Introduction

Lymphoma encloses a spectrum of different types of malignancies affecting the lymphatic system, which includes lymph nodes, spleen, thymus, and bone marrow. These compartments store lymphocytes, a type of white blood cell, that can develop into B-cells, responsible for antibody production, and T-cells, which identify and attack unhealthy or malignant cells and foreign antigens. Consequently, lymphocytes play a pivotal role in the body’s immune system, protecting against infections and diseases.

Lymphoma arises when these lymphocytes are transformed into cancerous cells that grow uncontrollably and are not eliminated by the body. The various regions of the lymphatic system where lymphomas are found and the different stages of lymphocyte proliferation generate the distinct subtypes of lymphomas.¹

There are two main categories of lymphomas: Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL), and more than eighty different subtypes. Although these subtypes may share similarities, they present particular clinical features and necessitate varied treatment options.

Apart from chemotherapy and radiotherapy, targeted strategies and immunotherapy have been approved as effective treatment strategies for lymphomas, vastly improving outcomes over the past few decades. By aiding the immune system to recognise and eliminate cancer cells, rituximab was the first immunotherapeutic agent used more than twenty years ago, granting the ongoing development and introduction of other novel therapies.²

Types of lymphoma

The diverse types of lymphoma require tailored therapeutic approaches that precisely target cancer cells, ensuring optimal results. Recognising the exact type of lymphoma in each patient is vital and it involves a thorough examination of lymphoma cells to determine the exact nature. The categorisation of lymphoma can be outlined as follows:

Non-Hodgkin’s lymphoma

Characterised by the absence of Reed-Sternberg cells, hallmark cells of HL, it is relatively more common than HL, affecting primarily adults over 65 years old.³ A mutation in the maturation of immune system cells, including B-cells, T-cells, or natural killer cells (NT), can lead to the different subtypes of NHL:

B-cell origin:

• Precursor B-lymphoblastic leukaemia/lymphoma (precursor B-cell acute lymphoblastic leukaemia)
• B-cell chronic lymphocytic leukaemia (CLL) /small lymphocytic lymphoma (SLL)
• Follicular lymphoma
• Mantle cell lymphoma
• Diffuse large B-cell lymphoma (DLBCL)⁴

T-cell origin:

• Precursor T-lymphoblastic lymphoma/leukaemia (precursor T-cell acute lymphoblastic leukaemia)
• Anaplastic large cell lymphoma (ALCL)⁴

Hodgkin’s lymphoma 

It is less common, occurring in 10% of all lymphoma diagnoses, and is highly curable with an 80% cure rate. It is more prevalent in patients aged between 20-40 years old and those over 55 years old. It is characterised by the presence of Reed-Sternberg cells,⁵ and is further subdivided according to unique clinical characteristics into nodular lymphocyte predominance HL (NLP-HL) and classical Hodgkin’s lymphoma (cHL), which accounts for 95% of cases.^4,5

Immunotherapy in lymphoma treatment

Cancer cells develop a tumour microenvironment, which, normally, cells from the innate and adaptive immune system can infiltrate, influencing tumour evolution. Nevertheless, tumour cells can evade and trick the natural antineoplastic processes of the immune system, resulting in the progression of malignancies.⁶ Tumour cells may express insufficient antigens normally recognised by the immune system, suppress the immune responses, and fuel the tumour microenvironment with cytokines that impair immune activation, response, and memory.

The latest advancements in comprehending the complexity of this tumour environment and the exact cells involved in each type of lymphoma are crucial for selecting the appropriate immunotherapeutic strategy. The proper approach is selected as such to address the pertinent issue and may involve stimulating antigen expression, directly acting on T-cells and NK cells, or impeding checkpoint signalling.⁷

In other words, immunotherapy may be defined as the use of therapeutic agents that modulate the immune system to target and eliminate cancer cells. Different categories have emerged for lymphoma treatment, including:⁸

Monoclonal antibodies

Antibodies act by recognising and binding to a specific antigen-protein found on the surface of cancerous cells, such as CD20 and CD52. Additionally, they can target unique receptors on immune cells, controlling their suppression to limit cancer immune resistance or recruiting an immune attack against malignant cells. One of the first monoclonal antibodies approved by the European Medicines Agency (EMA) for lymphoma is rituximab, targeting CD20 expressed on B-lymphoma cells.

Rituximab is used as the first-line treatment or in combination therapy for B-cell lymphomas such as DLBCL, follicular lymphoma, and CLL.^1,9 Subsequent development of monoclonal antibodies like obinutuzumab and ofatumumab, which also target CD20 in B-lymphoma cells and have unique characteristics, has contributed to improved outcomes in patients with various types of B-lymphocyte cancers.¹⁰

Antibody-drug conjugates (ADC)

The success of monoclonal antibodies gave way to more advanced developments by utilizing a toxic agent with anti-tumoural action. Specifically, this strategy incorporates the use of monoclonal antibodies attached to chemotherapeutic drugs via a stable chemical linker. Once bound to a specific antigen on the surface of a malignant cell, they enter the cell, where the linker degrades, releasing the cytotoxic agent, which halts cancerous cell division, resulting in cell death.

