundation, March 2009http://www.kff.org/insurance/upload/7692_02.pdf; *gross income and tax data from the Tax Foundationhttp://www.taxfoundation.org/news/show/250.html

Per capita health expenditure ~$8000Median adjusted gross income in 2007 ~$33,000*Median federal taxes per capita in 2007 ~$1,000Total Medicare expenditures in 2004 ~$3BMedicare expenditure per capita ~$1000

Transition from Post- to Pre-Symptomatic Medicine Requires System to Continuously Monitor Health of

Well People

Specifications:

-Comprehensive-Sensitive – Early Detection-Simple-Inexpensive-Specificity – What is Wrong?

Number of doublings

0 10 20 30 40

Number of tumor cells

0 103 106 109 1012

Volume of tumor

0 .000001 ml

.001 ml 1 ml 1,000 ml

Weight of tumor

0 1 microgm 1 milligm 1 gm 1 Kg

Clinically Detectable

Mammo-gram

Angiogenesis/metastasis

“Circulating” biomarkers

Oncogenic Signaling

Molecular Breast

Imaging

Breast Tumor Evolution

(1-2mm3)

(27)

Detection Method

Kim Lyerly, Duke University

Can Not Do Early Detection of Disease

Blood Dilution Problem

104 Improvement in Detection Needed

Sci Transl Med 3, 109ra116 (2011);Sharon S. Hori, et al.Detection Strategies and LimitationsMathematical Model Identifies Blood Biomarker-Based Early Cancer

The Immune System Detects and Amplifies Signal

• 108 to 109 antibodies exist in serum

• A single reactive B cell encounters antigen and is activated

• Produces 5,000 to 20,000 antibodies per minute

• Divides every 70 hours

• Signal is amplified ~1011 times in one week

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• Facile sampling of easily obtained blood/saliva

• No sample prep other than dilution• Potential for broad, specific pathogen

detection• Samples stable dry on filter paper for

weeks

dilute

apply

sample

monitor

ImmunoSignature Assay Components

Center for Innovations in Medicine

Array of 10K-330K, Addressable Random Sequence Peptides

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Immunosignature Process

Center for Innovations in Medicine

Add diluted blood

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Immunosignature Process

Center for Innovations in Medicine

Wash

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Immunosignature Process

Wash

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• One array for all samples, human and nonhuman

• Very small quantity of blood required

• Scalability and low cost array fabrication

Immunosignature Process

Nature Does Not Always Know Best

- Life occupies an infinitesimally small part of potential sequence space

- Therefore there are many other sequences that could be useful

- Peptides on array chosen to evenly sample random sequence space (3.5x105/ 1021 possibilities)

Consequences: Same set of peptides can be used for any diagnosis

Super-fine resolution of antibody diversity

Features of Immunosignatures

Same chip used for all diseases, all species

Detects all antibodies: sugars, non-linear, modifications

Historical sera samples work

No sample preparation

10-100x more sensitive than Elisa

Immunosignature Patterns from Various Monoclonal Antibodies

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Center for Innovations in Medicine

Classic Train/Test Example:Valley Fever

• 10,000 peptides on original array

• 120 patients screened and analyzed

• 100 most informative peptides selected and resynthesized

• Diagnostic array printed

Normal Infected

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John GalgianiUniv. of Arizona

Outperforms Existing Diagnostic

Patients with Valley Fever Patients that did not have Valley Fever

• 90 blinded samples from patients presenting at the clinic• Zero false positives (100% specificity)• Zero false negatives (100% sensitivity)

All Patients with Valley Fever Presented with Zero CF Titers, but were later shown to have the disease

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Immunosignaturing Brain TumorsCollaborator: Adrienne C. Scheck, BNI

Not only can immunosignaturing detect the brain tumor, it can distinguish accurately between the common types of brain tumors

100% accurate detection training and testing on samples taken years apart using printed arrays

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Alzheimer’s: Alzheimer’s Disease Neuroimaging Initiative (10K)

Disease: ADNI collection of serum samples from Alzheimer’s Disease (AD) and non-AD controlsFeature selection: 1 sided T-test, 50 peptides were selectedClassification: 4 samples were called normal when they were Alzheimer’s (FN)Sensitivity=89%, NPV=92%, Accuracy=95%, specificity and PPV=100%Interpretation: AD signature blends gradually into controls with no clearly defined threshold

