Immunosuppressives Flashcards
What are the three chemical types of immunosuppressives?
- Glucocorticoids
- Antibiotics
- Antibodies and fusion proteins
What are the two glucocorticoids we need to know? What are they used for?
- Dexamethasone
- Prednisone
- Treatment of cancers that express the requisite receptors
What are the two antibiotic immunosuppresives? What are they used for?
- Cyclosporine
- Tacrolimus
- Used to prevent rejection following bone marrow transplantation
What are other antibiotics that function as mTOR inhibitors?
Everlolimus, Temsirolimus
What are the five antibodies and fusion proteins? What are they used for?
- Alemtuzumab
- Denileukin Diftitux
- Ibritumomab
- Rituximab
- Tositumomab
- Used for special leukemia and lymphomas because they target unique CDs
What is the mechanism of action for glucocorticoids?
- Naturally occurring compound is cortisol
- Interfere with the concentration, distribution and function of leukocytes
- –Inc. neutrophils, dec. T & B lymphocytes, monocytes, eosinophils and basophils
- –End result is decrease in cytokine release, including DECREASES IN IL-2 and TNF-alpha
- Decreases size of lymph nodes and spleen
How are glucocorticoids used in cancer chemotherapy?
-Given at higher doses, using a “pulse” regimen (in comparison to their use with inflammatory disease like asthma, arthritis, lupus, etc.)
What specific type of cancer are glucocorticoids used for?
Those that express the requisite receptors (e.g. prednisone-sensitive lymphomas)
What dosing is given for cancer cells?
Chemotherapy
-High dose, “pulse”
What dosing is given to suppress a normal immune system?
Immuno-suppression
-Low dose, continuous
What are triggers from cell division and what type of cell division is there for cancer cells and for the normal immune system?
Cancer cells - Unstimulated, Random Cell Division
Normal Immune System - Cell division is triggered by a specific antigen and cell division is synchronized
What are immunosuppressive antibiotics used for?
- Prevent rejection following bone marrow transplant
2. Angiogenesis inhibitors
What immunosuppressive antibiotics prevent rejection of bone marrow transplants?
Cyclosporine, Tacrolimus
What immunosuppressive antibiotics act as angiogenesis inhibitors?
Everolimus, Temsirolimus
What two pathways involved in cell proliferation are these immunosuppressive antibiotics involved in?
- NFAT-mediated regulation of interleukin synthesis
2. mTOR regulation of cell growth and angiogenesis
What is the MOA for immunosuppressive antibiotics?
Interfere with intracellular processes that are key for cell proliferation and cytokine production and release
- The 1st step in the process that leads to IL-2 mediated cell proliferation is activation of receptor tyrosine kinases (RTKs)
- Immunosuppressive antibiotics do not interfere with this process; they interfere with one of two intracellular signaling cascades
What are the two intracellular signaling cascades immunosuppressive antibiotics interfere with?
- Antirejection
- Anti-angiogeneis and anti-proliferation
How does antirejection occur with immunosuppressive antibiotics?
-Binds to cytoplasmic proteins and inhibit calcineurin
–Cyclosporine binds to cyclophilin
–Tacrolimus binds to FK-binding protein
Calcineurin is necessary for activation of NFAT, a T cell specific transcription factor that is involved in the synesis of interleukins by activated T cells –> decreased release of IL-2 –> decreased activation of IL-2 receptor –> decreased cell proliferation
How does anti-angiogenesis and anti-proliferation occur with immunosuppressive antibiotics?
- Receptor tyrosine kinases can also increase expression of mTOR, an intracellular signaling molecule that increases cell division, increases bioenergetics and facilitates angiogenesis in many cell types
- EVEROLIMUS and TEMSIROLIMUS also function as mTOR inhibitors
What are the 5 antibodies and fusion proteins?
- Alemtuzumab
- Denileukin Diftitux
- Ibritumomab
- Rituximab
- Tositumomab
What types of antibodies have been designed to selectively recruit the immune system to destroy cancer cells?
- Ones that target CDs (CD 20 in NHL, and CD52 in B-CLL)
- Ones that target cell surface proteins (HER2, VEGF, EGFR) that are overexposed in specific cancers
What are general concepts of antibodies and fusion proteins?
- Typically prescribed when traditional chemotherapy has failed or when patient factors (esp. age) prevent the use of cytotoxic drugs
- Goal is to get the immune system to recognize, and kill the cell that is expressing antigen
- –Use immune system to suppress itself
What is the Target & Use of Rituximab, Ibritumomab (90Y), and Tositumomab (131I)?
Target - CD20
Use - B cell non-hodgkin lymphoma (NHL)
What is the Target & Use of Alemtuzumab?
Target - CD52
Use - B cell chronic lymphocytic leukemia (B-CLL)
What is Denileukin Diftitux? How does it work? What is it used for?
- Fusion protein that has diphtheria toxin coupled to IL-2
- –Diptheria toxin catalyzes the ADP-ribosylation of elongation factor-2 –> inhibits protein translation by inactivating EF2
- Goal is to kill cells expressing IL-2 receptors (activated T-lymphocytes, B lymphocytes and macrophages)
- Approved for use in cutaneous T-cell lymphoma
What resistance has developed against antibodies and fusion proteins?
-Changes in target protein that prevent the antibody from recognizing its antigen
What are the pharmacokinetics of antibodies and fusion proteins?
- IV admin.
- Long half-lives - detectable at least 3-6 months after completion of treatment
What toxicities are common to all antibodies?
- Infusion reactions (77% of patients on rituximab)
- Other hypersensitivity reactions: fever, muscle aches, headaches, rashes, anaphylaxis
- Mouse (MO)»_space; chimeric (XI) > humanized (ZU) for HAMA reaction - Infections - esp. reactivation of tuberculosis
- -Unknown effects on immunization, carcinogenesis, mutagenesis, impairment of fertility, pregnancy, nursing infants (human IgG is secreted in milk)
What toxicities are specific for anti-CD antibodies?
- Cardiac arrhythmias
- Tumor lysis syndrome
- ALEMTUZUMAB: cough, tightness in chest
- Suspicion that radiolabelled antibodies (IBRITUMOMAB, TOSITUMOMAB) may be more likely to cause birth defects (this hasn’t been tested!)
