Introduction

Definition of follicular lymphoma (FL)

Follicular lymphoma is a type of slow-growing blood cell cancer that specifically affects B-cells which is a type of white blood cell. It is classified as a type of solid tumour and is a form of non-Hodgkin lymphoma (NHL). It is a phenomenon where white blood cells in the lymphatic system will grow and divide abnormally, disrupting their normal function in defending the body against infectious and foreign substances. The abnormal white blood cells often develop in clumps known as ‘follicles’. Since B-cells are produced in lymph nodes, a prominent symptom of follicular lymphoma is swelling of the neck and armpits where the lymph nodes are found. It is prevalent among adults rather than in children.¹

Importance of targeted therapy

Like other cancer types, common treatment options for blood cancer include radiotherapy, chemotherapy, and targeted therapy. In this article, we will dive into the therapeutic role of targeted therapy for follicular lymphoma. The objective of targeted therapy is to target specific proteins that are important for the growth and spread of cancer cells.² 

Pathophysiology of follicular lymphoma

Genetic and molecular basis

A thorough understanding of the disease mechanism and cellular pathways is needed to develop effective targeted therapy to create specific molecules to target relevant proteins. Follicular lymphoma arises due to genetic mutations. An antiapoptotic protein is produced, causing an aggressive lymphoma as cell death is reduced. In some cases, the BCL-6 gene may experience a loss of function, which is crucial for the development of germinal centres and for stopping premature B-cells from leaving the germinal centre too early. Mutations in BCL-6 hinder the production of antibody-secreting B-cells, resulting in lymphoma.^1,3,4

Role of the immune system in FL progression

In the germinal centres, mature B-cells normally undergo selection based on their affinity to antigens. B-cells that are not selected will undergo death by default. However, in follicular lymphoma, the overexpression of antiapoptotic protein due to the BCL2 proto-oncogene prevents non-selected B-cells from experiencing apoptosis. This contributes to the upregulated cancer cell proliferation.^5,6

Current targeted therapies for follicular lymphoma

The conventional treatment for follicular lymphoma is chemotherapy, but its downsides include side effects and toxicity to non-target tissues. Nevertheless, various targeted therapies have been developed as an alternative to traditional chemotherapy due to its promising benefits. 

Monoclonal antibodies

Monoclonal antibodies are an example. Rituximab is the most common first-line therapeutic agent used for follicular lymphoma. This Type-I anti-CD20 antibody binds to CD20 protein located on the surface of cancerous white blood cells. It signals the immune system to destroy the cancerous B-cells. Other monoclonal antibodies like obinutuzumab and tositumomab, a genetically engineered Type-II anti-CD20 antibody, have been developed and tested in in vitro and in-vivo studies. The differences are lower toxicity and a different effect on the cellular pathway induced when compared to Rituximab. Overall, the Type-II monoclonal antibodies display higher efficacy in depleting B-cell activity.^7,8

Small molecule inhibitors

Alternatively, small molecule inhibitors are commonly used in B-cell lymphoma therapy. The Bruton tyrosine kinase inhibitor (BTKi) (a drug that prevents the activity of the BTK protein) binds to the B-cell antigen receptor. When activated, this receptor stimulates and maintains the proliferation of mature B-cells that can allow malignancies to occur. Small molecule inhibitors like these can further prevent the spread of different types of lymphoma. Furthermore, Phosphoinositide 3-Kinase (PI3K) inhibitors are not just used for follicular lymphoma treatment but also for solid and blood malignancies. Activated PI3K also causes malignancy development by promoting the survival and proliferation of cancer cells. Drugs like idelalisib and duvelisib received approval from the FDA but were later withdrawn due to immune-toxicity concerns that arose in clinical trials.^7,8,9,10

Immunomodulatory agents

Immunomodulatory agents are either aimed directly at tumour cells or the tumour microenvironment. For instance, lenalidomide is an immunomodulatory agent that aims to stimulate the production of T-cells as part of the upregulation of the immune system. This drug is often administered with Rituximab monoclonal antibody to treat follicular lymphoma.¹⁰

