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

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 1.Alpha (leukocyte interferon) –By virus infected leukocytes 2.Beta (fibroblast interferon) –By virus infected fibroblasts or epithelial cells 3.Gamma (immune interferon) –By activated T cells & NK cells According to origin 1.Natural human interferon 2.Synthetic pegylated interferon Type I Type II

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

6. Specific action of each type IFN alpha and beta –induction of inhibitory protein synthesis IFN ga mm a –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 Trade nameGeneric nameConventional interferon MultiferonHuman leukocyte Interferon-alpha (HuIFN-alpha-Le) Roferon AInterferon alpha 2a Intron-AInterferon alfa 2b RebifInterferon beta 1a, liquid form AvonexInterferon beta 1a, lyophilized BetaferonInterferon beta 1b ActmmuneInterferon gamma1b Pegylated interferon PegasysPegylated interferon alpha 2a Reiferon RetardPegylated interferon alpha 2a PegIntronPegylated interferon alpha 2b

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 9 –The recommended initial dose of Roferon-A is 9 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. Side Effects of IFN 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

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.

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)