بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. •Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy

3. •Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy

5. •Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy

6. Oncogenic Transformation of Normal Cells The transformation of normal cells into malignant cells: Spontaneously arising transformants resulting from random mutations or gene rearrangements during the normal processes of cell growth. The action of carcinogens, which may be chemical, physical or viral in nature. Chemical Carcinogens Physical Carcinogens Viral Oncogenes Cellular Oncogenes

11. •Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy

12. Oncogenes in Tumor Development

13. Cancer-associated Genes

14. Cancer-associated Genes

15. Cancer-associated Genes

16. Cancer-associated Genes

17. Cancer-associated Genes

18. Cancer-associated Genes

19. Process of Oncogenic Transformation Model of sequential genetic alterations leading to metastatic colon cancer. Each of the stages indicated is morphologically distinct, allowing for the determination of the sequence of genetic alterations.

20. Immunotherapy

21. •Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy

22. Tumor Antigens New Antigens : Tumor Specific Antigens (TSAs) Autologous Tissue Antigens: Tumor Associated Antigens (TAAs)

23. Tumor Specific Antigens (TSAs) 1) Mutated Proteins oncogenic abnormal function: p53, p21Ras, β-catenin, CDK-4 translocation: BCR-Abl (CML) secondary to genomic instability 2) Viral Proteins oncogenic EBV: EBNA1, LMP1, LMP2 (Hodgkin’s disease, nasopharyngeal cancer) HPV: E6, E7 (cervical cancer)

24. Tumor Specific Antigens (TSAs) 1) Mutated Proteins oncogenic abnormal function: p53, p21Ras, β-catenin, CDK-4 translocation: BCR-Abl (CML) secondary to genomic instability 2) Viral Proteins oncogenic EBV: EBNA1, LMP1, LMP2 (Hodgkin’s disease, nasopharyngeal cancer) HPV: E6, E7 (cervical cancer)

25. Tumor Associated Antigens (TAAs) 1) Cancer-testes (germ cell antigens) • expressed only in germ cells and tumors • unknown function • MAGE family: MAGE1, MAGE3, NY-ESO (melanoma, breast, glioma) 2) Differentiation Antigens • overexpressed in tumor, but also found in tissue of origin • melanosomal proteins: tyrosinase, gp100, Mart 1 (melanoma) • rearranged Ig and TCR genes (B and T cell lymphoma) 3) OverexpressedOncogenic Proteins • may reflect critical step in oncogenesis • WT1 -- regulates transcription/ MDM-2 -- blocks p53 function • survivin -- inhibits apoptosis/ • HER2/neu -- growth factor receptor • Telomerase-- prevents senescence

26. Tumor Associated Antigens (TAAs) 1) Cancer-testes (germ cell antigens) • expressed only in germ cells and tumors • unknown function • MAGE family: MAGE1, MAGE3, NY-ESO (melanoma, breast, glioma) 2) Differentiation Antigens • overexpressed in tumor, but also found in tissue of origin • melanosomal proteins: tyrosinase, gp100, Mart 1 (melanoma) • rearranged Ig and TCR genes (B and T cell lymphoma) 3) OverexpressedOncogenic Proteins • may reflect critical step in oncogenesis • WT1 -- regulates transcription/ MDM-2 -- blocks p53 function • survivin -- inhibits apoptosis/ • HER2/neu -- growth factor receptor • Telomerase-- prevents senescence

27. Tumor Associated Antigens (TAAs) 1) Cancer-testes (germ cell antigens) • expressed only in germ cells and tumors • unknown function • MAGE family: MAGE1, MAGE3, NY-ESO (melanoma, breast, glioma) 2) Differentiation Antigens • overexpressed in tumor, but also found in tissue of origin • melanosomal proteins: tyrosinase, gp100, Mart 1 (melanoma) • rearranged Ig and TCR genes (B and T cell lymphoma) 3) OverexpressedOncogenicProteins • may reflect critical step in oncogenesis • WT1 -- regulates transcription/ MDM-2 -- blocks p53 function • survivin -- inhibits apoptosis/ • HER2/neu -- growth factor receptor • Telomerase-- prevents senescence

28. Mechanisms for Generating Tumor-specific Transplantation Antigens (TSTA) and Tumor-associated Transplantation Antigens (TATA)

29. Utilization of Antigens 􀂄 Techniques for defining tumor antigens 􀂄 Antigens purified from cancer cells and identified by physicochemical techniques 􀂄 Tumor-specific T-cell clones tested against antigen negative cells that express the antigen via transfection by plasmids 􀂄 Synthetic peptides constructed to precisely identify antigenic site or epitope 􀂄 Immunodiagnosis 􀂄 TATA as useful tumor markers 􀂄 Released only from tumor tissue 􀂄 Specific for a given tumor type 􀂄 Detectable at low levels of tumor burden 􀂄 Has direct relationship to the tumor cell burden 􀂄 Present in all patients with tumor 􀂄 Tumors release antigen macromolecules that can be detected in vivo and in vitro

30. Immunodiagnosis 􀂄 Examples of TATA used for markers 􀂄 Alpha-Fetoprotein 􀂄 Beta-subunit of human chorionic gonadotropin (B-HCG) 􀂄 Prostate-specific antigen (PSA) 􀂄 CA 125 􀂄 Radio-labeled monoclonal antibody B72.3 􀂄 Carcinoembryonic Antigen (CEA) 􀂄 Protein-polysaccharide complex in colon carcinomas 􀂄 Immunoassay can detect increased levels in blood 􀂄 Specificity is low in certain cases, such as heavy cigarette smokers and other cancers

31. Diagnostics • Ideal Tumor Marker 1. Specific for tumor type. 2. Released only in response to tumor. 3. Results proportional to tumor mass. 4. Quantitatively reflects tumor response. 5. Elevated with low tumor burden.

32. Prognostic roles of tumor markers

45. •Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy

46. Host Immune Response to Tumor Circumstantial and Experimental Evidence of a Host Immune Response to Tumor Circumstantial Spontaneous regression Regression of tumor after sub-lethal doses of chemotherapy Regression of metastasis after resection of primary tumor Mononuclear cell infiltration of tumor High incidence of tumor after clinical immunosuppression High incidence of tumor in immunodeficiency diseases Increased incidence of tumors in aging Experimental Colony inhibition of tumors by sensitized lymphocytes Lymphocyte blast transformation in presence of tumor extracts Lymphocyte-enhanced cytotoxicity in patients with tumor Macrophage-enhanced phagocytosis in patients with tumor

47. Tumor Immunology • Cancer immunosurveilance: immune system can recognize and destroy nascent transformed cells • Cancer immunoediting: immune system kill and also induce changes in the tumor resulting in tumor escape and recurrence (epigenetic changes or Darwinian selection)