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CANCER AND IMMUNITY - THE NEXT FRONTIER IN CANCER TREATMENT

CANCER AND IMMUNITY - THE NEXT FRONTIER IN CANCER TREATMENT. Zheng Cui, MD/PhD Section of Tumor Biology Department of Pathology Wake Forest University School of Medicine Winston-Salem, NC, USA Telephone: 336-716-6185 Email: zhengcui@wfubmc.edu. Acknowledgement

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CANCER AND IMMUNITY - THE NEXT FRONTIER IN CANCER TREATMENT

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  1. CANCER AND IMMUNITY - THE NEXT FRONTIER IN CANCER TREATMENT Zheng Cui, MD/PhD Section of Tumor Biology Department of Pathology Wake Forest University School of Medicine Winston-Salem, NC, USA Telephone: 336-716-6185 Email: zhengcui@wfubmc.edu

  2. Acknowledgement This presentation is made possible by: Gailyn Waldron and Threshold, Inc. Barbara Shook and the Barbara Ingalls Shook Foundation

  3. Current cancer therapies: Chemo Kill growing cells systemically Surgeries Remove cancer at early stage Immunotherapies Repair a weak/bad immune system Radiation Kill live cells locally Targeted therapies: Herceptin, Gleevec

  4. Cancer Stats: Worldwide ~6,000,000,000 ~6,000,000 ~100/100K The US 300,000,000 600,000 ~200/100K US/W 1/20 1/10 2-fold Population: Yearly cancer death: Cancer mortality rate: (age-adjusted) 600 Mortality rate (per 100k population) CDC data Heart disease 400 200 The outlook of cancer treatment is not so good! Cancer Death Rate 1950 2004 >1600 cancer deaths a day in the US!

  5. May 8th, 2006

  6. May 8th, 2006 The second most blogged news story in May, 2006

  7. The most blogged news story in May: Britney Spears!

  8. Since then, she continues to make news….

  9. Lung cancer rate 0.08% 8% Smoking General population Smokers Why don’t most smokers have lung cancer in the face of intense carcinogen exposure?

  10. Cause of cancer: cell damage and aging Cell Damage Host protection DNA repair Clearance of cancer cells Cell Damage Host protection Younger and healthier Older

  11. Pathways to cancer treatment Pathway #1: why do we get cancer Modeling cancer in animals Understanding Cancer mechanisms Finding Molecular targets Testing Targets Developing human therapy Pathway #2: why don’t we get cancer Finding Cancer- Resistant Humans Developing human therapy

  12. Modeling Cancers in mice Aggressiveness Transplantable mouse cancer cell lines Too aggressive, too lethal, too rapid S180, EL4, L5178, L1210, J774, LL2, MethA etc. Carcinogen-induced cancers Takes months if not year Genetically engineered tumors Takes months if not year and often not malignant Cancer type Transplantable xenograft-human tumor cell lines Often not showing malignant properties • Spontaneous tumors at old age: • 81% of laboratory mice have cancers at their natural death • but often not aggressive Survival time

  13. CR Serendipitous discovery of a cancer-resistant mouse No exception 40 WT WT WT WT WT 30 20 Body Weight in Grams WT 10 0 1 9 17 25 33 41 49 57 Days After S180 Injections CR=cancer-resistant WT=cancer-sensitive CR Completely unexpected

  14. Survival after cancer challenge is based on inheritance: it is all in the DNA SR WT 24 40 37% M 9 18 F 15 22

  15. From a single mouse to a great legacy! Finally, they are available free to research community!

  16. Cancer cells are specifically killed by white cells that formed “rosettes”

  17. Cancer cell killing is dependent on cell-cell contact.

  18. Natural killer cells form rosettes and aggregates with tumor cells

  19. The surface of cancer cell is damaged before dying

  20. An overview of two arms of immune system Presence of pathogens Innate immunity: Natural Killer cells (NK) Macrophages (MΦ) Neutrophils (PMN) Complements (Within hours) Adaptive Immunity: B cells (antibodies) T cells (CTL) Dendritic cells (DC) Macrophages (Weeks)

  21. White cells are tracking down cancer cells Cell aggregation

  22. Cancer cells are ruptured by white cells Mixed pop-rosettes

  23. Cancer cells are ruptured by white cells Mixed pop

  24. A much larger cancer cell killed by a small white cell (neutrophil) Pmn-apop

  25. 200 WT-AT SR/CR, n=14 SR/CR-AT 180 WT, n=8 2500 160 AT 140 2000 120 1500 Tumor Volume relative to Controls (%) AT 100 Tumor Volume (mm3) 80 1000 60 500 40 20 0 0 1 3 5 7 9 11 13 15 17 0 2 4 6 8 10 12 14 16 18 20 Days after adoptive transfer of leukocytes Days After Cancer Establishment 100 80 AT (day 4) WT-AT, n=5 SR-AT, n=7 60 Survival (%) 40 20 0 0 4 8 12 16 20 24 28 32 36 40 44 Days Post-Tumor Injection Cure established cancers in WT mice by systemic WBC therapy Still alive after 18 months 1-day 8-day 12-day 18-day 23-day SR AT

