Tumor immunology with immunotherapy ppt

Immunology of surveillance and evading tumor. Immunology therapy including stem cell therapy

1. Tumor immunology -tumor antigen, response to tumor and evasion of the immune system, cancer immunotherapy, stem cell therapy

2. Cancer remains one of the leading causes of death globally, with an estimated 12.7 million cases around the world affecting both sexes equally. This number is expected to increase to 21 million by 2030. Appearance of a tumor (from the Latin word for “swelling”) results from ABNORMAL PROLIFERATION of cells, through the loss or modification of normal growth control. Cells which normally do not divide (e.g. muscle or kidney cells) may start proliferating, or cells which normally do proliferate (e.g. basal epithelial cells or hemopoeitic cells) may begin dividing in an uncontrolled fashion. Cancer

3. Carcinogens • Radiation : Ultraviolet light, sunshine; X-rays, radioactive elements induce DNA damage and chromosome breaks. • Chemical : smoke and tar, countless chemicals that damage DNA (mutagens). • Oncogenic viruses : insert DNA or cDNA copies of viral oncogens into the genome of host target cells. • Hereditary : certain oncogenes are inheritable.

4. Classification of cancer Carcinomas : epithelial origin involving the skin, mucous membranes, epithelial cells in glands Sarcomas : cancer of connective tissue. Lymphomas : T- B-cell, Hodgkin’s, Burkitt’s lymhomas ; - solid tumors Leukemias : disseminated tumors - may be lymphoid, myeloid, acute and chronic .

5. Tumor Immunology Tumor antigens •Effectors mechanisms in anti-tumor immunity •Mechanisms of tumor evasion of the Immune system •Immunotherapy for tumors

6. Tumor Antigen Many tumors can be shown to express cell surface antigens which are not expressed in the normal progenitor cells before the neoplastic transformation event. These antigens have been categorized based on their nature and distribution, resulting in a complex collection of acronyms, some of which are defined as:

7. Tumor Antigen Tumor-Specific Transplantation Antigens, or TSTA Chemical or radiation-induced tumors each generally express a unique neo-antigen, different from other tumors induced by the same or different agent. 2. Tumor-Associated Transplantation Antigens, or TATA Tumors induced by the same virus express antigens shared between different tumors. These consist of membrane-expressed virally encoded antigens, and have been termed Tumor-Associated Transplantation Antigens (since they are not, strictly speaking, tumor “specific”).

8. Tumor Antigen 3. Oncofetal antigens: These are TATAs which are more or less selectively expressed on tumors, but are also shared with some normal fetal or embryonic tissues. Examples include carcinoembryonic antigen (CEA, shared with healthy fetal gut tissue), and alpha-fetoprotein (AFP, also present in the serum of healthy infants, but decreasing by one year of age).

9. Tumors stimulate an immune response Animals can be immunized against tumors Immunity is transferable from immune to naïve animals Tumor specific antibodies and cell have been detected in humans with some malignancies

10. Oncogenesis proto- oncogenes tumor suppressor genes oncogenes carcinogen results in mutation dysfunctional tumor suppressor genes inherited defect increased GF increased GF receptors exaggerated response to GF loss of ability to repair damaged cells or induce apoptosis

11. Four mechanisms of oncogene activity to deregulate cell division

12. Cancer cells are different Escape normal intercellular communication Allow for rapid growth Increased mobility of cells Invade tissues Metastasis Evade the immune system 12

13. EXPERIMENTAL EVIDENCE FOR TUMOR ANTIGENS AND IMMUNE RESPONSE

14. Immunosurveillance • An hypothesis that states that a physiologic function of the immune system is to recognize and destroy malignantly transformed cells before they grow into tumors. • Implies that cells of the immune system recognize something “foreign” on transformed/tumor cells.

