Interferons dr. varun

INTERFERONS

Dr. Varun Goel
-

MEDICAL ONCOLOGIST
RAJIV GANDHI CANCER INSTITUTE, DELHI

INTRODUCTION
 Among the most powerful immunomodulatory
substances available for therapeutic use.

 Highly pleiotropic properties :
• immunomodulatory
• direct cytostatic
• direct cytotoxic.
• antiproliferative activity and
apoptotic effects

DISCOVERY OF INTERFERONS
 1957
 Isaacs and Lindenmann
 Did an experiment using chicken cell cultures
 Found a substance that interfered with viral
replication and was therefore named interferon
(“Interference factors”)
 Nagano and Kojima also independently
discovered this soluble antiviral protein

WHAT ARE INTERFERONS?

• Naturally occurring proteins and glycoproteins
• Secreted by eukaryotic cells in response to viral
infections, tumors, and other
biological inducers

• Strucurally, they are part of the helical cytokine
family which are characterized by an amino
acid chain that is 145-166 amino acids long

•
General Action of
WHEN A TISSUE CELL IS
Interferons
INFECTED BY A VIRUS, IT
RELEASES INTERFERON.
INTERFERON WILL
DIFFUSE TO THE
SURROUNDING CELLS.
WHEN IT BINDS TO
RECEPTORS ON THE
SURFACE OF THOSE
ADJACENT CELLS, THEY
BEGIN THE PRODUCTION
OF A PROTEIN THAT
PREVENTS THE
SYNTHESIS OF VIRAL
PROTEINS. THIS
PREVENTS THE SPREAD
OF THE VIRUS
THROUGHOUT THE BODY.

 Induce a state in which viral replication is
impaired by the synthesis of a number of
enzymes that interfere with cellular and viral
processes

 Anti-viral activity induces antiproliferative as
well as immunomodulatory activities.

 It is these additional functions induced by
interferons that resulted in their evaluation as
anticancer agents

 Humans -2 classes

 Type I family - α, β, δ, ε, κ, τ and ω subtypes.

 TypeII interferon family - γ interferon
subtype.

 Subtypes further subdivided for
pharmaceutical preparations (e.g., interferon
alfa-2a, interferon gamma-1b).

Type I interferons

- chromosome 9p
- all bind to the same receptor
- induced primarily in response to a viral
infection of a cell.

- Interferon α, ω - produced predominantly
from leukocytes,
- Interferon β - can be produced by most
cell types, esp. fibroblasts.

INTERFERON β induction by fibroblasts during viral
infection @

NFκ B Iκ B)

NFκ B
v@
(TRANSCRIPTION) @
INTERFERON - β

protein kinase R
Viral ds RNA (PKR),

@

 Viral induction of interferon- α in
leukocytes is less well understood

 Induction stimuli
- Classical -Viral infection
- proteins or DNA constructs of microbial
derivation, (bacterial endotoxins, CpG
dinucleotide repeats,) also stimulates
production of type I interferons.

 Type II interferons (Interferon γ )
- composed of a single subtype.
- binds to its own unique receptor
- produced by T lymphocytes and
natural killer (NK) cells
- in response to immune and
inflammatory stimuli.

 NK cells-part of the innate immune response
cells
-activation not dependent on antigen
recognition.

T cells- part of the adaptive immune response
- activated by stimulation of antigen- specific
T-cell receptor

 NK cells are stimulated to produce interferon- γ
when exposed to inflammatory cytokines (Tumor
necrosis factor-α and interleukin-12 (IL-12))
from macrophages.
 In a positive amplification loop, the interferon- γ
then stimulates the secretion of TNF- α and IL-12
from macrophages.

TNF –α +
IL-12
M NK

+ Interferon- γ

 The distinct receptors and the downstream
signaling that is initiated by ligand-receptor
interactions are responsible for the biologic
effects of the individual type I and type II
interferons.

BIOLOGIC EFFECTS OF
INTERFERONS
 Interferons ά and β bind to the
same receptor, which is
composed of two subunits

 The binding of either interferon-
ά or interferon- β to this receptor
results in the activation of Janus
tyrosine kinases Jak1 and Tyk2,
which results in the
phosphorylation of signal
transducers and activators of
transcription 1 and 2 (STAT1
and STAT2).

