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

2. Cancers arise from the uncontrolled proliferation and spread of clones of malignantly transformed cells.
Cancer is a major cause of disease and death. About 1 of 5 deaths in industrialised countries is from cancer.

3. The immune surveillance hypothesis
Frank Macfarlane Burnet 1956:
The immune system constantly checks our cells, and detects and destroys those that are malignantly transformed.

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

5. Four reasons immune surveillance may not work so well:

6. Tumors are «self», not «foreign»
Tumors are «self», not «foreign». They don’t have PAMPs, like pathogens do.
2) Most tumor cells lack HLA class II
and costimulatory molecules.

7. 3) Tumors that do not cause
inflammation may induce DC-
mediated tolerance.
4) Naive T cells circulate in blood,
lymph and secondary lymphoid
organs, and do not usually enter
peripheral tissues.

8. Sign of immune reaction to tumor: Lymphocytic inflammation.

9. Demonstration of tumor immunity

10. Tumor antigens: Tumor-specific Unique to individual tumors
Shared among 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/Abl chromosomal 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. Oncofetal antigens:
Silenced during development, de-repressed with malignant transformation.
Diagnostic tools.
Carcinoembryonic antigen (CD66) on many tumors, also expressed in liver and other tissues during inflammation.
α-Fetoprotein (also elevated in some non-neoplastic diseases).

19. Glycolipids and glycoproteins:
Gangliosides
Mucins

20. Tissue-specific differentiation antigens:
Prostate-specific antigen in prostate carcinomas CD20 on B cell lymphomas

21. Products of oncogenic viruses:
Papillomavirus E6 and E7 proteins (cervical carcinomas)
HPV vaccination
EBNA-1 protein of Epstein-Barr Virus (EBV-associated lymphomas, nasopharyngeal carcinoma)

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

23. NK cells
Kill many cells in vitro, especially cells with low expression of MHC class I.
ADCC
In vivo importance unclear.
LAK cells

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

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

26. Induction of CTL responses to tumors by dendritic cell cross-presentation.

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

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

29. Intrinsic mechanisms of evasion
Loss of antigen expression
Lack of costimulators or HLA class II
Inhibitory factors

30. Mechanisms by which tumors escape immune defenses

31. Extrinsic factors
Macrophages with M2 phenotype
Regulatory T cells
Myeloid-derived suppressor cells

32. Immunotherapy for tumors:
More specific and fewer side effects than current therapies.
Stimulation of active host immune responses or
Passive immunotherapy

33. Stimulation of active host immune responses
Vaccination with tumor antigens
Use of costimulators and cytokines
Blocking inhibitory pathways
Nonspecific stimulation

34. Type of Vaccine Vaccine Preparation
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. Dendritic cell-based tumor vaccines

36. Enhancement of tumor cell immunogenicity by transfection of costimulator and cytokine genes

37. Counteracting T-cell inhibition.

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

40. Non-specific stimulation by systemic cytokine therapy (a limited success).
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» of mouse Ig.

44. -monab -ximab -zumab -mumab

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

46. Rituximab,
CD20
Non-Hodgkin lymphoma, chronic lymphatic leukemia
Ofatumumab
Chronic lymphatic leukemia
Trastuzumab
Her2
Her2+ mamma cancer

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

48. Catumaksomab
EpCAM + CD3
Malign ascites (ascites is abnormal accumulation of fluid in the abdominal cavity).

49. Promotion of tumor growth by the immune system:
Chronic inflammation
Hepatitis B
Mutations caused by free radicals
Growth factors
M2 macrophages (VEGF, TGF-β)