Biological Response Modifiers (BRMs) and Their Role in Cancer Therapy: 1 Biological Response Modifiers (BRMs) and Their Role in Cancer Therapy What are Biological Response Modifiers?: 2 What are Biological Response Modifiers? Biological response modifiers, also known as BRMs, are substances that the human body produces naturally, as well as something that scientists can create in a lab. These substances have the ability to enhance one’s immune system to increase the body’s natural defense mechanisms against cancer and other infections. BRMs are used in immunotherapy/Biological response modifier therapy, a relatively new addition to the family of Cancer therapies. Slide 3: 3 Some antibodies, cytokines, and other immune system substances that can be produced in the laboratory are used in cancer treatment . Also substances naturally occurring in the environment in fruit bodies and fungi and other plant sources such as bioflavonoids and β -Glucans have been used to enhance the immune system’s defense mechanisms for centuries in the east. BRMs include interferons, interleukins, colony-stimulating factors, monoclonal antibodies and non specific immunomodulating substances as β -Glucans Researchers continue to discover new BRMs, to learn more about how they function, and to develop ways to use them in cancer therapy. Slide 4: 4 So What is a Tumor or Cancer? A tumor is an abnormal growth of cells to form a lump or mass of transformed cells. This abnormal growth occurs due to loss of regulatory control on cell division and the genes responsible for certain characteristics of the cell have undergone mutation. There are two types of tumors, benign tumor and malignant tumor. Benign tumor is usually encapsulated and confined to a single site, whereas the malignant tumor, the cells break off from the main tumor mass and travel through blood system and lodge themselves elsewhere and initiate new tumor formation at the site where they have lodged. Slide 5: 5 Cancers or malignant tumors grow in an uncontrolled manner, which invade the normal tissues due to metastasis and often grow at sites distant from the tissue of origin. In general, cancers are derived from only one or a few normal cells that have undergone a poorly defined process called malignant transformation. Cancers are known to arise from any tissue in the body. Those derived from epithelial cells are called carcinomars , are the most common kind of cancers. Sarcomas are malignant tumors of mesenchymal tissues arising from cells such as fibroblasts, muscles cells, and fat cells. Solid malignant tumors of lymphoid tissues are called lymphomas , bone marrow and blood borne malignant tumors of lymphocytes or other hematopoietic cells are called leukemias . Our Natural Immune Response to Tumors: 6 Our Natural Immune Response to Tumors Although tumors are derived from tissues of ones own body, the malignant transformation process leads to the expression of molecules on the tumor cells that are recognized by ones immune system as foreign bodies. Such molecules are called tumor antigens, which may induce immune responses directed at the tumor cells that express them. Slide 7: 7 Both humoral and cell mediated immune response to tumor antigens have been shown in vivo. The main effector mechanisms in anti-tumor immunity can be classified as follows: T-lymphocytes Natural Killer cells Macrophages Antibodies Slide 8: 8 Slide 9: 9 Role of T-Lymphocytes Dendritic cells/ Antigen presenting cells internalize tumor antigens, follow antigen processing and present antigens on Major histocompatibility complex (MHC) Class I molecules on their cell membrane surface. CD8/ T c lymphocytes bind to MHC Class I molecule-antigen complex from their T cell receptors. This activates the Tc cells which will derive into effector Cytotoxic T Lymphocytes (CTLs) CTLs will function by recognizing and killing potentially malignant cells that express peptides coded by mutant cellular genes and are present in association with class I MHC molecules by producing cytotoxins, which will destroy the tumor cells. T H lymphocytes will recognize tumor antigens presented on MHC Class II molecules, and they will derive into effector T H cells Effector T H lymphocytes will produce cytokines such as interferons (IFNs),& tumor necrosis factor (TNF) which can increase tumor cell Class I MHC expression and render the cells sensitive to lysis by CTLs. Also cytokines activate B lymphocytes, more T C lymphocytes, macrophages and Natural killer cells Slide 10: 10 Role of Natural Killer (NK) cells These are produced as a natural acquired immune