Immunity to tumors

1. Immunity to tumors • Tumor antigens • Immune system’s reaction to tumor antigens • How tumors evadethe immune system • Immunologic approaches to treatment of cancer

2. Cancers arise from theuncontrolledproliferation and spreadofclonesofmalignantlytransformedcells. Cancer is a major causeofdisease and death. About 1 of 5 deaths in industrialisedcountries is from cancer.

3. The immune surveillancehypothesis Frank MacfarlaneBurnet 1956: The immune system constantlychecksourcells, and detects and destroysthosethataremalignantlytransformed.

4. Contra: Most tumors are not more common in immunodeficientindividuals. Exception: Virus-induced tumors.

5. Four reasons immune surveillancemay not work so well:

6. Tumors are «self», not «foreign». Theydon’t have PAMPs, like pathogens do. 2) Most tumor cellslack HLA class II and costimulatorymolecules.

7. 3) Tumors that do not cause inflammationmayinduce DC- mediatedtolerance. 4) Naive T cellscirculate in blood, lymph and secondarylymphoid organs, and do not usuallyenter peripheraltissues.

8. Signof immune reaction to tumor: Lymphocyticinflammation.

9. Demonstrationof tumor immunity

10. Tumor antigens: • Tumor-specific • Unique to individual tumors • Sharedamong tumors • Tumor-associated • Viral antigens

11. Cloned CTL lines identify tumor antigens from melanoma.

12. Some tumor antigens:

13. Mutated forms of cellular genes not involved in tumorigenesis: Various mutated proteins in melanomas recognized by CTLs

14. Products of oncogenes and tumor suppressor genes: Oncogene products: Ras mutations (∼10% of human carcinomas), p210 tyrosine kinase product of Bcr/Ablchromosomal rearrangements (CML). Tumor suppressor gene products: Mutated p53 (present in ∼50% of human tumors).

15. Unmutated but overexpressed products of oncogenes: HER2/Neu(tyrosine kinase; breast and other carcinomas)

16. Products of genes that are silent in most normal tissues: Cancer/testis antigens expressed in melanomas and many carcinomas; normally expressed mainly in the testis and placenta

17. Normal proteins overexpressed in tumor cells: Tyrosinase, gp100, MART in melanomas (normally expressed in melanocytes)

18. Oncofetalantigens: Silenced during development, de-repressedwithmalignanttransformation. Diagnostictools. Carcinoembryonicantigen (CD66) on many tumors, also expressed in liver and other tissues during inflammation. α-Fetoprotein(alsoelevated in some non-neoplasticdiseases).

19. Glycolipids and glycoproteins: • Gangliosides • Mucins

20. Tissue-specific differentiation antigens: Prostate-specific antigen in prostate carcinomasCD20 on B cell lymphomas

21. Products ofoncogenicviruses: Papillomavirus E6 and E7 proteins (cervical carcinomas) HPV vaccination EBNA-1 protein ofEpstein-Barr Virus (EBV-associatedlymphomas, nasopharyngealcarcinoma)

22. Immune responses to tumors • Innate immunity • NK cells, macrophages • Adaptive immunity • T lymphocytes, antibodies

23. NK cells Kill manycells in vitro, especiallycellswithlowexpressionof MHC class I. ADCC In vivo importanceunclear. LAK cells

24. Macrophages M1 Mφ: Can kill tumor cells M2 Mφ: Canpromote tumor growth

25. The principalmechanismof adaptive tumor immunity is killing of tumor cells by CD8+CTLs.

26. Inductionof CTL responses to tumors by dendriticcell cross-presentation.

27. Antibodies Little evidence for in vivo killing of tumors by host antibodies.

28. Evasionof immune responses by tumors. Tumor editing – tumors become less immunogenic over time.

29. Intrinsicmechanismsofevasion • Loss of antigen expression • Lackofcostimulators or HLA class II • Inhibitoryfactors

30. Mechanisms by which tumors escape immune defenses

31. Extrinsicfactors • Macrophageswith M2 phenotype • Regulatory T cells • Myeloid-derivedsuppressorcells

32. Immunotherapy for tumors: • More specific and fewer side effectsthancurrenttherapies. • Stimulationofactive host immune responses or • Passive immunotherapy

33. Stimulationofactive host immune responses • Vaccinationwith tumor antigens • Useofcostimulators and cytokines • Blockinginhibitorypathways • Nonspecificstimulation

34. Tumor vaccines Type of Vaccine Vaccine Preparation Killed tumor vaccine Killed tumor cells + adjuvants Tumor cell lysates + adjuvants Purified tumor antigens Dendritic cell-based Dendritic cells pulsed with vaccines tumor antigens Dendritic cells transfected with genes encoding tumor antigens

35. Dendriticcell-based tumor vaccines

36. Enhancement of tumor cellimmunogenicity by transfectionofcostimulator and cytokine genes

37. Counteracting T-cellinhibition.

38. N Eng J Med July 11 2013 Nivolumab: Anti PD1 receptor Ipilimumab: Anti CTLA-4 (PD1 and CTLA-4 dampen T cellactivity.)

40. Non-specificstimulation by systemiccytokinetherapy (a limitedsuccess). IL-2 (Melanoma, renal & colon cancer) IFN-α (Melanoma, carcinoid tumor) TNF (Sarcoma, melanoma) GM-CSF (to promote bone marrow recovery)

41. Passive immunotherapy • Adoptive cellular therapy • Anti-tumor antibodies

42. Adoptive cellular therapy LAK cells

43. Anti-tumor antibodies. Mouse Ig is immunogenic for humans. «Humanization» ofmouseIg.

44. -monab -ximab -zumab -mumab

45. Mabs used in cancer treatment in Norway: Alemtuzumab CD52 Chroniclymphaticleukemia Bevacizumab VEGF Several cancer forms Cetuximab, Panitumumab EGFR EGFR+ colorectal cancer

46. Rituximab, CD20 Non-Hodgkinlymphoma, chroniclymphaticleukemia Ofatumumab CD20 Chroniclymphaticleukemia Trastuzumab Her2 Her2+ mamma cancer

47. Pertuzumab Her2R Her2+ mamma cancer Ipilimumab CTLA-4 Malignantmelanoma

48. Catumaksomab EpCAM + CD3 Malign ascites(ascites is abnormalaccumulationof fluid in theabdominal cavity).

49. Promotionof tumor growthby the immune system: • Chronicinflammation • Hepatitis B • Mutationscaused by freeradicals • Growth factors • M2 macrophages (VEGF, TGF-β)