James S. Welsh, MS, MD Northern Illinois University

1. James S. Welsh, MS, MD Northern Illinois University the AbscopalEffect, Contagious Cancers, Transplanted Cancers and Pregnancy: Clues to a genuine Cure for cancer?

2. Curious clues • Contagious cancers – should not occur • Transplanted cancers – should not thrive • Surrogate pregnancies – should not be possible • Gestational trophoblasticneoplasia – should not exist

3. Curious clues • Contagious cancers – should not occur • Transplanted cancers – should not thrive • Surrogate pregnancies – should not be possible • Gestational trophoblasticneoplasia – should not exist • And one more thing that should not happen…

4. A sad story • Young male in his 30’s with widespread metastatic melanoma • Metastases to lung, liver, lymph node and bone • Life expectancy ~4 months(?) • Severe pain in hip • Hypofractionated course of photon-based external beam radiotherapy

5. A sad story • Young male in his 30’s with widespread metastatic melanoma • Metastases to lung, liver, lymph node and bone • Life expectancy ~4 months(?) • Severe pain in hip • Hypofractionated course of photon-based external beam radiotherapy • Within 4 months ALL evidence of cancer was completely gone!

6. A man’s aggressive cancer mysteriously disappears as quickly as it arrived. Pick up the issue and enjoy the adventure”

7. “THE ABSCOPAL PHENOMENON: Anti-cancer action at a distance – Oncology’s equivalent to quantum entanglement”

8. “Disappearing Act”

9. The Abscopal Effect • So why is this sad????

10. The Abscopal Effect • So why is this sad???? • One of only two encounters with this… • Pursuit of the underlying mechanism and the ability to do it again at will has become an obsession…

11. So where does one begin the search???

12. So where does one begin the search???

19. Devil Facial Tumor Disease • First observed in 1996 • DFTD is a contagious cancer • Tumor cells directly transplanted from one animal to another • A xenograft • Typically causes death within 6-18 months • Species is threatened with extinction

20. Cytogenetic proofa. Normal karyotype (14 chromosomes, including XY)b, Karyotype of cancer cells

21. Devil Facial Tumor Disease • But if it’s a “transplanted organ” shouldn’t it be rejected???

22. Devil Facial Tumor Disease • But if it’s a “transplanted organ” shouldn’t it be rejected??? • Do I have to be extra careful in the clinic when doing procedures? • Are there any other examples of this in the animal kingdom?

25. Canine Transmissible Venereal Tumor(CTVT)“Sticker’s sarcoma”

26. Canine Transmissible Venereal Tumor • In immunologically compromised dogs • the tumor progresses, ulcerates, metastasizes and kills the dog • But in most dogs the tumors spontaneously regress after a period of logarithmic growth • Immunity develops and prevents successive occurrences

27. Molecular clock data suggest an ancient origin

28. How has CTVT survived for so long??? • CTVT has a unique trick to fool the immune system – but eventually the immune system gets wise and awakens • Clonally transmissible cancers in dogs and Tasmanian devilsE P Murchison. Oncogene. 2008 Dec;27 Suppl 2:S19-30

29. Immunological mechanisms of escape in canine transmissible venereal tumor • CTVT cells initially reduce their expression of MHC Class I molecules • reduces visibility to the host's immune system • MHC Class I downregulation allows it to escape adaptive immunity(T-cell–mediated immunity) • (which would occur if MHC I were fully expressed) • This trick also allows escape from innate immunity (natural killer cells) • (which would eradicate any cells completely devoid of MHC I)

30. Immunological mechanisms of escape in devil facial tumor disease • Some have proposed that the primary reason DFTD exists is because of the lack of genetic diversity in the population • All Tasmanian devils are closely related and so organ transplants would not be readily rejected

31. Immunological mechanisms of escape in devil facial tumor disease • Some have proposed that the primary reason DFTD exists is because of the lack of genetic diversity in the population • All Tasmanian devils are closely related and so organ transplants would not be readily rejected • Well, I REJECT THIS HYPOTHESIS!

