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Cancer Immunotherapy Oncogene-targeted Chemotherapies Angiogenisis inhibitors The Ultimate Cancer Therapy 5/24/2017 New Cancer Treatments 2 Most contemporary anticancer agents have two defects: 1) Poor selectivity toward cancer cells versus normal cells. 5/24/2017 2) Poor efficacy against slowgrowing tumors. New Cancer Treatments 3 Anti-cancer drugs discovered this way work by inhibiting cell replication (e.g.DNA polymerase, ribonucleotide reductase, DHFR etc). 5/24/2017 These drugs discriminate poorly between cancer and normal cells and thus have significant adverse side effects. New Cancer Treatments 4 Strategies for Developing New Anticancer Drugs 1) Identify the molecular "targets" that distinguish cancer cells from normal cells. 2) Identify compounds that interact selectively with these molecular "targets”. 5/24/2017 New Cancer Treatments 5 Principles of Cancer Therapy Total Cell Kill Minimize toxicity to normal cells Advanced cancers are heterogeneous. 5/24/2017 New Cancer Treatments 6 Experimental cancer immunotherapy is exploring a variety of approaches. Some of these are: • The enhancement of the costimulatory signal required for Tcell activation. • Genetically engineering tumor cells to secrete cytokines that may increase the intensity of the immune response against them. • The therapeutic use of cytokines, and • Increasing the activity of antigen5/24/2017 New Cancer Treatments 7 presenting cells. Tumor Antigens • Tumor cells display tumor-specific antigens and the more common tumor-associated antigens . Among the latter are oncofetal antigens and increased levels of normal oncogene products. • In contrast to tumor antigens induced by chemicals or radiation, virally encoded tumor antigens are shared by all tumors induced by the same virus. 5/24/2017 New Cancer Treatments 8 Tumor antigens recognized by T cells fall into one of four major categories: antigens encoded by genes with tumor-specific expression; antigens encoded by variant forms of normal genes that have been altered by mutation; certain antigens normally expressed only at certain stages of differentiation or differentiation lineages; antigens that are over-expressed in particular tumors. 5/24/2017 New Cancer Treatments 9 • The use of a variety of genetic, biochemical, and immunological approaches has allowed the identification of several tumorassociated antigens. In many cases the antigen is expressed on more than one type of tumor. • Common tumor antigens offer hope for the design of better therapies, detection, and monitoring, and have important implications for the possibility of anti-tumor immunization. 5/24/2017 New Cancer Treatments 10 Tumor Antigens 5/24/2017 New Cancer Treatments 11 Immune Response to Tumors • The immune response to tumors includes CTL-mediated lysis, NKcell activity, macrophagemediated tumor destruction, and destruction mediated by ADCC. • Several cytotoxic factors, including TNFa and TNFb , help to mediate tumor-cell killing. 5/24/2017 New Cancer Treatments 12 Tumors may evade the immune response by modulating their tumor antigens, by reducing their expression of class I MHC molecules, and by antibodymediated or immune complexmediated inhibition of CTL activity. 5/24/2017 New Cancer Treatments 13 Tumor Evasion of the Immune System 5/24/2017 New Cancer Treatments 14 5/24/2017 New Cancer Treatments 15 Cancer Immunotherapy 5/24/2017 New Cancer Treatments 16 Cancer Immunotherapy • A number of encouraging clinical results have been obtained with therapy using monoclonal antibodies against tumor-associated and (in a few cases) tumor-specific antigens. Coupling of antibodies against tumor antigens with toxins , chemotherapeutic agents, or radioactive elements is being examined. • The expectation is that such strategies will focus the toxic effects of these agents on the tumor and spare normal cells their deleterious effects. 5/24/2017 New Cancer Treatments 17 New approaches are being developed for antigen-specific immunotherapy of human cancers. Some are based on novel technology that employs cellsized (5 micron diameter) microspheres coated with cell surface antigens to present tumor antigen to CD8+ cells for generation of tumor-specific cytotoxic T lymphocytes (CTL). 5/24/2017 New Cancer Treatments 18 Cancer Immunotherapy 5/24/2017 New Cancer Treatments 19 Cancer Immunotherapy • Key elements in the design of strategies for vaccination against cancer are the identification of significant tumor antigens by genetic or biochemical approaches; the development of strategies for the effective presentation of tumor antigens; and the generation of activated populations of helper or cytotoxic T cells. • In the case of the few human cancers known to be caused by clearly identified tumor viruses, vaccination against those viruses or their subunits may be effective. 5/24/2017 New Cancer Treatments 20 The discovery of cellular growth factors which can directly suppress the malignant phenotype or which can harness the immune system to preferentially attack cancerous cells raises the prospect of developing other immune intervention therapies. 