 STAT1 and STAT2
phosphorylation results in their
heterodimerization, dissociation
from the interferon receptor, and
translocation to the nucleus.
 In nucleus, the STAT complex
associates with DNA-binding
protein p48 (interferon-
stimulated gene factor 3)
(ISGF3),which binds to the
interferon-stimulated response
element of ά- and β-responsive
genes.

 induction of interferon target
genes, responsible for the
biologic effects of interferons ά
and β .

INTERFERON- γ
 Interferon-γ binds as a
homodimer to the specific
interferon-γ receptor

 Dimerization of the
receptor activates the
Janus tyrosine kinases
Jak1 and Jak2, which
ultimately results in the
phosphorylation of STAT
proteins.

INTERFERON- γ
 Instead of activating
STAT1 and STAT2( as with
type I interferon receptor)
interferon-γ
activates two separate
STAT1 molecules.

form a homodimer known
as the - γ activated factor
(GAF)

translocates to the nucleus
and binds to γ -activating
sequences (GAS), elements
of interferon- γ inducible

 The antiviral activity of interferons is mediated by
three pathways.

- 2'-5' oligoadenylate synthetases

-dsRNA-dependent PKR

-Mx pathways.

2'-5' oligoadenylate synthetases
ATP

Adenosine oligomers (2'-5’A)
@
RIBONUCLEASE- L
(RNase L)

cleaves single-stranded RNA

inhibition of protein synthesis and hence cellular
proliferation

dsRNA-dependent PKR
PKR is activated by binding to dsRNA.
1) Once activated, PKR phosphorylates the
translation initiation factor eIF2, which inhibits
messenger RNA translation.
2)

3) PKR also can activate NFκ B, which can lead to
increased cytokine and chemokine levels.

4) Increased PKR activity can also induce apoptosis
by a Bcl2- and caspase-dependent mechanism.

dsRNA-dependent PKR

2.NFκ B CHEMOKINES
@ +
dsRNA CYTOKINES

PKR
P
_ mRNA
1.eIF2
translation

Eif2-Translation initiation factor

• Another group of proteins induced by
interferon that exhibits antiviral properties
is the Mx family of glutamyl
transpeptidases.
• MxA is produced during viral infections
and inhibits viral replication at the level
of transcription by binding to susceptible
viral nucleocapsids in the cytoplasm and
preventing their movement into the
nucleus.

EFFECTS OF INTERFERONS
IMMUNOLOGIC EFFECTS

 Cytokines regulate the innate immune system
natural killer (NK) cells, macrophages and
neutrophils.

 They also regulate the adaptive immune system,
the T and B cell immune responses.

Direct effects on tumor cells

Increased MHC class I antigen expression, increased
expression of tumor-associated antigens, increased
expression of adhesion molecules

Nonimmunologic effects

Antiangiogenesis effects*-
Following therapyendothelial cells damagecoagulative necrosis
Regulates expression of angiogenic basic fibroblast growt factor
(bFGF).

Direct cytostatic and cytotoxic effects on tumor cells

Antimetastatic effects on tumor cells

 Interferons induce hundreds of specific gene products, most
of which are important in regulation of cell proliferation and
apoptosis.

 Type I interferons- up-regulate cdk inhibitor p21
inhibition of the G1 to S phase transition.

Interferon-γ
- down-regulates c-myc transcription (essential in driving
cell-cycle progression.)
- induces Fas and Fas ligand, which can increase cell
sensitivity to apoptosis.

 Interferon-ά +anti-CD3 induces the surface expression of
tumor necrosis–related apoptosis-inducing ligand on
peripheral T cells.

 Interferons induce apoptosis by activation of several
members of the caspase pathway

 T1/2 of recombinant interferon alfa-2 varies between
2 and 8 hours in the blood after s.c. or I.m.
administration,& somewhat shorter after I.v.
administration.
 Oral delivery- impractical due to proteolytic
degradation.
 Peak plasma concentrations are highest after iv
administration.
 I.V. administration of interferon alfa is performed
daily (5 days per week in the most commonly used
regimen for adjuvant therapy of interferon)
S.c or I.m. administration is performed thrice weekly.
 Other dose schedules have been explored in the hopes
of maximizing certain properties of interferons while
minimizing toxicities (e.g., low-dose, twice-daily
schedules of subcutaneous interferon alfa in
"antiangiogenesis" trials).

