Desired and the adverse effects of interferons vary dramatically with dose, schedule, and route of administration, as well as pharmacologic manipulations of the interferon molecule .
It is an antiviral enzyme that counteracts viral attack by degrading viral RNA . The enzyme uses ATP
-Type I interferons inhibit the synthesis of bFGF, IL-8, and collagenase type IV, which are proangiogenic factors- treatment of infantile hemangiomas -inhibit endothelial cell migration -interferon- γ induces the chemokine IP-10, which is another angiogenic molecule. -gene for hypoxia-inducible factor 1 ά is induced by interferon- ά , which in turn activates transcription of vascular endothelial growth factor.
Most commonly studied with r-interferon a in Tt of hepatitis c and melanoma and with r-interferon γ
This serious complication was identified early in the initial trial of high-dose interferon alfa for adjuvant therapy of melanoma. Once careful monitoring was instituted with requirements for dosage reduction tied to serum transaminase elevations, there were no further cases of fatal hepatotoxicity on this trial or on subsequent cooperative group trials using the same dose and schedule
? Role of PROPHYLACTIC SSRI’S e.g. paroxetine, methylphenidate or exercise
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 ofWHEN A TISSUE CELL IS InterferonsINFECTED BY A VIRUS, ITRELEASES INTERFERON.INTERFERON WILLDIFFUSE TO THESURROUNDING CELLS.WHEN IT BINDS TORECEPTORS ON THESURFACE OF THOSEADJACENT CELLS, THEYBEGIN THE PRODUCTIONOF A PROTEIN THATPREVENTS THESYNTHESIS OF VIRALPROTEINS. THISPREVENTS THE SPREADOF THE VIRUSTHROUGHOUT 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 synthetasesATP Adenosine oligomers (2-5’A) @ RIBONUCLEASE- L (RNase L) cleaves single-stranded RNA inhibition of protein synthesis and hence cellular proliferation
dsRNA-dependent PKRPKR 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 translationEif2-Translation initiation factor
• Another group of proteins induced byinterferon that exhibits antiviral propertiesis the Mx family of glutamyltranspeptidases.• MxA is produced during viral infectionsand inhibits viral replication at the levelof transcription by binding to susceptibleviral nucleocapsids in the cytoplasm andpreventing their movement into thenucleus.
EFFECTS OF INTERFERONSIMMUNOLOGIC 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 moleculesNonimmunologic effects Antiangiogenesis effects*- Following therapyendothelial cells damagecoagulative 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 ONEFFICACY AND TOXICITYA 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 INTERFERONSPharmacology 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 Kaposis sarcoma,Philadelphia chromosome–positive CML -Interferon alfa-2b- hairy cell leukemia,AIDS– related Kaposis 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 InterferonsTumor types with established indicationsChronic myelogenous leukemiaHairy cell leukemiaNon-Hodgkins lymphomaAcquired immunodeficiency–related Kaposis sarcomaMalignant melanomaTumor types for which interferons are commonly usedRenal cell carcinomaBladder carcinoma (intravesical therapy)
Other tumor types for which interferonshave shown some evidence of activityColorectal carcinoma (with 5-fluorouracil)Carcinoid tumorDesmoid tumor (aggressive fibromatosis
"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, ODonnell 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 INTERFERONADMINISTRATION 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 METABOLICTOXICITIES 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 - Raynauds and Sjögrens syndromes. Common in females and longer duration of therapy Rhabdomyolysis Sarcoidosis
PHARMACOLOGIC MODIFICATION OFINTERFERONS 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 interferonformulation has biologic activity identical tounmodified 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.