Development of a Universal Prophylactic Cancer Vaccine International

Development of a Universal, Prophylactic Cancer Vaccine International Biotechnology Symposium Bio-Asia 2015 Inaugural RAACC Workshop Stephen Albert Johnston Stephen. johnston@asu. edu

Current Center for Innovations in Medicine Projects OBJECTIVE INVENTION Health Monitoring/ Early Diagnosis COMPANY Immunosignatures Health. Tell, Inc Universal Preventative Frameshift Antigens Cancer Vaccine Next. Gen Antibiotics, Anti-Virals Calviri, LLC Synbodies 2

Cancer Deaths Worldwide Developed (high-income/ industrialized): Developing & under-developed 29% of cancer countries: deaths 71% of cancer 2, 054, 897 deaths/yr. 5, 053, 872 deaths/yr. 7, 108, 769 total cancer deaths/yr. Source: World Health Statistics 2006, published by the World Health Organization (WHO). WHO.

Contribution of Cancer to HC Costs $250 B Direct Cancer Costs $2. 4 T Total Costs = 10% of Total HC Costs

“The total economic impact of premature death and disability from cancer worldwide was $895 billion in 2008. ”

WHO: Imminent global cancer 'disaster'

The Problem: CANCER Leading or 2 nd leading cause of death in US: 570, 280 Americans will die of cancer this year 1, 372, 900 Americans will get cancer this year - $86 B spent by National Cancer Instit. over 36 years in the War on Cancer Death Rate Per 100, 000 600 586. 8 1950 2002 500 400 300 240. 1 193. 9 180. 7 200 56. 0 100 48. 1 193. 4 22. 5 0 Heart Diseases Cerebrovascular Society. Pneumonia/ Source: American Cancer Diseases Influenza Cancer

• “When the stars come together cancer doesn’t stand a chance”

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

Positron Emission Therapy Construction: $100 M Cost/Trtment ~$30, 000 Physicists 10, 000

Personalized Medicine 1. Tumor DNA and/or RNA from ONE Individual is Sequenced 2. Analysis of Sequence Indicates the Right Drug to Use 3. Estimated Costs >$100, 000 US

Immunotherapy Checkpoint Inhibitors 1. Monoclonal antibodies that block immune suppression of natural anti-tumor response. 2. Very effective in minority of cases 3. Cost: >$ 100, 000

WHAT IS WRONG? ! • 1. Cancer is too difficult a problem and we should be content with very low return on investment and no solution to cancer in the developing world OR • 2 We have been fundamentally doing a poor job at research investment on cancer.

How to Eradicate Cancer Plan A: Preventative Cancer Vaccine Response Cancer Antigens Vaccine No Cancer Known Early Tumor Killed Plan B: Early Detection, Early Systemic Treatment 3: Systemic Treatment (anti-PD 1, CTLA 4) 1: Regular Health Monitoring Tumor Free

Personalization Paradigm Immunize with Irradiated tumor cells or cell lysate Challenge with tumor Mice are protected against the tumor for which they were immunized, but not a different tumor

Personalized Cancer Vaccine Robert H Vonderheide 2013 Nature Medicine

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

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

Neo-antigen for Vaccine Frame-shift Mutation: frame-shift peptide

Frameshift Transcripts Alternative Splicing Trans-splicing Microsatellite Mutation

Melanoma tumor

3 FS/500 bp sequences = 0. 6%

Prophylactic vaccine against B 16 melanoma 6 -21 m %survival 1 -78 m

Prophylactic vaccine against 4 T 1 breast cancer 1 -78 m no 6 -21 m Size mm 3

Prophylactic Cancer Vaccine Development N C C Bioinformatics PCR screen Genomics Serology screen Screen in Tumors Proteomics Test in mouse models

Homopolymer >7

Breast Cancer Patients 65 samples Health People 93 samples Serology Screen with FS peptide array FS peptides (300 peptides) Red indicates positive samples: above (average plus 2 fold of SD) of health

Dog Sera Samples Multiple dog cancer vs normal 800 FS peptites 116 cancer vs 52 normal Red indicates Median normalized value >5

Microsatellite FS protection BALB/c-4 T 1 model

Efficacy Trial Problem VACCINE 5000 CONTROL 5000 1 Year 1 Cancers 50 Cancers -Only non-lethal cancers were prevented -Tumors were just delayed -Tumors will be more lethal later

Prophylactic Cancer Vaccine for Dog • 50% dog will develop cancer after ten years old. • Most FS antigens identified in human cancers are highly conserved in dog cancers.

Table of FS Antigens in the Dog prophylactic Cancer Vaccine. Sequence confirmed: for miss-splicing and trans-splicing, the predicted transcripts were detected. For MS, the predicted MS were confirmed in the coding region of the genes.

Phase II Trial Design IMS Cancer Event Prevent Tumor Event IMS Vaccine Group Cancer Free “Volunteers” Control Group Safety: October 1, 2105 Crowd funding: December, 2015 Efficacy Trial: February 2015 No Cancer Event

A: Positron Emission Vaccine B: Prophylactic Plan A or B? Development: $200 B (1000 ctns) $1 B (Phase III) Cost/Year: $50 B $1 B ($100/shot) Cost/Trtment ~$30, 000 $100 Physicists 10, 000 0 Source: Mayo web site, http: //www. npr. org/blogs/health/2012/10/29/163635298/

Acknowledgments • Luhui Shen • Phillip Stafford • Tsukasa Oyama • • • Douglas Thamm Colorado State University Funding: Ji’an Zhang Kurt Whittmore Do. D CDRMP Innovator Award Josh Richer Keck Foundation Bart Legutki Calviri, LLC Zbigniew Cichacz John Lainson Hojoon Lee Pattie Madjidi / Penny Gwynne