Interferon therapy involves the use of interferons (IFNs), which are crucial proteins produced by the immune system in response to viral infections. These proteins play a vital role in modulating immune responses, defending against pathogens, and potentially combating cancer. By harnessing the power of interferons, this therapy aims to enhance the body’s natural defences.

Interferon can be remembered using the mnemonic "interferon":

• I - Impervious barrier against viruses
• N - Establish an immune system network
• T - Trigger immune responses
• E - Engage every single infected cell
• R - Induce antiviral and anticancer responses
• F - Form a resilient immune system
• E - Effective at preventing infections
• R - Stimulate immune cell reactions
• O - Control over viral reproduction
• N - Notable adjunctive agent for COVID-19 treatment

When stimulated by viral infections, human blood cells produce IFNs, which help modulate the immune system and defend the host. Moreover, IFN therapy shows great promise for future advancements, with ongoing research into its applications against viral infections and potential developments in cancer treatment.

Introduction and overview

No history of virology would be complete without a discussion of IFNs and the discovery and identification of cytokines (small proteins that influence the activity of the immune system and nearby cells), their function in innate immunity, and their pharmaceutical properties as antiviral and anti-cancer agents. The biotechnology revolution began by cloning the IFN gene and its synthesis in E. Coli. IFN was a coincidental finding, much like many other significant scientific breakthroughs. 

The phenomenon known as "viral interference"—the capacity of one virus to prevent the multiplication of another virus—was studied in 1957 by Alick Isaacs and Jean Lindenmann. Applying heat- or UV-inactivated influenza virus to the chorioallantoic membranes of 10-day-old chick embryos they discovered the development of a material that prevented the virus from reproducing and named it "interferon". 

Further studies revealed distinct protein characteristics, confirming that the discovered material belongs to the family of classical proteins. 

There are four subforms of IFN, called "alpha," "beta," "gamma," and "lambda", which all have distinct cellular receptors and ways of action. These days, IFNs serve clinically to treat autoimmune illnesses like multiple sclerosis (MS), malignancies like non-Hodgkin's lymphoma, and viral infections like hepatitis C.^1,2

Understanding IFNs

IFNs are glycoproteins with antiviral, anticancer, and immunomodulatory properties that are members of the cytokine family. The following table lists the various IFN types along with their specific functions.

Table 1 IFN subtypes and their features. 

Mechanism of action

Following IFN induction, they interact with cells having particular IFN receptors. Although IFN alpha (α), beta (ß), and gamma (γ) bind to the same receptor, the signalling induced by it is entirely distinct from each other. After this contact, a complex sequence of signal transduction events occurs, ultimately causing the synthesis of several proteins with various functions.¹

By starting signalling cascades that result in the development of gene products, including MHC class 1, B2 microglobulin, and others, IFNs have immune-modulatory effects with IFN-gamma as the main immunomodulatory.

During several phases of the viral replication cycle, such as entrance, transcription, RNA stability, translation, maturation, and release, IFNs have antiviral activity. The expression of antiviral genes mediates this effect.

Researchers believe that the actions of PKR and STAT1, the activation of CDK inhibitors, and the reduction of cyclin D and cell division cycle (CDC) 25A are responsible for the antiproliferative characteristics of IFNs.^1,4

Applications of IFN therapy

IFN therapy has a wide range of therapeutic applications across various medical fields. It is used to treat viral infections, including hepatitis B and C, as well as certain cancers like melanoma and multiple myeloma.⁴ The following table highlights several approved therapies, showcasing the versatility and importance of IFN therapy.

Table 2 IFN treatment options. 

Administration and dosage

Subcutaneous (SC), intramuscular (IM), intralesional, aerosol, topical, and perhaps intravenous (IV) are among the various routes of administration of IFNs. Different diseases will require different treatments:^4,7,9,10 

