CONTENT DEFENITION TYPES OF IMMUNOTHERAPY CYTOKINES CANCER VACCINES MONOCLONAL ANTIBODIES CYTOKINES INHIBITORS IV IMMUNOGLOBULINS IMMUNOSUPRESSENTS TYPES Active immunotherapy Passive immunotherapy Active immunotherapy It is the type of immunotherapy that attempts to stiumlate the host intrensic immune response to a disease Specific active immunotherapy Non specific active immunotherapy Specific active immunotherapy The generation of cellmediated and antibody immune responses focused on specific antegen. Eg.cancer vaccines Non specific immunotherapy the generation of general immune system response using cytokines Specific active immunotherapy Cancer vaccines Cellular therapies adjuvants . . Cancer vaccines cancer vaccines are active immunotherapy because they meant to triger the patient immune system to respond.part of the cell. cancer vaccines may contain cancer cells .or purified tumor specific antigen. Two catogories of cancer vaccine cell based in which the patient cancer cell is cultured with patients own immune system cells and derived back to the same patient.. . Vector based in which the engineered virus or oter vector is used to inntroduce cancer specific proteins and other molecule in order to stimulate the patient immune system to recoganise the tumor cells to fight the cancer. colorectal cancer.ovarian breast cancer Antigen vaccines-prostate. Dentritic cell vaccine DNA vaccines Vector based vaccines .Examples Tumor cell vaccines-kidney. Cellular therapies these are single type agent derived from the cancer patients which are modified in the labouratry to become more adapt at recognising and killing the tumor cells this type of immunotherapy is designed to boost specific part of immune system to cause tumor cell death Vaccines in contrast attempts to get the body immune system rect to specific antigen Eg.lympocyte activated killer cell therapy . cancer vaccines increases or boost the immune response to the particular system. Adjuvant immunotherapy an adjuvant is an any material which when injected together with an antigenic protein or other substance like monoclonal antbodies. BCG vaccine . Eg. IL2 promote T-cell and NK cell growth .IL-6 Indirect enhancement of antitumor response Eg.Non specific active immunotherapy Cytokines destruction of tumor cell by two mechanism direct antitumor eg.TNF alpha. Cytokine based therapy IL-2 IFN alpha GM-CSF metastatic melanoma RCC malignant melanoma hairy cell lukemia kaposis sarcoma lukemia Bone marrow /stem cell transplant chrons disease . . BCG therapy BCG as a treatment of choice in early form of bladder cancer exact mechanism not known activates both macrophage and lymphocytes Cell therapy the transfer of live .whole cells into the patient can also be used to achive non specific immunotherapy aginst cancer. when this combination of IL2 & LAK given to patient with advanced metastatic melanoma and RCC complete tumour regression can be achieved in 10 % of cases. . Example In metastatic melanoma patients.human pheripheral blood mononuclear cells(PBMCs) can be isolated and fed with IL-2 to generate class of cells called lymphokine activated cells(LAK). It do not stimulate a patient immune system to actively respond to a disease in the way vaccines does . Passive immunotherapy this comprised of antibodies and other immune system component that are made ouside the body and administerd to the patient to provide immunity against the disease. Monoclonal antibodies thearapy Cytokine inhibitors Tolerance induction IV immunoglobulin Immuno supressants Haemopoitic stem cell transplantation . gemtuzumab Radiolabelled antibodies eg. cetuximab. eg . monoclonal antibody therapy Types Naked monoclonal antibodies.tositumomab Chemolabelled antibodies eg.trastuzumab Conjugated monoclonal antibodies antibodies contain immunotoxin eg.brentuximab . . . infliximab Specific receptor can be blocked eg.etanercept Intracellular process which produce the active protien can be inhibited Cytokines can be neutralized in the circulation eg. CYTOKINES INHIBITOR these are cytokine specific substance that inhibit the biological actvities of specific cytokines in anumber of diffirent ways Production can be blocked eg.kineret . antibodies Mechanism of action uses kineret IL alpha antagonist Rheumatoid arthrites Sepsis osteoarthrites Ulcerative colitis Ankylosing spondylites Chrons disease Rheumatoid arthrites Psoriatic arthrites Ankylosing spondylites infliximab TNF alpha antagonistic enarcept TNF alpha antagonistic . Immune thrombocytopenia Acute infections. . Autoimmune diseases e.g.IV immunoglobulins It contains the pooled IgG extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months. It is mainly used as treatment in three major categories: Immune deficiencies . . IVIG dose Dosage of IVIG is dependent on indication. For primary immune dysfunction 100 to 400 mg/kg of body weight every 3 to 4 weeks is implemented. For neurological and autoimmune diseases 2 grams per kilogram of