Transcript spotlights on interleukin and interferon

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 mRNA
INF gene turn on
Transcription
Gene of Anti-viral
protein turn on
Transcription
Signaling transduction
Translation of
mRNA
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 (HuIFN-alpha-Le)
Multiferon
Interferon alpha 2a
Roferon A
Interferon alfa 2b
Intron-A
Interferon beta 1a, liquid form
Rebif
Interferon beta 1a, lyophilized
Avonex
Interferon beta 1b
Betaferon
Interferon gamma1b
Actmmune
Pegylated interferon
Pegylated interferon alpha 2a
Pegasys
Pegylated interferon alpha 2a
Reiferon 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
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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
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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 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 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
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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
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Hyperthyroidism
Hypothyroidism
Hypopituitarism
Vitiligo
Antiphospholipid syndrome
• Biochemical changes (autoantibodies)
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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:
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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)