15. Immune Surveillance of Tumors Normal cell Transformed (cancerous) but also antigenic Mutation or virus Dead Transformed (cancerous) but escapes from immune response Immune response Mutation Analogous to a bacterial population being treated with antibiotics such that antibiotics resistant mutants take over the population

16. Tumor Surveillance Macrophage/ Dendritic cell attack or antigen presentation CD8 cell-mediated cytotoxicity Antibody dependent cell mediated cytotoxicity (ADCC) Natural killer cells

17. Tumors can both activate and suppress immunity Tumors can activate the immune response (ex. expression of foreign antigen with MHCI) or suppress the immune response (activation of T regulatory cells that release IL-10 and TGF ) – the balance determines whether the cancer becomes clinically relevant or not.

18. Basic Tumor Immunosurveillance The presence of tumor cells and tumor antigens initiates the release of “danger” cytokines such as IFN  and heat shock proteins (HSP). These cause the activation and maturation of dendritic cells such that they present tumor antigens to CD8 and CD4 cells subsequent T cytotoxic destruction of the tumor cells occurs

19. Helper T cells CD4+ T cells: reacting to class II MHC peptide complex, they secret cytokines. cytotoxic T cell response (Th1 helper T cells) antibody response (Th2 helper T cells) Dendritic Cells The professional antigen-presenting cells In the final common pathway for activating naïveTcells .

20. MAC MHC II MAC T helper cell IL-2 T helper Memory cell T helper effectorcell IL-1 Interferon Macrophages and dendritic cells can directly attack tumor cells, or more commonly can express exogenous antigens (TSA’s or bits of killed tumor cells) to CD4 cells Tumor cell or tumor derived antigen Dendritic and Macrophage Presentation of Tumor Antigen to CD4 Cells

21. Cytotoxic T cells (CTLs)T cells(CTLs) CD8+ T cells: attaching to class I MHC peptide complex, they destroy cancer cells by perforating the membrane with enzymes or by triggering an apoptotic pathway.

22. 22 MAC or B cell (APC) MHC 1 T cytotoxic cell Perforins, apoptotic signals Exogenous antigen T cytotoxic memory cells T cytotoxic effector cells T Cytotoxic Cell Activity in Tumor Surveillance Cancer Cell T cytotoxic cell Endogenous antigen

23. Cytokines • Regulating the innate immune system: NK cells, macrophages and neutrophils ; and the adaptive immune system: T and B cells • IFN- α-- upregulating MHC class I tumor antigens and adhesion molecules; promoting activity of B and T cells, macrophages, and dendritic cells. • IL-2-- T cell growth factor that binds to a specific tripartite receptor on T cells. • IL- 12 – promoting NK and T cell activity and a growth factor for B cells • GM-CSF(Granulocyte- monocyte colony stimuating factor) --reconstituting antigen-presenting cells

24. Antibody - produced by B cells • Direct attack : blocking growth factor receptors, arresting proliferation of tumor cells, or inducing apoptosis. -- is not usually sufficient to completely protect the bo dy. • Indirect attack : -- major protective efforts (1) ADCC(antibody-dependent cell mediated cytotoxicity ) -- recruiting cells that have cytotoxicity , such as monocytes and macrophages . (2) CDC (complement dependent cytotoxicity ) -- binding to receptor, initiating the complement system, 'complement cascade’, resulting in a membrane attack complex causing cell lysis and death.

25. NATURAL KILLER CELL NK Target cell (infected or cancerous) Perforin and enzymes killer activating receptor Do not recognize tumor cell via antigen specific cell surface receptor, but rather through receptors that recognize loss of expression of MHC I molecules, therefore detect “missing self” common in cancer.

26. Tumor Escape Mechanisms Low immunogenicity Antigen modulation Immune suppression by tumor cells or T regulatory cells Induction of lymphocyte apoptosis

27. Lack of MHCI as a tumor escape mechanism Defects in mechanisms of MHCI production can render cancer cells “invisible” to CD8 cells

28. Tumors can escape immunity (and immunotherapy) by selecting for resistant clones that have occurred due to genetic instability

29. Immunoediting of cancer cells 29 Elimination refers to effective immune surveillance for clones that express TSA Equilibrium refers to the selection for resistant clones (red) Escape refers to the rapid proliferation of resistant clones in the immunocompetent host

30. 1) Tumor cell production of immune suppressants such as TGF- , 2) T regulatory cell stimulation with production of immune suppressants such as TGF-  1 2 Avoidance of tumor surveillance through release of immune suppressants

31. Tumor cells induce apoptosis in T lymphocytes via FAS activation Cancer cells express FAS ligand . Bind to FAS receptor on T lymphocytes leading to apoptosis.

