CONTENT DEFENITION TYPES OF IMMUNOTHERAPY CYTOKINES

CANCER VACCINES MONOCLONAL ANTIBODIES CYTOKINES INHIBITORS IV IMMUNOGLOBULINS IMMUNOSUPRESSENTS

TYPESActive 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. cancer vaccines may contain cancer cells ,part of the cell,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..

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

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.

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

Monoclonal antibodies thearapy Cytokine inhibitors Tolerance induction

IV immunoglobulin Immuno supressants Haemopoitic stem cell transplantation

monoclonal antibody therapy Types

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

TNF alpha antagonistic

enarcept

TNF alpha antagonistic

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

Antiproliferative / antimetabolic agents Sirolimus Everolimus Azathioprine

Mycophenolate Mofetil Others methotrexate, cyclophosphamide, thalidomide and

chlorambucil

Antibodies Antithymocyte globulin Anti CD3 monoclonal antibody

Muromonab Daclizumab, basiliximab

Anti IL-2 receptor antibody

Anti TNF alpha infliximab, etanercept

Immunosuppressants Organ transplantation Autoimmune diseasesProblem 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

conditions Psoriasis Inflammatory Bowel Disease, 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

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

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)

SirolimusUses 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

Uses Prevention of organ transplant rejection Rheumatoid arthritis

Toxicity - Azathioprine Bone marrow suppression- leukopenia,

thrombocytopenia, anemia Increased susceptibility to infection Hepatotoxicity Alopecia GI toxicity

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-CD3Antibody treatmentRapid 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