Alzheimer’s Disease Controls

Towards Comprehensive Testing

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Astrocytoma

Oligodendrogliom

a

MixedOligo/Astro

Pancreatic Healthy controls BC stage 2, 3Breast2nd tumor

MM Pancreatitis GBMOvarian Sarcoma

Lung

BC stage 4

Valley Fever

15 Diseases Simultaneously Analyzed

Cross Validation, 15 Diseases

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Transition from Post- to Pre-Symptomatic Medicine Requires System to Continuously Monitor Health of

Well People

Specifications:

-Comprehensive-Sensitive – Early Detection-Simple-Inexpensive-Specificity – What is Wrong?

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detected by image or symptoms start the treatment

detected by IMSstart the treatment

closely monitor by IMSevacuate the treatment

Anti-CTLA4Anti-PD-1

chemotherapy

Cancer is eradicated

With current diagnosis and treatment, the cancer death will be 585,720 in 2014.

Earlier diagnosis treatment, higher survival

Vision: Eradicating Cancer by Immunosignature Monitoring of Health

Platform 1: Printed Arrays of 10,000 Platform 1: Printed Arrays of 10,000 PeptidesPeptides

17 amino acids long, random sequence, and all amino acids except C are used. Two copies of the library are printed on a glass slide (~1200 peptides/cm2).Mass spectra available for all peptides spotted on the arrays.

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3333

• Scalable production• Low cost at high volume• Utilizes decades of

fabrication technology development

• Integrates with Electronics

Making it Inexpensive & Scalable:In situ synthesized peptide arrays

• Standard fabrication instruments• 8 micron features (high density)• 312 assays per wafer

3434

High density High information content High volume Low cost

Visualizing Features

330,000 peptides were synthesized in a 0.5 cm2 region (8 micron features, 13 microns on center). Binding of a monoclonal antibody to so many sequences give a broad dynamic range of signal (about 300:1).

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330K Arrays: Simultaneous Discrimination of 7 Infectious Diseases

127 blood samples from 7 diseases, 2 WNV miss-classified as normal

36The 330K synthesized arrays do an excellent job of distinguishing multiple diseases

Discriminating Four Cancers with the 330K Arrays

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Breast Esophogeal Glioblastoma Ovarian

Gates Foundation Vaccine Grants

Disease Deaths (millions/year)Grants for Vaccines

($millions)

Acute Diarrheal Illness (ADI) 2-3 $72.

Acute Lower Respiratory Infections (ALRI) 2 $139

HIV/AIDS 2.8 $421Malaria 1 $425

Tuberculosis 1.6 $107

Vaccine-Preventable Diseases 2 $66

Other Infectious Diseases ? $183

Cancer 5 $0.0

Apollo Projects in Healthcare

• 1. Universal, Preventative Cancer Vaccine

• 2. Inexpensive, Comprehensive Health Monitoring System for Early Diagnosis of Any Disease.

• 3. Synbodies: Solution to Antibiotic Problem

Problem

• Cancer kills ~8M people each year

• ~70% of deaths are in developing world

• Cost is >$1T worldwide, >1.5% of GDP

• Solutions being advanced (eg proton emission treatment, personal therapeutics) are only cures, expensive and unimaginative

Cancer Treatment Costs Too Much for Use in Developing World

• Breast cancer drug Herceptin: ~ $30,000 a year

• Colorectal, lung and breast cancer drug Avastin: ~ $50,000 a year

Contribution of Cancer to HC Costs

$2.4T Total Costs

$250B Direct Cancer Costs = 10% of

Total HCCosts

Anne Weston, picture of “How to Cure Cancer”, Time magazine web, June,2013

Solution

• Develop a preventative vaccine for all cancers

• Solves problems inherent in treating tumors

• Inexpensive, accessible to whole world

• Simple and Revolutionary

infection

vaccine

Foreign Antigen+

DANGER

Strong Immune Response

Aberrant tumor proteins

Foreign Antigen NO DANGER

TOLERANCESuppression of immuneresponse to tumor antigens

Willimsky, G. and T. Blankenstein. 2005. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance.Nature 437:141-146

The Problem with Therapeutic Cancer Vaccines

12

3

45

6

7

81

2

3

45

6

7

8

Protection

12

3

45

6

7

89

10

11

1213

8

14

NO Protection

8

910

11

1213

8

14

Protection ?