EFFECTS OF DOSE AND SCHEDULE ON
EFFICACY AND TOXICITY

A variety of doses, schedules, and routes of
administration of interferon have been tested in
clinical trials, particularly in the setting of adjuvant
therapy for melanoma patients

 No consistent observation that responses are linked
to a specific dose or schedule of administration.

 Responses are more common in patients with
small, generally soft tissue or lung nodules.

 Clinical trials have clearly established a greater
incidence of grade 3 and 4 toxicity for high-dose
regimens than for lower doses.

ONCOLOGIC APPLICATIONS OF
INTERFERONS
Pharmacology and Dosage
 Available in both natural and recombinant forms,

 Commercially available interferon formulations include

- human leukocyte–derived interferon alfa-n3 (Alferon N);
- recombinant "consensus" interferon, alfacon-1 (Infergen);
- recombinant interferon alfa-2a (Roferon-A);
- recombinant interferon alfa-2b (Intron A);
- recombinant interferon beta-1a (Avonex, Rebif);
- recombinant interferon beta-1b (Betaseron);
-recombinant interferon gamma-1b (Actimmune,InterMune).

Most of the oncologic experience has been
accumulated with interferon alfa-2a and alfa-
2b, which are approved by the U.S. FDA for
use in

-Interferon alfa-2a- hairy cell leukemia,AIDS –
related Kaposi's sarcoma,Philadelphia
chromosome–positive CML

-Interferon alfa-2b- hairy cell leukemia,AIDS–
related Kaposi's sarcoma,follicular lymphoma,
and malignant melanoma

Interferon alfa-n3 genital and perianal warts
(Alferon-N)
Interferon beta-1b multiple sclerosis
(Betaseron) and beta-
1a(Avonex)
Interferon gamma-1B chronic granulomatous
(Actimmune) disease and severe, malignant
osteopetrosis.
Interferon alfa-2b condylomata acuminata,
chronic hepatitis C, and
chronic hepatitis B.

Oncologic Applications of Interferons
Tumor types with established indications
Chronic myelogenous leukemia
Hairy cell leukemia
Non-Hodgkin's lymphoma
Acquired immunodeficiency–related Kaposi's sarcoma
Malignant melanoma
Tumor types for which interferons are commonly used

Renal cell carcinoma
Bladder carcinoma (intravesical therapy)

Other tumor types for which interferons
have shown some evidence of activity

Colorectal carcinoma (with 5-fluorouracil)

Carcinoid tumor

Desmoid tumor (aggressive fibromatosis

Human cancer targets of interferon therapy

 "palliative"treatment for CML
 only rarely results in a prolonged complete
cytogenetic response.

A patient who cannot tolerate tyrosine kinase
inhibitors might be offered IFNa with or without
another chemotherapy medication, cytarabine.

 In chronic phase CML, with use of interferon-α
(dose 5 x 106 U/m2/day or three times weekly)
Complete hematological response in ~70%

Complete cytogenetic response in ~ 25% cases.

o Its effects on remission duration and survival are
controversial.
 Silver R et al. An evidence-based analysis of the effect of busulfan, hydroxyurea,
interferon, and allogeneic bone marrow transplantation in treating the chronic
phase of chronic myeloid leukemia: developed for the American Society of
Hematology. Blood. 1999;94:1517-1536.

 In HCL interferon- α became first effective non-surgical
treatment.
 75% patients achieved partial or complete response.

 Median duration of response=1-2 yr but virtually all
patients eventually relapse.
Quesada J, Hersh EM, Manning J, et al. Treatment of hairycell
leukemia with recombinant alpha interferon. Blood.
1985;1986:493-497.

 Now cladribine is treatment of choice.

 Interferon-alpha is a very effective salvage
therapy for patients with hairy cell leukemia
relapsing after cladribine.

 Effective against some common forms of NHL,
particularly low-grade, follicular NHL in
advanced stages. sometimes combined with
chemotherapy
 In NHL, as a single agent, interferon-α modest activity
but significant toxicities.
 Remission duration are generally short.