5/24/2017 New Cancer Treatments 21 interleukins Interleukins activate the body's own lymphocytes to do their work. IL-2 has been found to be effective in some patients with melanoma or with renal cancer when it is administered alone or with a patient's own lymphocytes that have been treated with Il-2 outside the body. 5/24/2017 New Cancer Treatments 22 interferons 5/24/2017 Interferons act on the immune system by stimulating both T cells and macrophages. They also prevent cells from multiplying. Scientists believe that these two properties together enable interferon to fight some tumors effectively. Alpha interferon was the first FDAapproved biological response modifier for the treatment of cancer (it is effective against a rare form of leukemia). New Cancer Treatments 23 INFLAMMATORY MOLECULES, which include tumor necrosis factor (TNF) and other messenger molecules of the immune system as well as certain microbial products, can bring about an inflammatory reaction that destroys tissues at the tumor site. 5/24/2017 New Cancer Treatments 24 Tumor necrosis factor Tumor necrosis factor directly attacks and kills tumor cells. Currently, it is being tested alone and in conjunction with gamma interferon to determine its potential efficacy in the treatment of human cancers. B-cell growth factors stimulate the multiplication of antibodyproducing cells. The hematopoietic growth factors step up the production of both red and white blood cells in the bone marrow, thereby giving the body additional ammunition to fight disease and protect itself against the suppressive effects on the bone marrow of radiation and chemotherapy. 5/24/2017 New Cancer Treatments 25 Cancer vaccines are intended to induce T cells or other components of the immune system to recognize and vigorously attack malignant tissue. 5/24/2017 New Cancer Treatments 26 Growth Factors and Cancer Epidermal Growth Factor (EGF) Platelet-derived Growth Factor (PDGF) Fibroblast Growth Factor (FGF) Transforming Growth Factors Insulin-like Growth Factors (IGF1 and IGF2) Nerve Growth Factors Interleukins - Colony Stimulating Factors (CSF1, CSF2, Multi-CSF) 5/24/2017 New Cancer Treatments 27 Chemotherapy: the use of chemical reagents in disease processes that have toxic effects on microorganisms. Antineoplastic/anticancer agents-interfere with cell functions and kill or destroy malignant cells. 5/24/2017 New Cancer Treatments 28 Drugs in Clinical Trial Lovastatin is widely used for the treatment of high serum cholesterol. When used at high doses, the drug inhibits signal transduction leading to growth arrest of high-grade glioma cells. 5/24/2017 New Cancer Treatments 29 LIGHT-ACTIVATED MOLECULES Drugs that block activators of angiogenesis 5/24/2017 New Cancer Treatments 30 5/24/2017 Solid tumors (and even some blood cancers) can't grow beyond barely visible size until they get new blood vessels through the process of angiogenesis. In fact, many tumors remain at that relatively innocuous stage for years, and only become dangerous if and when they acquire blood circulation. New Cancer Treatments 31 5/24/2017 The European Union's commission of the European communities has granted marketing authorisation to Schering-Plough Corp.'s Temodal(R) (temozolomide) Capsules for the treatment ofpatients with glioblastoma showing progression or recurrence after standard therapy. New Cancer Treatments 32 ultrasound hyperthermia. Recombinant cytotoxins specific for cancer cells Intraoperative image-directed dye marking of tumor margins (methylene blue) Gamma Knife radiosurgery 5/24/2017 New Cancer Treatments 33 Cells of the immune system, like those of other body systems, can proliferate uncontrollably; the result is cancer. 5/24/2017 New Cancer Treatments 34 Leukemias are caused by the proliferation of white blood cells, or leukocytes. The uncontrolled growth of antibody-producing (plasma) cells can lead to multiple myeloma. Cancers of the lymphoid organs, known as lymphomas, include Hodgkin's disease. In general, these disorders can be treated-some of them very successfully-by drugs and/or irradiation. 5/24/2017 New Cancer Treatments 35 Burkitt's lymphoma is a solid tumor of B lymphocytes. It involves a reciprocal translocation has moved the proto-oncogene c-myc from its normal position on chromosome 8 to a location close to the enhancers of the antibody heavy chain genes on chromosome 14. 5/24/2017 New Cancer Treatments 36 Burkitt's Lymphoma 5/24/2017 New Cancer Treatments 37 Tumor Suppressor Genes Tumor Suppressor Genes, like other genes, are present in two copies per cell. When one copy is "knocked out", cell growth is still normal, relying on the surviving gene copy. Only when this second copy is also lost does abnormal proliferation take off. 5/24/2017 New Cancer Treatments 38 Examples of Tumor Supressor Genes DPC-4 involved in pancreatic cancer; participates in a cytoplasmic pathway that inhibits cell division NF-1 involved in neurofibromas of the nervous system and myeloid leukemia; codes for a protein that inhibits Ras, a cytoplasmic inhibitory protein NF-2 involved in cancers of the nervous system; codes for a nuclear protein RB involved in retinoblastoma as well as bone, bladder, small cell lung, and breast cancers; codes of the pRB protein, a nuclear protein that is a major brake in the cell cycle p53 involved in a wide range of tumors; inactive or lost in more than 50% of cancerous cells; codes for the cytoplasmic p53 protein that regulates cell division and can induce cells to kill themselves (apoptosis); inheritance of p53 mutations through the germ line is also associated with the Li-Fraumeni cancer syndrome WT1 involved in Wilms tumor of the kidneys BRCA1 involved in breast and ovarian cancer BRCA2 involved in breast cancer 5/24/2017 New Cancer Treatments 39 Cancer can also result from mistakes in the somatic recombination process that gives rise to antibodies and T cell receptor proteins. 5/24/2017 New Cancer Treatments 40