By

Salah Mabruok Khalaf

South Egypt Cancer Institute2013

MD Oncology Course Medical Oncology department

Spotlights on Interferon & interleukin

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)– 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

General Action of Interferonsvirus

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 cellHost 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 nameTrade name

Conventional interferon

Human leukocyte Interferon-alpha (HuIFN-alpha-Le) Multiferon

Interferon alpha 2a Roferon A

Interferon alfa 2bIntron-A

Interferon beta 1a, liquid form Rebif

Interferon beta 1a, lyophilized Avonex

Interferon beta 1b Betaferon

Interferon gamma1bActmmune

Pegylated interferon

Pegylated interferon alpha 2a Pegasys

Pegylated interferon alpha 2aReiferon Retard

Pegylated interferon alpha 2b PegIntron

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 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

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

Alpha Interferon-2a (Roferon A)

• Produced using recombinant DNA technology

• Non-glycosylated protein

• Short half life

• Larger reduction in renal clearance.

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.

Alpha Interferon-2a (Roferon A)

• CML

– The recommended initial dose of Roferon-A is 99 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 2a (Pegasys)

• Still under trials in cancer

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.

Pegylated interferon alpha 2b (PegIntron)

• 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– 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.

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)