Towards a World Without Patients

1. Center for Innovations in Medicine Towards a World Without Patients TRILOGY STEMS Group February 3, 2012 Stephen Albert Johnston Center for Innovations in Medicine Biodesign Institute Stephen.johnston@asu.edu

2. DISCLOSURE Relevant Financial Relationship(s) HealthTell, Inc Calviri, LLC

3. An Alternative Approach to Academic Science 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. 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

4. Big Problem or Challenge in Biomedicine Disruptive Innovation or Invention Chemistry Biology Immunology Computation Solution? CIM’s APPROACH to SCIENCE

5. CIM: Focus on TRANSFORMATIVE Technologies Blue Ocean Strategy by W. Chan Kim and Renee Mauborgne, 2005

6. 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

7. 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

8. 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.

9. How to Frighten a 20-year Old Me You http://flatrock.org.nz/topics/money_politics_law/boom_moves_along.htm

10. Post-Symptomatic Medicine To Pre-Symptomatic Health Per capita health expenditure ~$8000 Median adjusted gross income in 2007 ~$33,000* Median federal taxes per capita in 2007 ~$1,000 Total Medicare expenditures in 2004 ~$3B Medicare expenditure per capita ~$1000 2009 GNP $14.7T 2009 Health Care Costs $2.5T Graphs from “Trends in Health Care Costs and Spening, Kaiser Family Foundation, March 2009 http://www.kff.org/insurance/upload/7692_02.pdf; *gross income and tax data from the Tax Foundation http://www.taxfoundation.org/news/show/250.html

11. 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?

12. Breast Tumor Evolution Detection Method (27) (1-2mm3) Kim Lyerly, Duke University

13. 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 Limitations Mathematical Model Identifies Blood Biomarker-Based Early Cancer

14. 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

15. Center for Innovations in Medicine ImmunoSignature Assay Components sample dilute apply • 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 monitor

16. Center for Innovations in Medicine Immunosignature Process Array of 10K-330K, Addressable Random Sequence Peptides

17. Center for Innovations in Medicine Immunosignature Process Add diluted blood

18. Immunosignature Process Wash

19. Immunosignature Process • One array for all samples, human and nonhuman • Very small quantity of blood required • Scalability and low cost array fabrication Wash

20. 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

21. 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

22. Center for Innovations in Medicine Immunosignature Patterns from Various Monoclonal Antibodies

23. Classic Train/Test Example:Valley Fever Normal Infected • 10,000 peptides on original array • 120 patients screened and analyzed • 100 most informative peptides selected and resynthesized • Diagnostic array printed John Galgiani Univ. of Arizona

24. 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

25. Immunosignaturing Brain Tumors Collaborator: Adrienne C. Scheck, BNI 100% accurate detection training and testing on samples taken years apart using printed arrays Not only can immunosignaturing detect the brain tumor, it can distinguish accurately between the common types of brain tumors

26. Alzheimer’s: Alzheimer’s Disease Neuroimaging Initiative (10K) Alzheimer’s Disease Controls Disease: ADNI collection of serum samples from Alzheimer’s Disease (AD) and non-AD controls Feature selection: 1 sided T-test, 50 peptides were selected Classification: 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

27. Towards Comprehensive Testing Breast 2nd tumor Valley Fever Pancreatic Lung Ovarian MM Pancreatitis Healthy controls BC stage 2, 3 Mixed Oligo/Astro GBM Astrocytoma Sarcoma BC stage 4 Oligodendroglioma 15 Diseases Simultaneously Analyzed

28. Cross Validation, 15 Diseases

29. 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?

31. Vision: Eradicating Cancer by Immunosignature Monitoring of Health With current diagnosis and treatment, the cancer death will be 585,720 in 2014. detected by image or symptoms start the treatment Earlier diagnosis treatment, higher survival Anti-CTLA4 Anti-PD-1 chemotherapy Cancer is eradicated detected by IMS start the treatment closely monitor by IMS evacuate the treatment

32. Platform 1: Printed Arrays of 10,000 Peptides 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.

33. Making it Inexpensive & Scalable: In situ synthesized peptide arrays • Scalable production • Low cost at high volume • Utilizes decades of fabrication technology development • Integrates with Electronics 33

34. Fabrication Approach • Standard fabrication instruments • 8 micron features (high density) • 312 assays per wafer High density  High information content  High volume  Low cost 34

35. 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).

36. 330K Arrays: Simultaneous Discrimination of 7 Infectious Diseases 127 blood samples from 7 diseases, 2 WNV miss-classified as normal The 330K synthesized arrays do an excellent job of distinguishing multiple diseases

37. Discriminating Four Cancers with the 330K Arrays Esophogeal Glioblastoma Ovarian Breast

38. Gates Foundation Vaccine Grants

39. 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

40. 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 onlycures,expensive and unimaginative

41. 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

42. Contribution of Cancer to HC Costs $250B Direct Cancer Costs = 10% of Total HC Costs $2.4T Total Costs

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

44. Solution • Develop a preventative vaccine for all cancers • Solves problems inherent in treating tumors • Inexpensive, accessible to whole world • Simple and Revolutionary

46. The Problem with Therapeutic Cancer Vaccines Aberrant tumor proteins infection vaccine Foreign Antigen NO DANGER Foreign Antigen + DANGER TOLERANCE Suppression of immune response to tumor antigens Strong Immune Response Willimsky, G. and T. Blankenstein. 2005. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance.Nature 437:141-146

47. 9 9 1 1 1 10 10 8 8 8 2 2 2 14 14 3 3 3 11 11 7 7 7 8 8 4 4 4 6 6 6 13 13 5 5 5 12 12 NO Protection Protection B A 8 Protection ? C

48. 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

49. The Challenge: Find Enough Tumor Specific Antigens in Common Tumors 4 2 200 1 3 Tumor Specific Antigens Any Tumor Arising Would Have 100% Chance of Presenting One or More Antigens + + + VACCINE =

50. Backgroundsmc1a Frame Shift Splicing Wild Type smc1a Frame Shift smc1a 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.