Examples of ADCs include brentuximab vedotin, an antibody targeting CD30 found on lymphoma cells, connected to monomethyl auristatin E, an agent with cytotoxic effects. It is used in combination with chemotherapy for cHL, and other CD30+ T-cell lymphomas, including ALCL. Another ADC that has been developed using the same linker as brentuximab vedotin is polatuzumab vedotin, targeting CD79b found on B-lymphoma cells. It can be used in combination therapy or as second and third line therapy for DLBCL.^1,10

Bispecific antibodies

Designed to bind to two antigens or two epitopes (specific parts) of the same antigen, they can simultaneously bind to specific sites on T-cells and tumour antigens. More and more bispecific antibodies are getting approved by the EMA due to their potential for more targeted therapy with synergistic action. Most of them are bispecific T-cell engagers (BiTEs) linking the CD3 antigen of T-cells to CD19 or CD20 found on malignant cells hence act by directing T-cells to act against them, enhancing in this way their anti-tumoural action^2,10

Examples include blinatumomab, a CD19xCD3 BiTE used for relapsed or refractory B-precursor acute lymphoblastic leukaemia,¹¹ mosunetuzumab and epcoritamaba, which are both CD20xCD3 BiTEs used for patients with relapsed or refractory follicular lymphoma,¹² and relapsed or refractory DLBCL, respectively.¹³

Immunomodulating drugs

Immunomodulating drugs exhibit their anti-tumoural action by acting on the immune system, either by directly attacking malignant B-cells, altering the tumour microenvironment, hindering malignant cell supply, or stimulating the immune system.¹ Examples include lenalidomide approved by the EMA for mantle cell lymphoma and follicular lymphoma (used in combination therapy with rituximab).¹⁴

Immune checkpoint inhibitors

Checkpoints are substantial proteins found on cells that help the immune system distinguish healthy from tumoural cells to destroy them. In lymphoma, these immune checkpoints and their receptors are overexpressed, contributing to a more favourable microenvironment for cancer cells that exhibits immune resistance and immunosuppression. Immune checkpoint inhibitors target specific immune checkpoint proteins such as CTLA-4, PD-1, and its ligand PD-L1, all found on T-cells.

By blocking these checkpoints that normally act as ‘off switches’ for the immune system, they boost T-cell attacks against tumour cells. EMA-approved inhibitors include anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab, indicated for cHL. Immune-related adverse effects may frequently be associated with this strategy but are usually mild and rarely life-threatening. Current clinical trials are being conducted, exploring the potential of immune checkpoint inhibitors also used in combination treatment, analysing their effectiveness against various lymphoma types.²

CAR T-cell therapy 

This adaptive therapy consists of genetically engineered T-cells with a chimeric antigen receptor (CAR) to specifically target lymphoma cells. T-cells are extracted from each patient, are grown in the lab, and are synthesised with a specific region that binds to specific antigens found on lymphoma cells. The modified T-cells are then infused back into patients.

Further optimisation is crucial to avoid resistance and toxicities such as cytokine release syndrome.² The EMA has approved second-generation CAR T-cell agents, in specific facilities, including axicabtagene ciloleucel used for recurrent or refractory DLBCL and follicular lymphoma,¹⁵ tisagenlecleucel also used for relapse or refractory DLBCL and follicular lymphoma, and relapse or refractory B-cell acute lymphoblastic leukaemia in patients up to 25 years old.¹⁶

Summary

Lymphoma refers to a group of cancers of the lymphatic system involving immune cells. While traditional categorisation includes HL and NHL, with NHL being more common and HL being associated with higher survival rates, more detailed subtypes have been acknowledged that require specific treatment approaches. 

Chemotherapeutic agents and radiotherapy remain vital in cancer therapy, however, the emergence of immunotherapy holds great potential in cancer treatment. Novel approaches, including monoclonal antibodies, immune checkpoint inhibitors, and CAR T-cell therapy are immensely promising for managing lymphoma among other malignancies. These strategies focus on more targeted approaches, direct attacks on malignant cells and their microenvironment, and the overall modulation of the immune system to fight cancer cells.

Immunotherapeutic methodologies are currently being studied to deliver optimal results in cancer patients, even in those who have not responded well to other conventional treatments. Combining immunotherapy with other anticancer regimens allows the establishment of a more personalised approach suitable for the specific stage of the tumour and the state of the patient’s immune system. Despite limitations, including patient selection, which is decided by certified medical professionals, and potential immune-related adverse effects, immunotherapy stands as one of the most effective approved treatments for lymphoma.