1. Eshel Ben-Jacob Biochemistry & Cell Biology and CTBP, Rice University School of Physics & Astronomy, Tel Aviv University, Translating Cancer Data and Models to Clinical Practice Institute for Pure & Applied Mathematics, UCLA, Feb 10-14, 2014 Translating Cancer Data and Models to Clinical Practice Institute for Pure & Applied Mathematics, UCLA, Feb 10-14, 2014

2. Dormancy and Relapse Multiple Drug Resistance Metastasis Are little understood and clinically insuperable An even Greater Challenge is Posed by the Cancer–Immunity Interplay Cancer Continues to Elude Us

3. These small membrane vesicles carry signals to distant parts of the body, where they can impact multiple dimensions of cellular life. Clotilde Théry TheScientist July 1, 2011 Zhang and William “Exosomes and Cancer: A Newly Described Pathway of Immune Suppression” Clinical Cancer Research 2011 Camussi et al. “Exosome/microvesicle-mediated epigenetic reprogramming of cells” J. Am. Cancer Research 2011

4. Exosome secretion Bobrie et al Traffic (2011)

5. A Crash Course in Immunology Coaching the Immune System Exosome-mediated immunity Rethinking the Immune System Networked society of smart cells Dendritic cells (DC) play a key role in the society’s control and command Rethinking Cancer Networked society of smart cells Exosome-mediated tumorigenesis Exosome-based Cancer-Immunity Cyberwar

6. Generic Modeling of the Exosome-mediated Interplay Therapeutic Implications Reflections on the Generic Modeling Approach The Realistic Trap vs. The Reminiscence Syndrome Ben-Jacob Nature 2002 Simplifying the complexity by the art of generic modeling Rethinking the Cancer-Immunity Interplay

7. A Crash Course in Immunology The human body: 10 15 bacteria, 10 14 cells, 10 12 immune cells, 10 11 neurons Innate Immunity, Adaptive Immunity and Immune Memory The Dual Function of the Immune System

8. Innate Immunity: Natural Killer (NK) cells, Inflammation, Killer and Repair Macrophages The Complexity Adaptive Immunity: Naïve T cells, Natural Killer T cells, Cytotoxic T cells, Helper T cells, Regulatory T cells, Memory T cells, B lymphocytes, Memory B cells Killer and Repair Macrophages Immature Dendritic Cells Mature Dendritic Cells Dendritic CellNaïve T cells Helper T cells Innate-DC-Adaptive

9. M1 (killer) Macrophage Dendritic Cell

11. Immune Holography Immune development from Birth to Adulthood Madi et al. PNAS 2009, PLoS ONE 2011, Bransbburg-Zabary et al. Phys. Bio 2013 Networked Society of Smart Cells

12. Hypothesis Dendritic Cells (DC) Play a key role in the society’s control and command Dendritic Cells (DC) Play a key role in the society’s control and command Bone Marrow (BM) Progenitors Immature Dendritic cells Blood circulationTumor Stimulate the immune response DC and BM exosomes promote DC differentiation Mature DCs Ben-Jacob mAbs (monoclonoal antibodies) 2014

13. Exosomes from Antigen-presenting cells (APCs) Activation of NK cells Bone marrow exosome Dendritic cell (DC)DC exosome DC maturation and differentiation Progenitors Exosome-mediated immunity

14. Activation Inhibition Exosome-mediated immunity

15. A Crash Course in Immunology Coaching the Immune System Exosome-mediated immunity Rethinking the Immune System Networked society of smart cells Dendritic cells (DC) play a key role in the society’s control and command Rethinking Cancer Networked society of smart cells Exosome-mediated tumorigenesis Exosome-based Cancer-Immunity Cyberwar

16. Ben-Jacob, Coffey, Levine Opinion in Trends in Microbiology (2012) Cancer as a Networked Society of Smart Cells Learning from bacteria about cancer

17. Spying cells Kim et al Cell 2009 Self-seeding Circulating Tumor Cells (CTC) e.g. MMP1/ collagenase-1 e.g. IL-6, IL-8 EBJ et al Tim 2012

18. Path generating Path finding Ben-Jacob et al. 2012

19. Signals from the Primary tumor Kaplan et al Nature 2005

21. Wendler et al. J. Extracellular Vesicles July 2013 Exosome-mediated tumorigenesis

22. Azmi et al. Cancer Metastasis Rev. May 2013

23. Rethinking the Cancer-Immunity Interplay A battle between two networked societies of smart cells Tumor Can Evade and Deceive the Immune System Example: Tumor-Associated-Macrophages (TAMs) Bone marrow-derived leukocytes are solicited and directed by cancer to adopt unique phenotypes that can facilitate Tumor growth and survival. Cancer Continues to Elude Us

24. Exosome-based Cyber-war Between Cancer and the Immune System Exosome-based Cyber-war Between Cancer and the Immune System Munich et al. OncoImmunology Oct 2012 Yu et al. Journal of Immunology Dec 2007 Tumor exosomes IL-6 and Stat3 Blocking DC differentiation

25. Towards Dialysis of Tumor Exosomes FedExosomes: Engineering Therapeutic Exosomes that Truly Deliver FedExosomes: Engineering Therapeutic Exosomes that Truly Deliver Using Bacteria to Coach Dendritic Cells Exosome-based Cancer Vaccination?