  26. Cure of mouse prostate cancer by white cell infusion White cell infusion Cancer cell challenges n=7 100 SR/CR AT Dr. Yong Chen Cancer Biology WFUSM 80 60 Survival % No AT 40 n=10 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Age (Months)

  27. It is a permanent, complete cure of cancer! WT PTEN-KO PTEN-KO + SR Normal Cancer Scars

  28. The innate immunity of cancer-resistant mice can cure cancer Genetically defined No need for further manipulation Involves the innate immunity that has been mostly ignored Highly effective: survival of million times more lethal doses No side effect Kill different cancers Transferable to treat established cancers in ordinary mice

  29. Cancer-resistance and humans Why do we have natural protection against cancers: Humans and other large, long-living animals must have exceptional natural resistance and immunity against malignancy in order to survive beyond reproductive ages Why don’t normal mice have meaningful resistance or immunity against malignancy?

  30. Mice in the wild have a tough life and don’t live long enough to get cancer. Therefore, there was no natural selection for resistance against cancers.

  31. If humans do have cancer-resistance, can we measure it? Can we inject cancer cells into humans to find out? Probably not!?

  32. Cancer Cells White blood cells Incubation % killed 70 30 40 / 70 = 57.3% Killed

  33. Manual test of cancer cell killing activity: How well the white cells can kill cancer cells in test tubes Cancer cells with white cells (Ratio at 50:1) (some survival) Control: cancer cells without white cells (100% survival)

  34. 1 1 3 3 2 2 Automated real-time recording of cancer cells killed by WBC Hela + non-killing control cells: 1:20 Hela control Hela + WBC: 1:20 21 42 63 84 105 Time in h Time point of manual assays Plating target cells =0% kill =30% kill Addition of effector cells =50% kill

  35. Identifying cancer-resistant mice without a cancer cell challenge Killing in Test tubes Litter mates Resistant/Survival after challenge - 1 + 2 - 3 + 4 - 5 - 6 + 7

  36. Test-tube cancer resistance results using cancer-resistant and non-resistant mice 100.0 87.5 75.0 62.5 In vitro cancer kill activity (target cells killed %) 50.0 37.5 25.0 12.5 0 WT Mice SR mice

  37. Mouse cancer-resistance by age 100.0 S180 cells 87.5 75.0 62.5 In vitro cancer kill activity (S180 cells killed %) 50.0 37.5 25.0 12.5 0 WT Mice Young SR mice Old SR mice Old SR mice cancer cells

  38. SR mice Humans <50y Humans >50y Humans >50y, Ca Human cancer-resistance by age 100.0 87.5 Hela cells 75.0 62.5 In vitro cancer kill activity (target cells killed %) 50.0 37.5 25.0 12.5 0 WT Mice

  39. Automated recording of cancer cell kill White cells that don’t kill cancer cells White cells that kill cancer cells

  40. Rosette formation leading to cancer cell kill Mouse S180 cells SR mouse WBC Hela cells Human WBC Cancer patient No rosettes

  41. Surveillance by human white cells

  42. Cancer cell killed by a smart bomb (white cell)

  43. Stability of cancer-killing activity in human WBC Recovery in 3 days 100 80 60 % of cancer cells killed 40 20 0 2 4 6 8 10 12 14 16 Time span in weeks Stress

  44. Stability of cancer-killing activity in human WBC Recovery in 3 months 100 80 60 % of cancer cells killed 40 20 0 2 4 6 8 10 12 14 16 Time span in weeks Stress

  45. Seasonality of CKA activity? 100 80 60 Higher mortality rate in elderly Influenza season Lower immune responses Severe mood swing (SAD) % of cancer cells killed 40 20 0 Aug Sep Oct Nov Dec Jan Feb Mar Northern Hemisphere: Shorter daylight Lower intensity of sunlight radiation Lower temperature Vitamin D deficiency

  46. Chester Southam: Injecting human subjects (Inmates and ca patients) with live cancer cells Healthy humans were resistant to cancer cells. Cancer patients lost cancer resistance while retained antimicrobeial resistance. Ethical and legal problems Elected to the president of AACR in 1968 Science 25 January 1957 125: 158-160

  47. Possible effects of aging and stress on CKA of human WBC 75% 25%

  48. Anticancer protection can be lost due to: • Genetics • Aging • Stress • Seasonal changes • Too many cancer cells (increased carcinogenesis) • Too few immune cells (immune suppression)

  49. A new cancer treatment concept: To replace a weak/bad immune system with a validated, functional one rather than to repair it

  50. Healthy volunteers CKA screening White cells

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