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By Salah Mabruok Khalaf South Egypt Cancer Institute 2013

Spotlights on Interferon & interleukin. MD Oncology Course Medical Oncology department. By Salah Mabruok Khalaf South Egypt Cancer Institute 2013. Interferons. Origin of the name and definition. Origin of the name

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By Salah Mabruok Khalaf South Egypt Cancer Institute 2013

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  1. Spotlights on Interferon & interleukin MD Oncology Course Medical Oncology department By Salah Mabruok Khalaf South Egypt Cancer Institute 2013

  2. Interferons

  3. Origin of the name and definition • Origin of the name • Interferons are named after their ability to "interfere" with viral replication within host cells. • Definition • Natural interferons are glycoproteins and proteins made and released by host cells to counteract both micro-organisms; viruses, bacteria, parasites and tumor cells.

  4. Types of interferon According to pharmacological structure • Alpha (leukocyte interferon) • By virus infected leukocytes • Beta (fibroblast interferon) • By virus infected fibroblasts or epithelial cells • Gamma (immune interferon) • By activated T cells & NK cells According to origin • Natural human interferon • Synthetic pegylated interferon Type I Type II

  5. General Action of Interferons Block viral replication virus Virus RNA Formation of anti-viral protein Virus infection Translation of mRNA INF gene turn on Transcription Gene of Anti-viral protein turn on Transcription Signaling transduction Translation of mRNA Interferon molecules INF binding Host cell Host cell

  6. Specific action of each type • IFN alpha and beta • induction of inhibitory protein synthesis • IFN gamma • increase class II MHC(major histocompatibility complex) molecules of APC • increase ability of Macrophages to resist viral infection and kill other cells if infected • All IFN • increase class I MHC molecules • increase activity of NK cells

  7. Pharmaceutical forms of interferons

  8. PEG-interferon • PEG-interferon is a pegylated interferon. The PEG (polyethylene glycol) make the followings: • Protect IFN from enzymatic degradation thus lowers systemic clearance • Allows less frequent dosing • Achieve higher/sustained serum level

  9. Indications for Interferon • Alpha 2a • AIDS-related Kaposi's sarcoma • Leukemia (Chronic myeloid) • Lymphomas (Low grade) • Plasma cell tumors (Multiple myeloma) • Hepatitis B & C • Hairy cell leukemia • Advanced Melanoma • Beta • Multiple Sclerosis • Gamma • Chronic Granulomatous disease • Chronic Myeloid Leukemia • Metastatic renal cell Carcinoma

  10. FDA approval for Interferon in cancer • Alpha 2a • AIDS-related Kaposi's sarcoma • Hairy cell leukemia • Leukemia (Chronic myeloid) • Kinney: Metastatic renal cell carcinoma (with bevacizumab) • Alpha 2b • AIDS-related Kaposi's sarcoma • Hairy cell leukemia • Melanoma

  11. Alpha Interferon-2a (Roferon A) • Produced using recombinant DNA technology • Non-glycosylated protein • Short half life • Larger reduction in renal clearance.

  12. Alpha Interferon-2a (Roferon A) • AIDS-related Kaposi's sarcoma • Induction: 36 MIU IM daily for 4-10 wk. • Maintenance: 36 MIU IM 3 times wkly. • HCL • The induction dose of Roferon-A is 3 MIU daily for 16 to 24 weeks, administered as a subcutaneous injection. • The recommended maintenance dose is 3 MIU, tiw. • Dose reduction by one-half or withholding of individual doses may be needed when severe adverse reactions occur. • The use of doses higher than 3 MIU is not recommended in hairy cell leukemia.

  13. Alpha Interferon-2a (Roferon A) • CML • The recommended initial dose of Roferon-A is9 MIU daily administered as a subcutaneous injection. • Based on clinical experience,3 short-term tolerance may be improved by gradually increasing the dose of Roferon-A over the first week of administration • 3 MIU daily for 3 days then 6 MIU daily for 3 days then target dose of 9 MIU daily for the duration of the treatment period. • The optimal dose and duration of therapy have not yet been determined. • Kidney cancer: Renal cell carcinoma (in combination with vinblastine) • 18 MIU SC or IM 3 times wkly.

