HODGKIN LYMPHOMA, EPSTEIN-BARR VIRUS, AND CAR-T THERAPY

Martinotti R, Kontochristos L. Hodgkin Lymphoma, Epstein-Barr Virus, and CAR-T therapy.  International Journal of Infection. 2025;9(2):57-62.

R. Martinotti^1* and L. Kontochristos²

¹ Department of Oncology, “La Sapienza” University, Rome, Italy;
² Department of Orthopedics and Traumatology, IRCCS Galeazzi Hospital, Sant’Ambrogio, Milano, Italy.

*Correspondence to:
Riccardo Martinotti, M.D.,
Department of Oncology,
“La Sapienza” University,
Rome, Italy.
e-mail: riccardo.martinotti@uniroma1.it

Received: 16 April, 2025 Accepted: 18 July, 2025

ISSN 1972-6945 [online] Copyright 2025 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Hodgkin lymphoma (HL) is a type of cancer that originates from B lymphocytes, and is one of the most common cancers in young people. Epstein-Barr virus (EBV) infection plays a significant role and increases the risk factor in approximately one-third of affected patients. Treatment of HL generally relies on a combination of chemotherapy and, in some cases, radiation therapy. Chemotherapy and immunotherapy have revolutionized treatment, leading to cure rates in nearly 80% of cases. In recent years, immunotherapy has greatly improved the disease outcome. Immunotherapy with chimeric antigen receptor t-cell therapy (CAR-T) and novel bispecific antibodies (bsAbs) has reduced the risk of relapse and increased survival in lymphoma patients.

KEYWORDS: Hodgkin lymphoma, Epstein-Barr virus, CAR-T therapy, immunotherapy, tumor, lymphocyte

INTRODUCTION

Hodgkin lymphoma (HL) is a malignant tumor of the lymphatic system which originates from B lymphocytes (1), a type of white blood cell essential to the adaptive immune system and originate and mature in the bone marrow where they develop to produce antibodies (Fig.1). The disease is characterized by the uncontrolled growth of lymphocytes that are essential for defending the body against foreign agents. This lymphoma is distinguished from other types of non-Hodgkin lymphoma (NHL) by the characteristic presence of Reed Sternberg cells which are visible under the microscope (2).

Fig. 1. The generation of mature B cells from bone marrow stem cells.

In Italy, there are approximately 1,200 new diagnoses of HL per year, with a higher incidence among young people, especially in the 15 to 30 years old age group (3). The most common symptoms include swollen lymph nodes that are often located in the neck, armpits, and/or groin, persistent fever, especially in the evening and without apparent cause, heavy night sweats, unexplained weight loss, fatigue, and widespread or localized itching (4).

Treatment of HL depends on the stage of the disease. In general, treatment is based on a combination of chemotherapy and in some cases, radiotherapy (5). A crucial contribution to improving treatment came from the Italian oncologist Gianni Bonadonna who devised the basic chemotherapy regimen still used today in the treatment of HL (6). In recent years, research has made further progress (7). For the forms most resistant to traditional treatments, the introduction of immunotherapy has represented a turning point, significantly improving the prospects for treatment. Currently, thanks to the integration of different therapeutic strategies, recovery is possible in almost 80% of cases of HL (8).

DISCUSSION

There is no specific cause for the development of HL, but some factors can increase the risk (9). Among these, the Epstein-Barr virus (EBV) plays a significant role in about a third of cases (10). This virus that causes mononucleosis can infect lymphocytes and alter their behaviour, promoting tumour development (11). However, the presence of EBV is neither necessary nor sufficient to cause HL (12).  Many patients with HL show no traces of the virus, while most people infected with EBV do not develop lymphoma (13).

Lymphomas represent a significant part of the diagnoses of blood diseases and are divided into two large categories: HL and NHL. Fortunately, thanks to progress in research, the outlook for patients has improved significantly (14).  The arrival of increasingly effective and targeted therapies, such as immunotherapy, chimeric antigen receptor t-cell therapy (CAR-T), and new bispecific antibodies (bsAbs), have reduced the risk of relapses and increased survival and the chances of recovery (15).

