Introduction

Non-Hodgkin Lymphoma is a type of cancer that affects parts of the immune system, predominantly developing within the lymphatic system. Without treatment, non-Hodgkin Lymphoma leads to a decrease in the immune system’s ability to battle infections, and can further invade important organs. 

There are multiple treatments available for non-Hodgkin Lymphoma, with standards of care such as chemotherapy, radiotherapy, and monoclonal antibodies therapy (molecules that are injected and aids the immune system in identifying pathogens or cancerous cells).¹ 

Interferon therapy is another treatment that can be used for non-Hodgkin Lymphoma, which has historically shown some clinical use. However, the side effects of interferon therapy have hindered its use as a sole cancer treatment. Nevertheless, interferon therapy has shown to be useful after the cancer has been treated or as an adjuvant. Current clinical studies have shown potential for interferon therapy to have future use. This will be explored below.

The lymphatic system and lymphoma

What is the lymphatic system?

The blood is composed of different cells: red blood cells (RBCs), white blood cells (WBCs), platelets, and plasma. In plasma, there are nutrients, waste products, antibodies, blood cells and more. Capillaries are a network between veins and arteries, and are responsible for the exchange of materials between blood and tissues. During this process, plasma seeps out and is absorbed by tissues, but not all of it is absorbed, leaving behind a product (lymph). 

The lymphatic system consists of the transport of lymph, or lymphatic fluid. These fluids carry protein-rich substances that are seeped out of blood vessels, and are transported via lymph capillaries (smaller tubes) and lymph vessels (bigger tubes). Lymph also transport important immune cells, such as lymphocytes, that are responsible for fighting back against infection. These vessels eventually connect into organs such as the spleen, lymph nodes, thymus, bone marrow, and tonsils.² Figure 1 (taken from the National Cancer Institute) shows an overview of the lymphatic system.

Figure 1 The Lymphatic System. Lymphatic organs (tonsils, thymus, spleen and bone marrow) and their connections with the lymph vessels. Figure taken from the National Cancer Institute.

What is lymphoma?

Lymphomas encompass a group of cancers that affect the lymphatic system and lymphocytes.

These lymphocytes are further classified into different cells, including B cells, T cells, and NK (Natural Killer) cells.³ There are two types of lymphoma: 

• Hodgkin Lymphoma (HL).
• Non-Hodgkin Lymphoma (NHL). 

Individuals with HL have the presence of Reed-Sternberg cells; lymphocytes that contain one or more nuclei (structures that contain chromosomes and DNA), and are abnormally large. In comparison, individuals with NHL do not have these cells. 

NHL subtypes

Within the scope of NHL, there are many subtypes, but they are generally classified into two groups. These are: 

• Aggressive, high-grade NHL and 
• Indolent (slow) low-grade NHL. 

According to the NHS, treatment for low-grade tumours does not need to be immediate, although its ability to be completely cured is lower than that of high-grade tumours (which need to be immediately treated). However, some subtypes can fall into both categories. Below shows the subtypes following the World Health Organisation (WHO)⁴ classification. WHO classifies subtypes based on what type of lymphocyte cells they affect. (Retrieved and modified from the Leukemia and Lymphoma Society). For the purpose of simplicity not all subtypes are shown, a more specific version of the categories can be viewed from an article by Professor Armitage et al⁵

Signs and symptoms

Signs and symptoms of NHL are as follows (NHS):

Diagnosis & treatments

NHL is generally diagnosed by taking a sample of a person’s swollen lymph node (known as a biopsy). After a biopsy returns showing NHL is present, further tests will be conducted to check the spread of the cancer. These tests include:

• Blood tests
• Chest X-ray
• Bone marrow sample (local anaesthetic is used)
• CT can
• Magnetic Resonance Imaging (MRI)
• PET scan
• Lumbar puncture

Current treatments for NHL include chemotherapy, and radiotherapy. However, challenges of NHL and the dysfunction of the lympathic system include having a weakened immune system, which alongside treatment, can weaken the immune system further. Thus, treatments such as monoclonal antibodies and interferon therapy have been analysed in their potential use for NHL. 

Interferon therapy

What are interferons?

Interferons (IFNs) are a type of signalling protein “signalling,” in the sense that these proteins signal cells to take a certain action by activating genes (known as the signal transduction pathway).⁶ In the case of IFNs, these actions are immune-related they help in inhibiting the growth of viruses and cells. 

IFNs are produced when a cell recognises foreign genetic materials inside it. This recognition is mediated by receptors (macromolecules), which detect viral components and activate signalling pathways. Once produced, IFNs are secreted from the infected cell and bind to IFN receptors on neighbouring cells. This binding triggers a domino-effect on signalling that causes the expression of IFN-stimulated genes, which work to inhibit viral replication and spread, and can also enhance the immune system's response to tumours.⁶

The JAK-STAT Pathway

There are different types of IFNs, and generally fall into two classes: type I IFNs and type II IFN. Both classes of IFNs are bound to kinases (a type of protein [enzyme] that speeds up specific biological reactions).⁷ Activation of these kinases results in the activation of another type of kinase, STAT (signal transducer and activator).⁷ Both STAT1 and STAT2 are responsible for analysing the genes and producing the proteins that aid in tissue repair, inflammation, and the death of cells (apoptosis).^7,8

Type I IFNs:⁷

• Consist of alpha (ɑ; IFN-ɑ) and beta (β; IFN-β) families, along with a few others.⁷ 
• All bind to a common receptor (type I IFN receptor). 
•  Bound to kinases known as tyrosine kinase 2 (TYK2) and Janus Activated Kinase 1 (JAK1).
• Both STAT1 or STAT2 are activated.