32. Cancer Immunotherapy Immunotherapy is the most recent advanced technique in cancer therapy. Cancer Immunotherapy is the use of immune system to reject Cancer. The main purpose of this premise is stimulating the patient’s immune system to attack the malignant tumour cells that are responsible for the disease. Immunotherapy works to harness the innate powers of the immune system to fight cancer. It fights cancer more powerfully, to offer long-term protection, with less side effects. It may hold greater potential than current treatments, due to unique properties of Immune System.

33. History Although cancer immunotherapy is being touted as a recent breakthrough in cancer treatment, its origins at Memorial Sloan Kettering go back more than a century. In the 1890s, William Coley , a surgeon at New York Cancer Hospital (the predecessor to Memorial Sloan Kettering) discovered cancer patients who suffered from infections after surgery often fared better than those who did not. His finding led to the development of Coley’s toxins, a cocktail of inactive bacteria injected into tumors that occasionally resulted in complete remission. But eventually the use of this treatment fell out of favor.

34. In the 1960s, research by Memorial Sloan Kettering investigator Lloyd Old led to the discovery of antibody receptors on the surface of cancer cells, which enabled the development of the first cancer vaccines and led to the understanding of how certain white blood cells, known as T cells or T lymphocytes, can be trained to recognize cancer.

35. Types of Cancer Immunotherapy

36. Monoclonal Antibodies Monoclonal antibody( mAbs ) therapy, is most widely used, and a form of P assive I mmunotherapy. It is a targeted therapy, directed to a single target on a cancer cell, usually an antigen or a receptor site on the cancer cell. It binds to Cancer cell-surface specific antigens . When it recognize the antigen against which it is directed, they fit together like two pieces of a puzzle, setting of a cascade of events leading to tumour cell death. Examples: A vastin , E rbitux , R ituxan , H erceptin , C ampath , Z evalin , B exxar etc.

37. Types of Monoclonal Antibodies Naked mAbs Naked mAbs work alone, and are referred to as "naked" because they are unmodified. Mark targets for immune system - bind to targets and make them more visible. The immune system is triggered and then destroys the target. Attach to antigens that are responsible for sending important signals that contribute to the target's reproduction. Binding to cell receptors, so that proteins that trigger growth are blocked. Usually used in cancer treatments. Conjugated mAbs Conjugated mAbs are modified with additional material. Radio immunotherapy (RIT) - These mAbs have radioactive particles directly attached, and deliver them directly to cancerous cells to kill them. Chemolabeled - These mAbs have a chemotherapy drug attached to their structures, which would normally be too powerful if delivered by itself. This drug kills the cancerous cell.

38. Cytokines [Active Immunotherapy] Cytokines are a large group of proteins, that function as short range mediators involved in essentially all biological processes. Cytokines serve as molecular messengers between cells. They have important rate-limiting signals. These are chemically made by some immune system cells. They are injected, either under the skin, into a muscle, or into a vein.

39. Most common Cytokines are Interleukins They act as chemical signals between white blood cells. Interlukin-2 (IL-2) help immune system cells grow and divide more quickly. A man-made version of IL-2 is approved to treat advanced kidney cancer and metastatic melanoma. IL-2 can be used as a single treatment for cancer, or can be combined with chemotherapy or with other cytokines such as Interferon- α Interferons These interferon (IFN) are chemicals, helping body to resist virus infection and cancer. Types of (IFN) are: 1. IFN- α , 2. IFN- β , 3. IFN- γ Only INF- α is used to treat cancer. It is used to treat these cancers: Hairy cell leukemia, Chronic myeloid leukemia, Follicular non-hodgkin’s lymphoma, cutaneous t-cell lymphoma, kidney cancer, melanoma, kaposi Sarcoma.