A B

C

Strategy

• Find neo-antigens that occur in >5% of all tumors

• Pool enough neo-antigens (~10-20) to anticipate presentation by any new tumor

• Vaccinate before tumor presents neo-antigens

The Challenge: Find Enough Tumor Specific Antigens in Common

Tumors 1 2002 3 4

TumorSpecificAntigens

VACCINE = + + +Any Tumor Arising Would Have 100% Chance of PresentingOne or More Antigens

Background smc1a Frame Shift Splicing

Frame-Shift transcript of smc1a is caused by alternative splicing exon1 to exon 4.The splicing causes reading frame shift of exon4 and generates a 17 amino acids long FS peptide.

Wild Type smc1a

Frame Shift smc1a

BALB-NeuT tumor progression curve

0 50

25

50

75

100

Control Individual

15 25 35

3Ags pool

Age (week)

% t

um

or

nu

mb

er <

10

Fig: The tumor inhibition of FS antigens in BALB-NeuT mouse breast tumor model. Control vs individual antigen or pool antigens p<0.0001; Individual antigen vs. pool antigens p<0.005

Red labled Median normalized value >10; sorted by sample types, the same color code, white is normal sample. 345 peptide have at least 1 sample >10

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

4.50

5.00N1 N6 N1

1N1

6N2

1N2

6N3

1N3

6N4

1N4

6N5

1N5

6N6

1N6

6N7

1N7

6N8

1N8

6N9

1BC

2BC

7BC

12BC

17BC

22BC

27BC

32BC

37BC

42BC

47BC

52BC

57BC

62BC

67BC

72BC

77BC

82BC

87BC

92

Nor

mal

ized

sig

nal v

alue

Positive rate of one peptide of ODZ4-NRG in normal and breast cancer samples. Normal: 3.2%; Breast cancer: 54.7%

Phase II Trial Design

IMS

Cancer FreeVolunteer

Vaccine Group

Control Group

Cancer Event

No Cancer Event

Cancer Event

No Cancer Event

Cancer Prevent Event

IMS

Solution to Conducting Phase II Efficacy Trial in Humans:

DOGS36% Lifetime Risk of Cancer$5M to Conduct TrialUse Immunosignatures to Shorten Trial, Decrease CostFast to Market$100M/yr Sales in USAIf It Works for Dogs – Will Likely Work for People

Company: Calviri, LLC

Development: $200B (1000 ctns) $1B (Phase III)

Cost/Year: $50B $1B ($100/shot)

Cost/Trtment ~$30,000 $100

Physicists 10,000 0

(A) Proton Emission (B) PreventativeCancer Vaccine

Plan A or B?

Source: Mayo web site, http://www.npr.org/blogs/health/2012/10/29/163635298/

Acknowledgements• Innovations In Medicine

– Neal Woodbury, co-director– Chris Diehnelt– John Lainson– Zbigniew Cichacz– Phillip Stafford– Zhan-Gong Zhao– Donnie Shepard– Bart Legutki– Andrey Loskutov– Penny Gwynne– Loren Howell– Douglas Daniel– Rebecca Halperin– Lucas Restrepo– Luhui Shen– Hu Duan– Debra Hansen– Pattie Madjidi

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• HealthTell, Inc. – Bill Colston– Kathryn Sykes– David Smith– Fabrication Team

• NextVal, Inc.– Matthew Greving

• Complex Adaptive Systems Initiative– George Poste

• Other Collaborators– John Galgiani, U. of Arizona– Hoda Anton-Culver, UC Irvine– Sam Hanash, Fred Hutchinson Cancer Center– Adi Gazdar, UT Southwestern– Adrienne Scheck, Mayo Clinic– Dawn E. Jaroszewki, Mayo Clinic

$Funding: The Biodesign Institute at ASUHealthTell, Inc.DTRA, NSF, DARPA, ARO