response to tumors. The mechanism of lysis of tumor cells by NK cells is the same as that of CTLs, but they do not express T cell antigen receptor, and they kill targets in an MHC unrestricted manner. They produce cytotoxins such as perforin that lyse altered cells. The tumoricidal activity of NK cells is enhanced by cytokines, including interferons, TNF, interleukin-2 (IL-2) and interleukin-12 (IL-12). Hence NK cell activity depends on the concurrent stimulation of T cells and macrophages, which in turn produce these cytokines. Slide 11: 11 Role of Antibodies Tumor bearing hosts do produce antibodies against tumor antigens even though T cell mediates effective anti-tumor immune responses. Antibodies binding to target antigens mark those sites for destruction mainly in two ways; Via Complement System – Complement proteins will bind to the altered cells at the site of antigen-antibody complex, they will form pores on the affected cell’s membrane and thereby induce lysis of the cell by swelling. antibody dependent cell mediated cytotoxicity in which, Fc receptor bearing macrophages or NK cells mediate the killing. Slide 12: 12 Role of Macrophages Like NK cells, macrophages are known to preferentially lyse the tumor cells and they are known to possess Fc receptors, which can be targeted to tumor cells coated with antibodies. Macrophages involve in various mechanisms to kill tumor cells, which include the release of lysosomal enzymes, relative oxygen metabolites and in mice nitric oxide. Activated macrophage is known to secrete the cytokine tumor necrosis factor (TNF-α), which is capable of selectively killing tumor cells and not normal cells. TNF-α kills tumors by binding of TNF-α to cell surface receptors which is directly toxic to tumor cells Cause cell death by production of free radicals- Free radical toxicity (Tumor cells do not produce superoxide dismutase, therefore are susceptible to free radicals) Slide 13: 13 In spite the immune response being developed against cancer cells, they still survive and thrive in the body by evading the immune response. Evasion of immune response by cancerous cells is achieved by changing the antigenic molecules repeatedly thereby confusing the immune system. Cancer is one of the leading causes of death in the world at present. Slide 14: 14 Classical Cancer Therapies: 15 Classical Cancer Therapies Chemotherapy - Chemotherapy is the treatment of cancer using specific chemical agents or drugs that are selectively destructive to malignant cells and tissues Radiation Therapy - Radiation therapy uses high energy, penetrating waves or particles such as x-rays, gamma rays, proton rays or neutron rays to destroy cancer cells or keep them from reproducing. Surgery – Remove tumor mass by surgery Slide 16: 16 Treatment Long-term side effects Late side effects Chemotherapy Neuropathy Kidney failure Heart failure Infertility Liver problems Cataracts Infertility Liver problems Osteoporosis 2nd primary cancer Radiation Therapy Skin sensitivity Cataracts Heart problems Hypothyroidism Lung disease Memory problems Surgery Scars Chronic pain Lymphedema So how are BRMs used in Cancer Therapy?: 17 So how are BRMs used in Cancer Therapy? Stop, control, or suppress processes that permit cancer growth. Make cancer cells more recognizable and, therefore, more susceptible to destruction by the immune system. Boost the killing power of immune system cells, such as T cells, NK cells, and macrophages. Alter the growth patterns of cancer cells to promote behavior like that of healthy cells. Block or reverse the process that changes a normal cell or a pre-cancerous cell into a cancerous cell. Enhance the body's ability to repair or replace normal cells damaged or destroyed by other forms of cancer treatment, such as chemotherapy or radiation. Prevent cancer cells from spreading to other parts of the body. Types of BRMs: 18 Types of BRMs Interferons Interleukins Monoclonal Antibodies β – Glucans and derivatives Each of these enhance the immune system’s defense mechanisms… Interferons: 19 Interferons Interferons (IFNs) are types of cytokines that occur naturally in the body. They were the first cytokines produced in the laboratory for use as BRMs. There are three major types of interferons; interferon alpha, interferon beta, and interferon gamma; Macrophages and lymphocytes are responsible for production of IFN-alpha, whereas fibroblasts and epithelial cells are involved in producing IFN-beta. IFN-gamma is produced by CD4+, CD8+ and natural killer (NK) cells. Slide 20: 20 IFN-gamma has been shown to potentiate DNA fragmentation and