26. FedExosomes: Engineering Therapeutic Exosomes that Truly Deliver Marcus and Leonard, Parmaceuticals (2013)

27. A B C Marleau et al. J. Translational Medicine 2012 Towards Dialysis of Tumor Exosomes

28. Using Bacteria to Coach Dendritic Cells Ben-Jacob et al Trends in Microbiology 2012 Next: Engineering Exosome-secreting Bacteria

29. Exosome-based cancer Vaccination? Escudier et al. Journal of Translational Medicine 2005 Tan et al International Jornal of Nanomedicine 2010

30. Generic Modeling of the Exosome-mediated Interplay Therapeutic Implications Reflections on the Generic Modeling Approach The Realistic Trap vs. The Reminiscence Syndrome Ben-Jacob Nature 2002 Simplifying the complexity by the art of generic modeling Rethinking the Cancer-Immunity Interplay

31. Mingyang Lu, Rice Univ.Bin Huang, Rice Univ. Jose’ Onuchic, Rice Univ.Sam Hanash, MD Anderson Eshel Ben-Jacob, Rice And Tel Aviv Univ. Support at Rice Support at Tel Aviv: The Tauber Family Funds and the Maguey-Glass Chair Support at Rice

32. Bobrie et al Traffic (2011)

33. Reduced model (to 3 components) Population dynamics Cancer BiologyPhysics/mathematic Cell-Cell Communication Network Associate with Stages of Cancer Cancer Tumorigenesis Theraputic Strategies Steady States / Stability Cancer-immunity Landscape Transition Rate Problem Treatment Simulations Our Generic Modeling Approach

34. Cancer Dendritic Cells Killer Cells D C K Generic Modeling of the Exosome-based Cancer-Immunity Interplay Generic Modeling of the Exosome-based Cancer-Immunity Interplay The CDK Model With Mingyang Lu, Bin Huang and Jose’ Onuchic, CTBP, and Sam Hanash, MD Anderson Exosomes

35. A Surprise Prediction The Existence of an Intermediate Cancer State It is hard to fight cancer Stable State Saddle point

36. The effect of immune recognition The meaning of steady-state solutions in light of tumorigenesis The Singular Effect of Exosomes The Effect of Time Delay Therapeutic implications Reassuring retrospect agreement The need for two stage therapy The risk of over treatment

37. The Effect of DC Recognition of Cancer 1

38. [ (1-  ] The effect of immune recognition  = 0.1  = 0.6  = 1.0

39. The Singular Effect of Exosomes The Absences of Intermediate State The Absences of Intermediate State k DK = 0.05 k DK = 0.15 Removing the exosome-based communication

40. 5 days15 days The Effect of Time Delay

41. Therapeutic Implications 30 days radiation 40% reduction Cancer cells Why?

43. Standish et al 2008 J Soc Integr Oncol. Immune Defects in Breast Cancer Patients after Radiotherapy Reassuring retrospect agreement Simulations No fitting! DC Days

44. Stage II Therapy: I2LT Inducing Intermediate to Low Cancer State Transitions Therapeutic Implications – The Need for Two Stage therapy Therapeutic Implications – The Need for Two Stage therapy Stage I Therapy: H2IT Inducing High to Intermediate Cancer State Transitions

45. Therapeutic Implications: H2IT More efficient protocols – Alternating Therapy 10 days Radiation, 10 days DC therapy, ….. Radiation DC Therapy Intermediate State

46. Surprise Prediction Risk of Extra Treatment

47. 4 days Radiation, 2 days DC therapy, ….. H2IT by Optimal Path Therapy

48. Stage II Therapy: I2LT Inducing Intermediate to Low Cancer State Transitions Radiation

49. Stage II Therapy: I2LT Inducing Intermediate to Low Cancer State Transitions Radiation DC Therapy

50. Stage II Therapy: I2LT Inducing Intermediate to Low Cancer State Transitions DC Therapy

51. The End New Hope Understanding the Role of Exosomes Rethinking the Interplay Between Cancer and the Immune System Rethinking the Interplay Between Cancer and the Immune System The Existence of Intermediate State Optimal Path Based Alternating Therapy Two stage Therapy