40. Adoptive Cell Therapy Adoptive cell transfer (ACT) is the transfer of cells into a patient; as a form of cancer immunotherapy. It requires the generation of tumour-antigen-reactive-T cells. The cells are most commonly derived from the immune system, with the goal of transferring improved immune functionality and characteristics along with the cells back to the patient. Interleukin-2 is normally added to the extracted T cells to boost their effectiveness, but in high doses it can have a toxic effect. The reduced number of injected T cells is accompanied by reduced IL-2, thereby reducing side effects.

41. Adoptive Cell therapy

42. Limitations of Adoptive Cell Therapy Not all tumour infiltrating lymphocytes grow well enough in culture to generate the quantity of cells that would be required to produce a useful anti-tumour effect when they are infused into the patient. Not all tumour infiltrating lymphocytes can be made, in culture, to become more adept at killing the tumour upon return to the patient. Autologous therapy is cumbersome and does not easily lend itself to the commercial scale mass production techniques necessary to reach the multitude of cancer patients world-wide.

43. Cancer Vaccines Unlike other vaccines, which defends the immune system from germs, C ancer vaccines make person’s immune system attack cancer cells.

44. There are two Broad Types of Cancer Vaccines 1. Preventive Vaccines: which are intended to prevent cancer from developing in healthy people. 2. Treatment Vaccines: which are intended to treat an existing cancer by strengthening the body’s natural defence against the cancer. Cancer preventive vaccines target infectious agent that cause or contribute to the development of cancer.

45. Limitations of Cancer Vaccines Today, most cancer vaccines are targeted: that means it made against a specific tumour cell antigenic target. The limitations of targeted vaccines are very similar to the limitations of other targeted change, the target vaccine becomes ineffective. Not all antigen are same Autologous vaccine therapy presents many manufacturing challenges. Autologous therapy is costly Many cancer vaccines are poorly immunogenic and require the use of adjuvants to elicit an effective immune response. The addition of adjuvants may increase immunogenicity of vaccine, but may also increase toxicity.

46. Limitations of Immunotherapy Many mAbs are not administered as first-line therapy: mAbs are usually administered as a second, third, or last resort cancer treatment when the immune system is already weakened by chemotherapy, surgery and radiation. This may limit their effectiveness. Not all antigens are the same: All cancers may "look" the same, but they are not. Not all patients' cancers may express the antigen against which a specific monoclonal antibody is targeted. In general, response rates to these "targeted therapies" appear to be around 20 to 30 percent. To optimize this type of therapy, it will be necessary to identify each subgroup of patients with a specific cancer and develop therapies targeted to, or directed specifically at, their individual cancers.

47. Tumour cells mutate: as a result of chemotherapy and radiation treatment, and therefore the target antigen on the tumour cell at which the therapy is aimed also can be changed. If the target changes, then the mAbs, which target those specific antigens, could become ineffective.           Toxicity: associated with some targeted therapies can be significant.

48. What are stem cells ? Stem cells are unspecialized cells that continually renew themselves through cell division. Unlike other cells, stem cells begin as "blanks" without a dedicated task, but with an ability to become specialized. Just like the stem of a plant will produce branches, leaves, and flowers, so stem cells can usually produce many different kinds of cells. Stem Cell Therapy

49. ADULT STEM CELLS Are stem cells found in the umbilical cord (after live birth), fat, bone marrow, tissue, organs, blood, etc. of a human being. These cells are removed from the body of the patient and manipulated in the laboratory. After the cells multiply, the healthy cells are separated from the diseased cells and reinserted back into the body of the patient. Human clinical trials show that these new cells go to the diseased or injured body part and begin to generate healthy cells and tissue; the cells are especially successful because they contain the exact DNA of the patient, preventing cell rejection.

50. FETAL STEM CELLS Are stem cells taken from the tissues of aborted or miscarried fetuses. The stem cells are extracted from the fetus, treated in the laboratory, and then inserted into the body of the suffering patient. No medical treatment derived from fetal stem cells has successfully treated a human disease .