apoptotic cell death. IFN-alpha and IFN-gamma potentiate tumor cytotoxicity Induction of MHC expression on tumor cell surfaces by IFNs is responsible for enhanced efficacy of host cell-mediated immunity and tumor elimination. The U.S. Food and Drug Administration (FDA) have approved the use of interferon alpha for the treatment of certain types of cancer, including hairy cell leukemia, melanoma, chronic myeloid leukemia, and AIDS-related Kaposi's sarcoma. Anti-tumor activity of Interferons Interleukins: 21 Interleukins Interleukin (IL)-2 is also a cytokine naturally occurring in our body and is produced by mature T lymphocytes during an immune response after receiving a signal from an antigen-presenting cell (APC). Anti-tumor activity of Interleukin It acts as an anti-tumor agent by increasing the cytolytic activity of antigen-specific cytotoxic T lymphocytes and natural killer (NK) cells by increasing the gene expression of the genes responsible for encoding the lytic component of cytotoxic granules, i.e., perforin and granzymes. Monoclonal Antibodies (mAb): 22 Monoclonal Antibodies (mAb) mAb are clones of similar antibodies that are directed against specific target antigens. Kohler and Milstein, in 1975, were the first ones to develop techniques for producing monoclonal antibodies (mAb). Slide 23: 23 Slide 24: 24 They activate the immune effector functions and facilitate the destruction of malignant cells by complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC). In CDC, the mAb bind to specific antigens, leading to activation and cascade of the complement system, which in turn leads to destruction of tumor cells. In ADCC, the Fab domain of mAb binds to the tumor antigen and Fc domain binds to Fc receptors present on effector cells i.e., monocytes, macrophages, and NK cells thus forming a bridge between effector and target cells. This induces effector cell activation, leading to increased Phagocytosis by neutrophils, monocytes, and macrophages. There is increased cytotoxicity of NK cells as they cause release of cell-lysing molecules responsible for tumor cell lysis. Monoclonal Abs carrying radioisotopes may also prove useful in diagnosing certain cancers, such as colorectal, ovarian, and prostate. Role of mAbs Slide 25: 25 β – Glucans and derivatives: Naturally occurring BRMs: 26 β – Glucans and derivatives: Naturally occurring BRMs β-Glucan occur naturally in some fungi and plants as components of the cell wall. Common sources are Medicinal mushrooms, bakers yeast and grains such as oats and barley. Ganoderma lucidium Trametes versicolor Slide 27: 27 β-Glucan is a natural polysaccharide (complex sugar molecule) made up of chains of many glucose sugar units. It is referred to as a Biological Response modifier (BRM) because of its ability to potentiate the immune system. Researchers suggest that β-Glucan is one of the safest immunomodulators available for human consumption. β-Glucan is only found in nature and can not be synthesized in the laboratory. Slide 28: 28 β-Glucans promote cancer cell elimination by enhancing the activity of macrophages, neutrophils, T cells, NK cells and B cells with appropriate antibodies (including enhancing the cancer cell killing ability of processed monoclonal antibodies). Macrophages and other immune cells are better enabled to attack the cancerous cells, therefore hindering or stopping cancer’s multiplication and spread. Research at Harvard University has shown that the Macrophage has receptor sites on its surface that are specific to β-Glucan. This activates macrophages to initiate its cytotoxic and Phagocytic activities. Various types of β-Glucan derivatives are now proven to be clinically applicable such as Lentinans, PSK and PSP Other Naturally occurring BRMs: 29 Other Naturally occurring BRMs From Lemons & Lime - Vitamin C: powerful antioxidant and acts against cancer cells - Limonin & Limonene: prevent cellular changes that might lead to cancer Parsnips - Reduces risk of cancer Tangerines - Vitamin C & β– cryptoxanthine: antioxidant property act against cancer cells Papaya - Carotinoids: reduce risk of cancer Slide 30: 30 Biological Response Modifiers appear to be extremely useful in fighting cancers and aiding against a variety of disorders by stimulating the immune system. Also there is the fact that there are no harmful side effects to the patients. Any discomforts in the body during treatment will last only during that period. They prevent immuno-suppression. And do not lead to cause secondary diseases. These factors make the role of BRMs in Cancer therapy very significant. Thank You.