Spotlights on Interferon interleukin MD Oncology Course Medical

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

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.

Types of interferon According to pharmacological structure 1. Alpha (leukocyte interferon) – By virus infected leukocytes 2. Beta (fibroblast interferon) Type I – 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 II

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

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

Pharmaceutical forms of interferons Generic name Trade name Conventional interferon Human leukocyte Interferon-alpha (Hu. IFN-alpha-Le) Multiferon Interferon alpha 2 a Roferon A Interferon alfa 2 b Intron-A Interferon beta 1 a, liquid form Rebif Interferon beta 1 a, lyophilized Avonex Interferon beta 1 b Betaferon Interferon gamma 1 b Actmmune Pegylated interferon alpha 2 a Pegasys Pegylated interferon alpha 2 a Reiferon Retard Pegylated interferon alpha 2 b Peg. Intron

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

Indications for Interferon • Alpha 2 a – – – – 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

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

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

Alpha Interferon-2 a (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.

Alpha Interferon-2 a (Roferon A( • CML – 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.

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

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

Pegylated interferon alpha 2 b (Peg. Intron) • Still under trials in cancer

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

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

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)

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.

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.

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)

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)