Eshel Ben-Jacob

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

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

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

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

7. A Crash Course in Immunology The human body: 1015 bacteria, 1014 cells, 1012 immune cells, 1011 neurons The Dual Function of the Immune System Innate Immunity, Adaptive Immunity and Immune Memory

8. The Complexity Innate Immunity: Natural Killer (NK) cells, Inflammation, Killer and Repair Macrophages 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 Helper T cells Innate-DC-Adaptive Dendritic Cell Naïve T cells

9. M1 (killer) Macrophage Dendritic Cell

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

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

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

14. Exosome-mediated immunity Inhibition Activation

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

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

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

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

23. Cancer Continues to Elude Us 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. Rethinking the Cancer-Immunity Interplay A battle between two networked societies of smart cells

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

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

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

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

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

31. Support at Rice Support at Rice 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 Tel Aviv: The Tauber Family Funds and the Maguey-Glass Chair

32. Bobrie et al Traffic (2011)

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

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

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

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 risk of over treatment The need for two stage therapy

37. 1 The Effect of DC Recognition of Cancer

38. [ (1- r) + r ] r = 1.0 The effect of immune recognition r = 0.1 r = 0.6

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

40. The Effect of Time Delay 5 days 15 days

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

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

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

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

46. Surprise Prediction Risk of Extra Treatment

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