51. In one of the most well-known human clinical trials using fetal stem cells, the cells were inserted into the brains of Parkinson’s patients. Unfortunately, the unpredictable young cells created terratomas (masses of tissue with hair and teeth) and tumors, and the majority of patients experienced increased symptoms.

52. EMBRYONIC STEM CELLS Are stem cells derived from human embryos created through in vitro fertilization (the union of sperm and egg in the laboratory).

53. Couples can legally donate their unborn embryonic children to research by signing consent forms. Embryonic stem cells extracted from donated embryos are used to start stem cell lines, and these stem cells are used for clinical trials.

54. No animal or human clinical trials have shown improvement or recovery from illness or disease through the use of embryonic stem cells ; in fact, embryonic stem cells are known to create tumors -because of their young and unpredictable nature -and are often rejected due to the DNA mismatch.

55. The obvious ethical issue Extracting stem cells from embryos remaining from in vitro fertilization does result in the death of those embryos and, consequently, has severe ethical implications. During development, cells derived from these stem cells become progressively more specialized. It's normally a one-way street -- in the body, embryonic stem cells don't stick around long. National Institute of Health

56. Placenta a Source of Stem Cells Placental stem cells, like umbilical cord blood and bone marrow stem cells, can be used to cure chronic blood-related disorders such as sickle cell disease, Thalasemia , and leukaemia.

57. Umbilical Cord Blood Stem Cell Transplant Umbilical cord blood stem cell transplants are less prone to rejection than either bone marrow or peripheral blood stem cells. This is probably because the cells have not yet developed the features that can be recognized and attacked by the recipient's immune system

58. Autologous – Stem Cells Sources of the patient's own stem cells ( autologous ) are either the cells from patient's own body or his or her cord blood. For autologous transplants physicians now usually collect stem cells from the peripheral blood rather than the marrow This procedure is easier, unlike a bone marrow harvest, it can take place outside of an operating room and the patient does not have to be under general anaesthesia.

59. Allogeneic – Stem Cells Sources of stem cells from another donor (allogeneic) are primarily relatives (familial-allogeneic) or completely unrelated donors (unrelated-allogeneic). The stem cells in this situation are extracted from either the donor's body or cord blood

60. Xenogenic - Stem Cells In this stem cells from different species are transplanted, e.g. striatal porcine fetal ventral mesencephalic (FVM) xenotransplants for Parkinson's disease. This has no major ethical concerns and a large amount of tissue is available, however life long immunosupression and risk of rejection are the major limitations

61. How Does Cell Therapy Work? Stem cells can be used to generate healthy and functioning specialized cells, which can then replace diseased or dysfunctional cells. It is similar to the process of organ transplantation only the treatment consists of transplanting cells instead of organs.

62. Diseases Cured by Stem Cell Therapies Any disease in which there is tissue degeneration can be a potential candidate for stem cell therapies. Major Progress in Several Important Health problems Alzheimer’s disease Parkinson’s disease Spinal cord injury Heart disease Severe burns Diabetes

63. Applications of Stem Cells Cell Replacement Therapies Cells could be stimulated to develop into specialized cells that represent renewable sources of cells and tissue for transplantation. Cell replacement therapy could treat injuries and various genetic and degenerative conditions including muscular dystrophies, retinal degeneration, Alzheimer disease, Parkinson's disease, arthritis, diabetes, spinal cord injuries, and blood disorders such as hemophilia. Cont..

64. Bone marrow transplants are an example of cell therapy in which the stem cells in a donor's marrow are used to replace the blood cells of the victims of leukemia. Cell therapy is also being used in experiments to graft new skin cells to treat serious burn victims, and to grow new corneas for the sight-impaired. In all of these uses, the goal is for the healthy cells to become integrated into the body and begin to function like the patient's own cells.

65. Obstacles of Stem Cell Research How to find the right type of stem cells? How to put the stem cells into the right place? Will the stem cells perform the desired function in the body? Differentiation protocols for many cell types have not been developed.

66. Possible Uses of Stem Cell Technology 1. Replaceable tissues/organs 2. Repair of defective cell types 3. Delivery of genetic therapies 4. Delivery chemotherapeutic agents

67. Thank you