32. Immunological mechanisms of escape in devil facial tumor disease • Some have proposed that the primary reason DFTD exists is because of the lack of genetic diversity in the population • All Tasmanian devils are closely related and so organ transplants would not be readily rejected • Well, I REJECT THIS HYPOTHESIS! • These tumors are grossly, histologically, cytogenetically and molecularly VERY different from any living Tasmanian devil… • There is something else going on

33. The future of DFTD and the Tasmanian devil??? • Will the devil (and the disease) go extinct? • Will natural selection (in the cancer) create a less virulent tumor that doesn’t kill all its hosts??? • This may be what happened with the dog tumor • Will natural selection (in the Tasmanian devil) create a kinder, gentler devil • The “Tasmanian Angel”?

34. The Tasmanian Angel

35. Similarities and Differences: A biologist’s perspective • Both are rare (extremely rare) examples of a contagious cancer • Both can be thought of as transplanted parasites • DFTD emergedrecentlyand is highly virulent • CTVT probably arose thousands of years agobut typically does NOT kill its host • One is lethal, the other has evolved to survive with its host

36. Similarities and Differences: A physician’s perspective

37. Similarities and Differences: A physician’s perspective • One is relentlessly progressive and uniformly fatal • The other spontaneously regresses • Thus one behaves like most human cancers while the other behaves like what we wish human cancers would do… • How can we force human cancers to behave like dogs rather than devils??? • Devil  dog transition

38. Another line of reasoning… • Suppose an organ or tissue is intentionally or accidentally transferred to another person? • What usually happens in Man?

39. Organ transplants • Organ transplantation requires a high degree of genetic similarities (“a match”) • Even with a good match, chronic immunosupression is required • Without immunosupression poor matches (and even good ones) are vigorously rejected • So what about cancer?

40. What about an accidentally transplanted cancer? • Man Gets Woman's Cancer from Kidney Transplant - CBS News(May 2010) • “... The scenario was unique…. A man had gotten a transplanted kidney from a woman who had uterine cancer and didn't know it…” • He died of cancer only seven months after receiving the transplant

41. How can this happen??!?! • One might expect cancer to be rejected • Does the necessary immunosupressionimpede the rejection process? • “Contaminated” vital organ transplants (heart , lungand liver) are almost always rapidly fatal • What about non-vital organs???

42. Renal transplants • Kidneys are not completely indispensible • Immunosupression could be halted • Kidney (and cancer) should be rejected • Kidney can be removed • Patient could be put on dialysis and given another kidney • This is what often happens

43. Renal transplants • Kidneys are not completely indispensible • Immunosupression could be halted • Kidney (and cancer) should be rejected • Kidney can be removed • Patient could be put on dialysis and given another kidney • This is what often happens • But not always….

44. Example of kidney being rejected while the cancerous cargo is left unmolested!!! Strauss and Thomas. Lancet Oncol 2010; 11: 790–96

45. Melanoma has been transferred through organ donation up to 32 yrsafter treatment! • Suggests that cancer can remain dormant for decades (maybe forever?) • But can be reactivated upon transplantation into a recipient 1.) The immune system must be keeping these cancer cells in check in the donor 2.) The recipient’s immunosuppression is NOT the only reason why the cancer can redevelop 3.) The fact that a transplanted cancer can thrive unmolested in the recipient suggests it has some form of “invisibility” to the immune system

46. Is there another example where something is completely untouched by the immune system?

47. Is there another example where something is completely untouched by the immune system? • Yes of course • For survival of the species…

48. Is there another example where something is completely untouched by the immune system? • Yes of course • For survival of the species… • Pregnancy is normally given complete sanctuary from the immune system

49. How profound is the suppression of the immune response in pregnancy? • Extreme! • First, mother and embryo/fetus are only half-related (semiallogeneic)

50. How profound is the suppression of the immune response in pregnancy? • Extreme! • First, mother and embryo/fetus are only half-related (semiallogeneic) • Second, surrogate mothers who are not related at all are possible - no genetic relationship at all to embryo