• IFN alpha (α)-SC injections for treating chronic viral hepatitis are given 10 million international units (MIU) three times a week for 24 weeks with ribavirin
• 3 MIU is used for non-Hodgkin lymphoma, hairy cell leukaemia and multiple myeloma patients until tumour progression ceases
• For patients with chronic myeloid leukaemia (CML), 10 MIU of IFN alpha (α) and cytarabine are administered three to five times a week until tumour growth ceases
• Adjuvant therapy for melanoma treatment involves SC injections of 3 to 10 MIU three times a week 
• Topical, SC, and intralesional methods of delivery existent for genital warts and herpes infections
• IFN beta (β)-SC injection of 250 micrograms (µg) of IFN-beta 1b for treating MS. FN beta (β) 1a is given three times a week with 22 to 42 µg dosage and IM injection of FN beta (β) 1a at a dose of 30 µg each week
• IFN gamma (γ)-treatment for CGD involves three weekly SC injections into the deltoid or anterior thigh

Monitoring

Complete blood counts (CBC), creatinine, alanine aminotransferase (ALT), lactic dehydrogenase (LDH), electrolytes, triglycerides, and blood sugar tests should be carried out: 

• weekly for the first four weeks of IFN alpha (α) therapy
• monthly for one through three, and then 
• every three months after that

Before beginning treatment and then every six months after, patients receiving IFN beta (ß) should undergo tests for blood counts and liver function. Furthermore, patients must undergo screening every six months for the development of neutralising antibodies during the initial two years of treatment. It is important to routinely screen patients receiving IFN gamma (γ) for anti-IFN antibodies, thrombocytopenia, leucopenia and elevated transaminases.^1,3

Side effects

A significant obstacle to the therapeutic application of IFNs has been the frequency and severity of side effects. The image below illustrates some typical and less common IFN therapy side effects.

Common side effects include:^1,6,7

• Injection site erythema
• Autoimmune reactions 
• Anorexia and alopecia
• Anaemia
• Neutrophil reduction
• Hypertension
• Erectile dysfunction (ED)
• Bone marrow suppression

FAQs

Should one evaluate any considerations and contraindications before using IFN therapy?

IFN contraindications include kidney failure, cirrhosis, hepatitis, autoimmune illness, prior immunosuppressive treatment, organ transplantation, epilepsy, severe mental and neurological diseases, and psoriasis. According to study findings, intrauterine growth and the child's development during the first four years of life were not impaired by exposure to IFN beta (ß) therapy during pregnancy or lactation. Children who get 48 weeks of IFN alpha (α) as an antiviral monotherapy respond effectively and tolerate it well.^1,8,9

Which IFN is now used instead of IFN-alfa 2a in treating cutaneous T-cell lymphoma (CTCL)?

IFN-alfa 2a, no longer available in the UK, is replaced with pegylated-IFN, which showed a high response rate without additional toxicity.¹⁴

How effective is IFN therapy for COVID-19?

Research by Buchynskyi et al. indicates that IFN-α may increase the number of patients discharged from the hospital but has no beneficial effect on the survival of inpatient COVID-19 patients. Davoudi-Monfared et al. (2020) assessed IFN beta (ß)-1a in severe COVID-19 cases in another randomised study. Compared to the control group, the study group saw a greater discharge rate on day 14 (66.7% vs. 43.6%) and a lower death rate after 28 days (19% vs. 44%).¹⁰

What are the research initiatives and prospects for IFN therapy?

IFN gamma (γ) and nivolumab are under study for safety in patients with metastatic solid tumours using a dose-escalation trial. IFN-γ stimulation raises circulating chemokines and paucity of immune-related adverse events that need further investigation, according to post hoc analysis. More investigation is essential to clarify the safety and efficacy of IFN therapy in treating SARS-CoV-2 and to identify the best IFN treatment plan for clinical application.

The use of human intestinal enteroids (HIEs) to study the mechanisms of human intestine virus pathogenesis is a recent development. This method allows investigation of the innate immune responses mediated by IFNs and IFN-stimulated genes and the interactions between intestinal epithelial cells and enteric viruses.^11,12,13

Summary

• The immune system responds to viruses by producing proteins called IFNs for controlling immune responses and preventing viral replication
• There are four different types of IFNs: alpha (α), beta (ß), gamma (γ) and lambda (λ). They function by stimulating multiple immune cells to identify and eliminate cancerous or infected cells while preventing the spread of viruses within host cells
• An essential component of contemporary medicine, IFN therapy activates the body's defences against several illnesses, from cancer to viral infections
• There is optimism for better treatment outcomes and patient care as IFN therapy continues to progress, thanks to the cooperation of researchers and medical professionals