Introduction

Follicular lymphoma (FL), the most common type of non-Hodgkin lymphoma, develops when special white blood cells called B cells become cancerous. These abnormal B cells, known as lymphoma cells, slowly build up in the lymph nodes but can also affect other areas of the body. Around 2,300 people are diagnosed with FL every year in the UK, making up 20% of non-Hodgkin lymphoma diagnoses.¹

Immunotherapy is a cancer treatment that enhances the immune system’s ability to “see” and attack cancer cells, often with fewer and less severe side effects than traditional therapies. Additionally, immunotherapy is associated with greater remission length and a reduced likelihood of relapse. Immunotherapy can also be tailored to the specific cancer type and area affected, again increasing its success.²

Pathophysiology of follicular lymphoma

Genetic and molecular basis

FL can be caused by mutations (or changes) in the information, and genes, within cells. The most common genetic alteration seen in FL patients is t(14;18), where part of chromosome 14 swaps places, or translocates, with part of chromosome 18. This causes BCL2, a well-known carcinogenic gene enabling cells to survive ‘destruct’ signals, to become overexpressed. Consequentially, t(14;18) cells can evade death and divide uncontrollably, a key characteristic of cancer cells.

Mutations in epigenetic regulators, responsible for managing the expression of DNA and genes in cells to control their behaviour, cause dysregulated gene expression (e.g., CREBBP/EP300) and silence genes (e.g., EZH2) to promote survival and proliferation of FL cells.

Additionally, cell survival and proliferation can be enhanced by molecular pathways, such as PI3K/AKT/mTOR and NF-κB. Alterations in these pathways are often seen in FL patients, enhancing cell and malignancy growth.³

Immune evasion mechanisms

The development of FL is heavily influenced by cellular interactions with the immune system. Cancer cells create a tumour microenvironment, which helps the cancer grow and develop. This microenvironment is highly immunosuppressive, preventing the immune system from eliciting a response and destroying the cancer. Additionally, the cancer is able to utilise immune cells, such as T helper cells, to support the growth and survival of FL rather than destroy it. FL cells can also exploit the immune system through its checkpoints, expressing markers such as PD-1, which act as “stop” signals to the immune system and ultimately prevent immune attack.

Types of immunotherapy used in follicular lymphoma

Immunotherapy aims to boost the immune system and overwhelm the cancer with immune cells, which can prevent cancer-mediated immune manipulation to stop the growth of the cancer. There are four main types of immunotherapy used to treat FL:⁴

1. Monoclonal antibodies: the immune system produces antibodies as keys to switching off “bad” cells such as bacteria and cancer cells. Monoclonal antibodies are manufactured by scientists to specifically attach to certain targets that are present in the cancer cells to destroy them. There are three main monoclonal antibodies used in FL treatment, silencing CD20 on B cells, which become transformed in this cancer:
   • Rituximab is often used in combination with chemotherapy, termed chemotherapeutics, but can be used stand-alone
   • Obinutuzumab is also used in chemotherapy
   • Ofatumumab is used as a last resort when other treatments have little to no response

These are often injected directly into the veins, giving quick effects and minimal side effects in the long term.

2. Immune checkpoint inhibitors: drugs, such as pembrolizumab, block the checkpoints causing immune responses to halt, enhancing the success of immune attack. These are also administered through the veins every 3 to 6 weeks, with side effects typically lasting a few hours after receiving
3. Chimeric antigen receptor (CAR) T-cell therapy: immune cells called T cells are removed from the patient's blood and altered to express CARs on their surface. CARs are able to attach to the surface of FL cells and destroy them when infused back into the patient. CAR T-cell therapy is highly targeted to the cancer; however, side effects can be more severe due to the intensity of the immune response they cause
4. Bispecific T-cell engagers (BiTEs) are antibodies designed to attach to two unique targets, giving them the ability to attach to CD20 on FL cells and CD3 on T cells. This technique brings immune cells closer to the cancer cells, causing a specific and controlled immune attack. This treatment can also bring around severe side effects due to the intensity of the immune response, in addition to less severe but instant effects

Challenges and limitations

While immunotherapy is an exciting and innovative cancer treatment, it comes with several challenges and limitations. While many FL patients benefit from immunotherapy, some people’s cancer cells are able to resist or hide from the boosted immune system, preventing the therapy from working. Immunotherapy is also less harsh than other options, like chemotherapy, but can still cause side effects. Immunotherapy mainly causes minor and short-lasting effects such as nausea, headaches, and diarrhoea; however, in treatments where the immune attack is intense, more intense inflammation of major organs can occur, causing organ failure and more severe complications. 

Immunotherapies can be extremely costly due to their engineered and often personalised nature. This discourages bodies such as the NHS from funding these treatments where they are not a last resort, leaving patients with therapies that may not be as effective. FL is also a complex disease, with different patients requiring different modifications within the same treatments, making drug development difficult. Even if the modified therapy works, to begin with, patients can become resistant over time, leading to disease relapse.

Since immunotherapy is a new treatment for FL, there is limited scientific knowledge on its long-term effects and safety. Therefore, more research is needed to conclude the future of immunotherapy in these patients and any long-term consequences patients may face.

Summary

• FL is a common type of non-Hodgkin lymphoma where B cells become cancerous, primarily affecting lymph nodes and sometimes other body areas
• Immunotherapy enhances the immune system's ability to target and destroy cancer cells, offering benefits like fewer side effects and longer remission compared to traditional therapies
• FL is often driven by genetic mutations like the t(14;18) translocation, leading to overexpression of the BCL2 gene, and by mutations in epigenetic regulators, which disrupt normal gene expression
• FL cells evade the immune system by creating an immunosuppressive tumour microenvironment and using immune checkpoints like PD-1 to avoid immune detection
• Four main immunotherapy approaches used in FL include monoclonal antibodies (e.g., Rituximab), immune checkpoint inhibitors, CAR T-cell therapy, and bispecific T-cell engagers (BiTEs)
• Immunotherapy faces challenges like variability in patient response, potential for severe side effects, high costs, and the development of resistance over time
• Due to its relatively recent introduction, more research is needed to understand the long-term safety and effectiveness of immunotherapy in treating FL