Lenalidomide causes the degradation of certain transcription factors and subsequent release of cytokines; the immune system will be stimulated as T-cells and natural killer cell production increases. This mechanism can combat the spread of tumours. The increase in cytokines also reduces the level of anti-apoptotic proteins.⁷

CAR-T cell therapy

Chimeric antigen receptor (CAR-T) cell therapy serves as an alternative treatment option for follicular lymphoma patients who do not respond well to other therapies like monoclonal antibodies. This is also the case for patients who experience recurrences of symptoms. We classify these cases of follicular lymphoma as a relapsed/ refractory disease.¹¹

The genetically engineered T-cells target antigens found on cancerous B-cells like CD19 and CD20. Patients in clinical trials demonstrated a high response rate to the therapy. Recent studies have suggested that using CAR-T cells expressing various receptors for a combined effect on cancerous B-cells has an improved efficacy. However, the downsides of utilising this technology include the high costs and low accessibility involved in developing CAR-T cells for individual patients with follicular lymphoma heterogeneity.¹²

Future directions in targeted therapy

Personalised medicine

Several clinical trials are in progress to evaluate the efficacy of new therapies to improve personalised medicine for follicular lymphoma. There is a growing interest in identifying cancer biomarkers and performing subsequent genetic sequencing to allow healthcare professionals to predict a patient’s response to a certain intervention. Biomarkers of interest include macrophages (found in the tumour microenvironment), granzyme B (found on cytotoxic T-cells), and FOXP1 (found on B-cells). Further studies on these biomarkers will allow for risk stratification when assessing the effects of different combinations of therapeutic agents. This is because the molecular pathways and disease mechanisms leading to follicular lymphoma can be understood.^11,13

Combination therapy

An emerging field of study is the usage of bispecific T-cell engaging (BiTE) antibodies that bind to either the CD20 receptor on B-cell tumours or the CD3 receptors on effector T cells. The purpose is to stimulate an immune response in the host to kill off the cancer cells. BiTEs like mosunetuzumab and epcoritamab are more advantageous than CAR T-cell therapy as it is less time-consuming because T-cells do not need to be collected from the patient and genetically modified specifically for each patient. Many studies revolved around testing the synergistic therapeutic effects of BiTE when administered with targeted therapy. This includes lenalidomide as an immunomodulatory agent.⁷

Summary

Follicular lymphoma (FL) is a slow-growing blood cancer that affects B-cells, which are a type of white blood cell. It is categorized as a solid tumour and a form of non-Hodgkin lymphoma (NHL). In FL, white blood cells in the lymphatic system grow abnormally, forming clumps called “follicles,” which disrupt their normal immune function. A common symptom is swelling in the neck and armpits due to enlarged lymph nodes, and it mainly occurs in adults.

Common treatments for FL include radiotherapy, chemotherapy, and targeted therapy, which aims to focus on specific proteins that promote the growth and spread of cancer cells. Traditionally, chemotherapy has been the main treatment for FL, but it can have negative side effects. Therefore, targeted therapies are being explored as effective alternatives.

Monoclonal antibodies, like Rituximab, are widely used to treat FL. Newer antibodies, such as obinutuzumab and tositumomab, have been tested for lower toxicity and better efficiency in depleting B-cells. Additionally, small molecule inhibitors, like Bruton tyrosine kinase inhibitors (BTKis), are effective in B-cell lymphoma by preventing the activation of proteins that encourage B-cell proliferation.

Immunomodulatory agents, like lenalidomide, enhance the immune response by increasing T-cell and natural killer cell production. They often work alongside monoclonal antibodies for better results. CAR-T cell therapy is another option for patients whose cancer has not responded to other treatments. Looking forward, research is focused on personalised medicine and identifying cancer biomarkers to predict treatment responses. Combination therapies, like bispecific T-cell engaging (BiTE) antibodies, are also being studied to stimulate immune responses against cancer more efficiently than traditional CAR-T therapies.