body weight is implemented for three to six months over a five day course once a month. Then maintenance therapy of 100 to 400 mg/kg of body weight every 3 to 4 weeks follows. Mechanism of action. Blockade of Fc receptors mononuclear or polynuclear phagocytes Inhibition of complement consumption by pathogenic antibodies Interference with T cell regulation and cytokine release Feedback inhibition of autoantibody synthesis by auto reactive B cells . FDA-approved indications Allogeneic bone marrow transplant Chronic lymphocytic leukemia Idiopathic thrombocytopenic purpura Pediatric HIV Primary immunodeficiencies Kawasaki disease Kidney transplant with a high antibody recipient or with an ABO incompatible donor . immunosupressents Glucocorticoids Calcineurin inhibitors Cyclosporine Tacrolimus Antiproliferative / antimetabolic agents Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others – methotrexate. thalidomide and chlorambucil . cyclophosphamide. Antibodies Antithymocyte globulin Anti CD3 monoclonal antibody Muromonab Daclizumab. etanercept . basiliximab Anti IL-2 receptor antibody – Anti TNF alpha – infliximab. Immunosuppressants Organ transplantation Autoimmune diseases Problem Life long use Infection. cancers Nephrotoxicity Diabetogenic . Monocytes display poor chemotaxis Broad anti-inflammatory effects on multiple components of cellular immunity .glucocorticoids Induce redistribution of lymphocytes – decrease in peripheral blood lymphocyte counts Intracellular receptors – regulate gene transcription Down regulation of IL-1. IL-6 Inhibition of T cell proliferation Neutrophils. Uses of glucocorticoids Transplant rejection GVH – BM transplantation Autoimmune diseases – RA. Hematological conditions Psoriasis Inflammatory Bowel Disease. SLE. Eye conditions . toxicity Growth retardation Avascular Necrosis of Bone Risk of Infection Poor wound healing Cataract Hyperglycemia Hypertension . Calcineurin inhibitors Cyclosporine Tacrolimus Most effective immunosuppressive drugs Target intracellular signaling pathways Blocks Induction of cytokine genes . . uveitis Psoriasis Aplastic anemia Skin Conditions. Alopecia Areata.Cyclosporine More effective against T-cell dependent immune mechanisms – transplant rejection. Pemphigus vulgaris. IBD.Atopic dermatitis. Lichen planus. Pyoderma gangrenosum . Liver. Oral Uses Organ transplantation: Kidney. autoimmunity IV. Heart Rheumatoid arthritis. Toxicity : Cyclosporine Renal dysfunction Tremor Hirsuitism Hypertension Hyperlipidemia Gum hyperplasia Hyperuricemia – worsens gout Calcineurin inhibitors + Glucocorticoids = Diabetogenic . Tacrolimus Inhibits T-cell activation by inhibiting calcineurin Use Prophylaxis of solid-organ allograft rejection . infections .Tacrolimus Nephrotoxicity Neurotoxicity-Tremor.Toxicity . headache. motor disturbances. seizures GI Complaints Hypertension Hyperglycemia Risk of tumors. Antiproliferative and Antimetabolic drugs Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others: Methotrexate Cyclophosphamide Thalidomide Chlorambucil . Sirolimus Inhibits T-cell activation and Proliferation Complexes with an immunophilin. Inhibits a key enzyme in cell cycle progression – mammalian target of rapamycin (mTOR) . tumors Drug Interactions: CYP 3A4 .Sirolimus Uses Prophylaxis of organ transplant rejection along with other drugs Toxicity Increase in serum cholesterol. Triglycerides Anemia Thrombocytopenia Hypokalemia Fever GI effects Risk of infection. Everolimus Shorter half life compared to sirolimus Shorter time taken to reach steady state Similar toxicity. drug interactions . Azathioprine Purine antimetabolite Incorporation of false nucleotide 6 Thio-IMP 6Thio-GMP 6Thio-GTP Inhibition of cell proliferation Impairment of lymphocyte function Uses Prevention of organ transplant rejection Rheumatoid arthritis . thrombocytopenia.Toxicity .Azathioprine Bone marrow suppression. anemia Increased susceptibility to infection Hepatotoxicity Alopecia GI toxicity .leukopenia. Antibodies Against lymphocyte cellsurface antigens Polyclonal / Monoclonal . Anti-thymocyte Globulin Purified gamma globulin from serum of rabbits immunized with human thymocytes Cytotoxic to lymphocytes & block lymphocyte function Uses Induction of immunosuppression – transplantation Treatment of acute transplant rejection Toxicity Hypersensitivity Risk of infection. Malignancy . Anti-CD3 Monoclonal Antibody Muromonab-CD3 Binds to CD3. a component of T-cell receptor complex involved in antigen recognition cell signaling & proliferation . Muromonab-CD3 Antibody treatment Rapid internalization of T-cell receptor Prevents subsequent antigen recognition . Chills. Headache. weakness .Uses Treatment of acute organ transplant rejection Toxicity “Cytokine release syndrome” High fever. Tremor. myalgia. arthralgia. monocytes.Campath-1H (Alemtuzumab) Targets CD52 – expressed on lymphocytes. Macrophages Extensive lympholysis – Prolonged T & B cell depletion Uses Renal transplantation .