 Low dose interferon-α with standard chemo 
 Reduction in rate of transformation to higher grade lymphoma
 Moderate prolongation of remission duration

 BUT no effect on overall survival

 High-dose IFN is the only treatment showing
activity against melanoma in the adjuvant
setting.

 only medication for people with high-risk
malignant melanoma that has been shown to
improve both relapse-free survival and overall
survival.
 Simone Mocellin et al.Interferon Alpha Adjuvant Therapy in Patients
With High-Risk Melanoma: A Systematic Review and Meta-analysis. J
Natl Cancer Inst 2010;102:1–9

 Response rates for metastatic melanoma with
IFN-α2 as a single agent ~15%, comparable to
cytotoxic agents used alone.
 When combined with chemotherapy and IL-2,
response rates can >45%,
 but with increased toxicity and
 with no marked prolongation in progression-free
survival or overall survival.
 Tawbi HA, Kirkwood JM. Management of metastatic
melanoma. Semin Oncol. 2007;34:532-545

 5-year estimated RFS (relapse-free survival) rates
for the high-dose interferon, low-dose interferon, and
observation groups were 44%, 40%, and 35%,
respectively. Neither high-dose interferon nor low-
dose interferon yielded an OS benefit when
compared with observation (hazard ratio [HR] =
1.0; P = .995).
 Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-
dose interferon alfa-2b in high-risk melanoma: first analysis
of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12):
2444-58, 2000

 IFN-a2a and IFN-a2b were among the first agents to
be used therapeutically for AIDS-associated KS

 yet a role for IFN-a in combination with agents that
target angiogenesis

 recently, a case report described how ocular adnexal
and conjunctival KS was successfully treated with
intra-lesional IFN-a2b, leading to a dramatic decrease
in tumor mass
 Qureshi YA et al. Intralesional interferon alpha-2b therapy for
adnexal Kaposi sarcoma. Cornea 28(8):941–943.

 Response rates from 4% to 26% have been reported in
trials IFN-α2 in metastatic renal carcinoma, with a mean
response of 15% in cumulative summary of several
trials.
 Bukowski RM. Cytokine therapy for metastatic renal cell carcinoma. Semin Urol Oncol. 2001;19:148-
154.

 In two randomized trials comparing IFN-α alone or in
combination with other treatments, a statistically
significant increases in survival resulted.
 Members of the MRC Renal Cancer Collaborators. Interferon-á and survival in metastatic renal carcinoma: early results of a
randomized controlled trial. Lancet. 1999:14-17.

 IFN-α in midgut carcinoid tumors, a mean response rate
of ~50% resulted.
 Moertel C et al. J Clin Oncol. 1989;7:865-868.

 Objective tumor regression occurs less frequently but
can include both primary tumors and hepatic metastases.

 Other solid tumors, such as ovarian, bladder, and basal
cell carcinomas, have responded to IFN-α administered
regionally, particularly in patients with lesser tumor bulk
 Greenway H, Cornell RC, Tanner DJ, et al. Treatment of basal cell carcinoma with intralesional
interferon. J Acad Dermatol. 1986;15:437-443.
 Belldegrun A, Franklin JR, O'Donnell MA, et al. Superficial bladder carcinoma: the role of
interferon alpha. J Urol. 1998;159:1793-1801.
 Berek J, Markman M, Stonebraker B, et al. Intraperitoneal interferon-alpha in residual ovarian
carcinoma: a Phase II Gynecologic Oncology Group study. Gynecol Oncol.

CLINICAL TOXICITY OF INTERFERON
ADMINISTRATION

 ConstitutionalToxicities
 Hematologic Toxicities

 Organ Toxicities

 Neuropsychiatric Toxicities

 Endocrine and Metabolic Toxicities

 Potential Drug Interactions

CONSTITUTIONAL TOXICITY
 Most common toxicities
 Schedule and dose dependent.
 Acute administration can result in
-fever, chills, myalgias, arthralgias, headache, nausea,
vomiting, and fatigue.
- Rigors - uncommon.
- Fatigue usually increases with repetitive dosing until a
baseline level of fatigue is reached

 Appropriate timing of administration (e.g., at or just
before bedtime) can limit the impact of symptoms.
 Anorexia and weight loss -commonly seen with
higher-dose regimens

HEMATOLOGIC TOXICITIES
 Hematologic toxicities
-anemia, neutropenia, and thrombocytopenia.
Appear to be dose related, rarely reported in lower-dose
regimens.