  14. Pegylated interferon alpha 2a (Pegasys) • Still under trials in cancer

  15. Alpha Interferon-2b (Intron-A( • AIDS-related Kaposi's sarcoma • 30 MIU/m2 SC 3-5 times/wk. Lower doses (10-12 MIU/m2/day) have been used effectively. • Concomitant administration w/ AZT in AIDS patients w/ Kaposi's sarcoma • Initially 3-5 MIU/m2 daily; AZT 100 mg 4 hrly. • May increase Intron A by 5-10 MIU/m2 daily; AZT dose may increase to 200 mg 4 hrly. • Hairy cell leukemia • 3-30 MIU/m2 SC 3, 5 or 7 times/wk. • Malignant melanoma • 20 MIU/m2 IV daily for 5 times/wk for 4 wk, then 10 MIU/m2 SC 3 times/wk for 48 wk.

  16. Pegylated interferon alpha 2b (PegIntron) • Still under trials in cancer

  17. Immune reaction Autoimmunity Flu-like symptoms Headache Fatigue or asthenia Myalgia, arthralgia Fever, chills Nausea, vomiting, diarrhea Depression of patient Depression of BM Neutropenia Anemia Thrombocytopenia Allergy: Injection site reaction Alopecia Side Effects of IFN

  18. Autoimmunity as a complication of therapy with IFN-α • Clinical syndromes • Hyperthyroidism • Hypothyroidism • Hypopituitarism • Vitiligo • Antiphospholipid syndrome • Biochemical changes (autoantibodies) • Antithyroglobulin antibodies • Anti-thyroid microsomal antibodies • Antinuclear antibodies • Anti-DNA antibodies • Antiplatelet antibodies • Anti–islet-cell antibodies.

  19. Interleukin 2

  20. Definition and Origin of name • Origin of name • The term interleukin derives from (inter-) "as a means of communication", and (-leukin) "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes • Definition • Interleukins are a group of cytokines  (secreted proteins / signaling molecules) that were first seen to be expressed by white blood cells (leukocytes)

  21. Mechanism of action and Dose • Mechanism of action • Immunotherapy with IL-2 activates cytotoxic T-cell against RCC • Dose and adminstration • Interleukin-2 is administered via intravenous (IV) injection as high dose (HD) (usually defined as 600,000 – 720,000 units/kg). • Lower dosage IV and subcutaneous IL-2 are also prescribed for kidney cancer, but HD IL-2 is the only regimen that has FDA approval.

  22. Indications • Indication • High-dose IL-2 is an FDA approved, inpatient therapy to treat metastatic melanoma and metastatic renal cell carcinoma. • Used for patients that can Tolerate side effects because of significant morbidity and 4% mortality associated with high-dose IL-2 making this therapy very difficult and applicable to only small minority of patients.

  23. Predictive biomarker in RCC treatment with INterleukin • Predictive biomarker (Carbonic anhydrase IX (CA IX) level) • RCC has high expression of CA IX, a protein under the control of those HIFs that are upregulated  the patients benefit from high-dose IL-2 most dramatically (They tend to be the patients who get complete remissions, and they may even have high response rates of up to 50% compared with the 23% in low level of CAI IX)

  24. Side effects of interleukin 2 • Ischemia and Infarction of heart • Neurological: • Sleeping disorder • Depression • Confusion • Convulsion • Coma • Thromboctopinea, anemia, leucopenia • Edema of lung (Pulmonary edema) and Capillary leak syndrome • Runny stiffy nose and Rash or dry, itchy skin • Low blood pressure • ECG changes: arrhythmias • Kidney Affection: insufficiency or failure • Intestinal: Diarrhea • Nausea/vomiting • Flu-like syndrome (may include fever, chills, tiredness, headache, muscle and joint pain)

  25. Thank you for attention

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