HL mainly affects young people, with a peak incidence around the age of twenty, but it can also appear at an advanced age. Over 80% of patients survive five years after diagnosis, thanks to available therapies (7). On the other hand, NHLs are more common in people over age 60 and include heterogeneous forms (16). Although they progress rapidly, the aggressive forms offer greater chances of recovery compared to the so-called indolent lymphomas, which evolve more slowly and are more difficult to eradicate (17).

EBV is associated with several cancers, especially with mixed cellularity and lymphocyte depletion subtypes, including HL (18). This association involves complex biochemical and cellular mechanisms. EBV is known to cause infectious mononucleosis and is a member of the gamma-herpesvirus family that infects B cells and epithelial cells (19). EBV causes a latent infection in B lymphocytes (20). In type II latency, HL expresses Epstein-Barr nuclear antigen 1 (EBNA1), latent membrane protein (LMP)1, and 2A-B (21). These proteins serve for proliferation and allow survival and protection against immune cells (22).

LMP1 is an oncogenic protein and develops similar functions to CD40, a constitutive factor of B cells involved in the activation of the NF-kB pathway (23). LMP1 activates TNF receptor-associated factors (TRAFs) implicated in the nuclear translocation of NF-κB (24).  These reactions upregulate genes that promote cell survival and inflammation (25). In addition, LMP1 is implicated in the synthesis of IL-6 and IL-13, cytokines that activate the JAK/STAT signaling pathway, promoting proliferation and immune evasion (26). Through the PI3K/AKT pathway, LMP1 is involved in apoptosis and metabolic changes that promote tumor cell proliferation (27). LMP2A is implicated in cell survival by mimicking the B-cell receptor’s (BCR) function (28). This allows B-cell survival even without BCRs, which are often downregulated or nonfunctional in Hodgkin-Reed-Sternberg cells (29). LMP2A activates SYK kinases and the PI3K pathway, promoting cell viability and immune evasion (30).  In HL, malignant cells produce the cytokines IL-10 and TGF-β that suppress the immune system (31).

Therapy

In general, today’s therapy against lymphomas can include immunotherapy, CAR-T therapy, or bsAbs (32).  Immunotherapy works by boosting the immune system, removing the brakes that the tumor uses to escape the control of natural defenses. This is a strategy that makes the immune system more effective in recognizing and attacking malignant cells (33).

CAR-T therapy is a personalized and innovative technique (34).  The patient’s T lymphocytes are removed, genetically modified to recognize a specific target present on the tumor cells, and reinfused into the body (35). These enhanced cells multiply and attack the tumor with precision (Fig.2).

Fig. 2. Mechanisms involved in the generation of chimeric antigen receptor t-cell therapy (CAR-T) to destroy tumor cells.

BsAbs are engineered antibodies designed to bind to two different antigens (epitopes) at the same time (36). They differ from conventional monoclonal antibodies that target only one antigen. This ability to attack a dual target gives them unique therapeutic advantages, especially in cancer immunotherapy (37). The bsAbs are a further evolution of immunotherapy. They bind simultaneously to the tumor and healthy T lymphocytes, putting them in direct contact (38). This stimulates the targeted response that allows the lymphocytes to selectively eliminate cancer cells (Fig.3).

Fig. 3. Bispecific antibodies (bsAbs) are engineered antibodies produced by B cells that bind tumor and healthy cells.

In recent years, research has transformed the therapeutic landscape (39). New strategies such as immunotherapy, CAR-T therapy, and bsAbs are significantly improving patients’ outlook (38). For diffuse large B-cell lymphomas, which represent approximately 30% of NHLs, new options are available that can reduce the risk of disease progression and increase the chances of recovery (40). Progress continues even for patients with relapsed or refractory forms. BsAbs are capable of activating the immune system to distinguish tumor cells and are one of the most promising innovations. These treatments are often administered in a less invasive way than traditional therapies, and lasting responses are being obtained even in very complex clinical situations. Today, the challenge is not only to develop more effective treatments but to make them available to all patients, while ensuring an adequate quality of life (41). The latest generation of therapies are helping to improve both of these dimensions, offering new hope to those facing a diagnosis of blood cancer, including HL.

CONCLUSIONS

HL is a cancer of the lymphatic system that originates from B lymphocytes and primarily affects young people. Its origin is unknown, but EBV infection plays an important role. Immunotherapy with CAR-T cells and bsAbs is generating great expectations for treating HL.

Conflict of interest

The authors declare that they have no conflict of interest.

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