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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
Cancer vaccines
cancer vaccines are active immunotherapy because they meant to triger the patient immune system to respond. cancer vaccines may contain cancer cells ,part of the cell,or purified tumor specific antigen.
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..
Examples Tumor cell vaccines-kidney,ovarian breast cancer Antigen vaccines-prostate,colorectal cancer. Dentritic cell vaccine DNA vaccines Vector based vaccines
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
Adjuvant immunotherapy
an adjuvant is an any material which when injected together with an antigenic protein or other substance like monoclonal antbodies,cancer vaccines increases or boost the immune response to the particular system. Eg; BCG vaccine
Non specific active immunotherapy Cytokines destruction of tumor cell by two mechanism direct antitumor eg;TNF alpha,IL-6 Indirect enhancement of antitumor response Eg;IL2 promote T-cell and NK cell growth
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.
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). 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.
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. It do not stimulate a patient immune system to actively respond to a disease in the way vaccines does
IV immunoglobulin
Immuno supressants Haemopoitic stem cell transplantation
Naked monoclonal antibodies, eg . cetuximab;trastuzumab Conjugated monoclonal antibodies antibodies contain immunotoxin eg.gemtuzumab Radiolabelled antibodies eg;tositumomab Chemolabelled antibodies eg;brentuximab
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.etanercept Intracellular process which produce the active protien can be inhibited Cytokines can be neutralized in the circulation eg;infliximab Specific receptor 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
enarcept
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 . Autoimmune diseases e.g. Immune thrombocytopenia Acute infections.
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
Mycophenolate Mofetil
Others methotrexate, cyclophosphamide, thalidomide and
chlorambucil
Immunosuppressants
Organ transplantation
Autoimmune diseases
Problem Life long use Infection, cancers Nephrotoxicity Diabetogenic
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, Monocytes display poor chemotaxis Broad anti-inflammatory effects on multiple components of cellular immunity
Uses of glucocorticoids
Transplant rejection
GVH BM transplantation Autoimmune diseases RA, SLE, Hematological
toxicity
Growth retardation
Avascular Necrosis of Bone Risk of Infection
Calcineurin inhibitors
Cyclosporine
Tacrolimus
Most effective immunosuppressive drugs Target intracellular signaling pathways Blocks Induction of cytokine genes
Cyclosporine
More effective against T-cell dependent immune mechanisms transplant rejection, autoimmunity IV, Oral
Uses Organ transplantation: Kidney, Liver, Heart Rheumatoid arthritis, IBD, uveitis Psoriasis Aplastic anemia Skin Conditions- Atopic dermatitis, Alopecia Areata, Pemphigus vulgaris, Lichen planus, Pyoderma gangrenosum
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
Toxicity - Tacrolimus
Nephrotoxicity Neurotoxicity-Tremor, headache, motor disturbances, seizures GI Complaints Hypertension Hyperglycemia Risk of tumors, infections
Thalidomide
Chlorambucil
Sirolimus
Inhibits T-cell activation and Proliferation
Complexes with an immunophilin, Inhibits a key
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, tumors Drug Interactions: CYP 3A4
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
Toxicity - Azathioprine
Bone marrow suppression- 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
involved in
antigen recognition cell signaling & proliferation
Muromonab-CD3
Antibody treatment
Rapid internalization of T-cell receptor Prevents subsequent antigen recognition
Uses
Treatment of acute organ transplant rejection
Toxicity Cytokine release syndrome High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness
Campath-1H (Alemtuzumab)
Targets CD52 expressed on lymphocytes, monocytes,
Macrophages Extensive lympholysis Prolonged T & B cell depletion Uses Renal transplantation