Type II IFN:⁷

• Only consists of gamma (ɣ; IFN-ɣ)
• Binds to a separate receptor (type II IFN receptor).⁷ 
• Bound to JAK1 and JAK2.⁷
• Only activates STAT1.⁷

Both classes of IFNs are bound to kinases (a type of protein [enzyme] that speeds up specific biological reactions).⁷ Activation of these kinases results in the activation of another type of kinase, STAT (signal transducer and activator).⁷ Both STAT1 and STAT2 are responsible for analysing the genes and producing the proteins that aid in tissue repair, inflammation, and the death of cells (apoptosis).^7,8

Clinical use of interferons

IFNs can be made in the lab to treat diseases, and in the case of cancer, can be used to prevent further growth of cancer cells by activating  the JAK-STAT pathway. Although all subtypes of interferons have been studied intensively, clinically active use of interferons for lymphoma diseases mainly use IFN-ɑ. Literature regarding IFN-ɣ use in lymphoma is limited, and IFN-β use is generally restricted to treating multiple sclerosis.⁹ 

A 1981 study conducted by the National Cancer Institute on IFN-ɑ showed limited results for patients with aggressive (high-grade tumour) NHL, with only a 15% response to the drug. However, ithas shown to be very effective (54% response) in low-grade NHL, particularly in Cutaneous T-cell Lymphoma (CTCL).^9,10 The study additionally used high doses of the therapy, causing toxic side effects such as:

• Anorexia,
• Occasional mental confusion, 
• Renal failure (resolved after dose reduction), 
• Fever
• Herpes lesions.^9,10 

The dose was subsequently reduced, but also led to reduction of the drug’s efficacy. Since the study, IFN-ɑ has been approved to treat low-grade CTCL (which include mycosis fungoides [MF] and Sezary syndrome [SS]).^7,9,11

Side effects

Side effects of IFN in CTCL are generally limited to fevers and fatigue, but an exhaustive list is shown below:⁹

A few hours after IFN injection to around two weeks of treatment

• Fever
• Fatigue
• Chills
• Muscle pain 
• Join pain
• Headaches

Chronic effects, generally dose related (reduction in dose leads to reduction in these symptoms)

• Fatigue
• Appetite loss
• Weight loss 
• Anaemia
• Platelet deficiency
• Lower WBC count

Other side effects (less common)

• Depression
• Increased irritability
• Thyroid dysfunction 
• Altered taste
• Diarrhoea
• Peripheral neuropathy
• Visual and auditory impairments
• Inducing or worsening of autoimmune disorders

How does interferon therapy work?

In the context of CTCL, IFN-ɑ is injected under the skin and helps stop cancer from multiplying further, it also increases the immune systems response to recognise cancer cells.⁹ 

More specifically, IFN-ɑ is able to indirectly activate CD8+ T cells and NK cells via the JAK-STAT pathway. This is achieved thanks to IFN-ɑ’s ability to increase the production of major histocompatibility complex (MHC) class I molecules on the surface of cells.⁹ MHC I molecules are responsible for presenting antigens to CD8+ T cells, therefore increasing immune system response.¹² 

The therapy is also able to slow down the production of a subtype of helper T cells known as T_H2 cells.⁹ These cells produce signalling proteins called Interleukin 4 and 5 (IL-4 & IL-5). Overexpression of IL-4 leads to the prevention of T_H1, which are necessary for tumour suppression.^9,13 Similarly, the overexpression of IL-5 can lead to the growth of immune cells called eosinophils.^9,14 Eosinophils are cells which contain enzymes that are released during infection and allergic reactions. In surplus, it can lead to eventual tissue damage an environment that is not helpful for fighting against cancer.¹⁴ However, prolonged interferon therapy can lead to an increased resistance of the therapy, meaning that the therapy isn’t as effective.

Studies have shown that sole use of interferon therapy, although promising, requires further investigation, possibly alongside other therapies to treat cancer.⁹ This is due to resultsvarying between individuals, and leading to reduced dosage across patients. Additionally, as it is more effective in early stages of CTCL, it is difficult for it to completely cure late stage cancer.⁹ 

Recent clinical studies have looked into combination therapy (the use of multiple therapies to treat NHL alongside interferon therapy), which have shown promising results.⁹ One example includes  the use of psoralen plus ultraviolet light phototherapy (PUVA) and IFN-α,^9,15 demonstrating higher complete response rates (89%). However, the studies are not standardised in their randomisation, and therefore require further analysis.⁹

Summary

• Non-Hodgkin Lymphoma is an umbrella term for a group of cancers related to the lymphatic system, which can be divided into aggressive or indolent cancers that affect different lymphocytes. 
• As the lymphatic system is partially responsible for the immune system, unwanted growth can lead to increased infection and eventual death. 
• There are multiple therapies currently used in standard care, including chemotherapy, radiotherapy and monoclonal antibodies. 
• Interferon therapy has been approved for specific NHL subtypes, such as Cutaneous T cell Lymphoma, but has not been approved for other types of NHL subtypes. 
• Current clinical trials look hopeful in the use of interferon therapy alongside other therapies, but needs to be researched further.