 Neutropenia requiring dosage reduction reported in
26% to 60% of patients receiving high-dose
interferon-α.

 Neutropenic fevers or infections requiring
antibiotic administration or hospitalization are quite
rare.

 Thrombocytopenia -rarely severe enough to
warrant dosage reductions.

ORGAN TOXICITIES
 CVS-
-SVT esp AF- risk increased in elderly
patients & with preexisting cardiac disease.
-reversible cardiomyopathy – rare
- Hypotension

o Kidneys
-Reversible proteinuria - 15% to 20% of pts.
-Nephrotic syndrome rare
-Interstitial nephritis.

 Thrombotic microangiopathy in patients with CML
treated for several years.
 Skin -macular rashes ,
-psoriatic-type skin reactions –resolve
with discontinuation of therapy.

ORGAN TOXICITIES-CONTD

Acute hepatic toxicity
High-dose interferon regimens

- manifested as increase in serum levels
of SGOT,SGPT
- can be fatal
- fatal complications can be avoided with
careful monitoring and appropriate dosage
modification.

RETINOPATHY
 Associated with type I interferon therapy

- includes retinal hemorrhages, cotton-wool spots

- can be unilateral or bilateral.

- Incidence of interferon retinopathy-18% to 86% in different
series.
- DM may be an associated risk factor

- rarely results in any visual disturbance and disappears
spontaneously during treatment or resolves after interferon is
discontinued.

NEUROPSYCHIATRIC TOXICITIES

 The neuropsychiatric or neurocognitive
toxicities

- subtle changes detected only by formal
testing
- overt with depression, hypomania, or
suicidal ideation requiring discontinuation of
interferon and active intervention.

ENDOCRINE AND METABOLIC
TOXICITIES
 Thyroid abnormalities -in 5% to 31% of patients
- 70% to 80% with thyroid disorders while on interferon
have detectable thyroid autoantibodies,
Exact mechanism unknown.
- may be a manifestation of increased risk of autoimmune
disorders that has been seen in patients taking interferon.

 Metabolic alterations in the blood lipid profile
- hypertriglyceridemia
- elevated levels of LDL, secondary to inhibition of
lipoprotein lipase.
- plasma cholesterol level in 15% to 40% of patients.

OTHERS
Autoimmune phenomena
- Thyroid disorders
- Rheumatoid arthritis
- Raynaud's and Sjögren's syndromes.
Common in females and longer
duration of therapy
 Rhabdomyolysis
 Sarcoidosis

PHARMACOLOGIC MODIFICATION OF
INTERFERONS

 The relatively short half-life of interferons requires
repetitive dosing to maintain exposure to biologically
effective concentrations.
 A pharmacologic approach to improving interferon
efficacy and decreasing toxicity has been to couple the
recombinant interferon molecule with a polyethylene
glycol moiety ("pegylation").
 This slows metabolism of the interferon, providing
more sustained levels of exposure, but also diminishes
the specific activity of the interferon, because steric
interference decreases binding affinity with its
receptor.

2 pegylated interferons commercially available, each
using different form of PEG: -
branched-chain pegylated interferon alfa-2a
(Pegasys)
straight-chain pegylated) interferon alfa-2b (PEG-
Intron).

In comparable concentrations,each pegylated interferon
formulation has biologic activity identical to
unmodified recombinant molecule.

POTENTIAL DRUG INTERACTIONS
 Not been extensively examined,
 Inhibition of the activity of cytochrome P-450
(isozymes CYP1A2 and CYP2D) within 24 hours of
the first intravenous dose.
After 26 days of treatment, significant inhibition of
CYP2C19 was found.
 Implication -
-Activity of drugs metabolized by these enzymes may
be diminished after interferon therapy.
Such drugs include tricyclic antidepressants, SSRIs,
theophylline, phenytoin, and many others

 However, clinically significant drug-interferon
interactions have not been reported.

Interferons dr. varun

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Editor's Notes