CAR-T THERAPY FOR LYMPHOMAS ASSOCIATED WITH INFECTIONS

Candeloro AS, Stuard S. CAR-T therapy for lymphomas associated with infections. International Journal of Infection. 2025;9(1):17-21.

A.S. Candeloro¹ and S. Stuard^2*

¹ Department of Oncology, University “Gabriele D’Annunzio” of Chieti-Pescara, Chieti, Italy;
² Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.

*Correspondence to:
Stefano Stuard,
Fresenius Medical Care Deutschland GmbH,
Bad Homburg, Germany.
e-mail: Stefano.stuard@freseniusmedicalcare.com

Received: 24 January, 2025 Accepted: 03 March, 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

Lymphomas are blood cancers which are divided into Hodgkin and non-Hodgkin lymphomas. There has been significant progress treating lymphomas with the advent of immunotherapy, including chimeric antigen receptor T cell (CAR-T) therapy. This therapy allows engineered lymphocytes to directly and selectively eliminate tumor cells. CAR-T therapy is a new personalized technique approved for some aggressive B-cell lymphomas, which express the CD19 target. CAR-T therapy is significantly improving the life expectancy of lymphoma patients. Viral or bacterial infections can increase the risk of developing some types of lymphoma. For example, Epstein-Barr virus (EBV) is associated with Burkitt’s lymphoma and Hodgkin lymphoma, while Helicobacter pylori is associated with mucosal lymphoma. Although EBV does not often cause serious damage, it can cause some lymphomas in immunocompromised individuals. Specific CAR-T can be used against viral antigens such as those expressed by EBV, although more research is needed.

KEYWORDS: CAR-T therapy, lymphoma, CD19 target, immunotherapy, infection

INTRODUCTION

Every year in industrialized countries, the number of individuals diagnosed with blood cancers such as leukemia, myeloma, and lymphoma is increasing (1). Lymphomas are divided into two main categories: Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (2). Thanks to advances in research, the outlook for lymphoma patients has improved significantly. Until a few years ago, chemotherapy was the classic treatment for blood cancers, including lymphomas. Today, this strategy can be combined with immunotherapy (3), a completely different approach from chemotherapy that consists of stimulating the immune system to recognize and fight tumor cells. This can be done thanks to three new categories of drugs: immunotherapeutics, bispecific antibodies, and chimeric antigen receptor T cell (CAR-T) therapy (4).

Immunotherapeutics work by strengthening the immune system to make it more effective in recognizing and attacking cancer cells (5). Bispecific antibodies are drugs that represent a further evolution of immunotherapy (6). They bind to the tumor and healthy T lymphocytes at the same time, putting them in direct contact. This stimulates the targeted response that allows the lymphocytes to directly and selectively eliminate tumor cells.

The arrival of new, increasingly effective and targeted therapies, such as CAR-T immunotherapy and new bispecific antibodies has reduced the risk of relapses and has increased survival and the chances of recovery (7). So, in recent years, research has transformed therapeutic strategies with the advent of immunotherapy. CAR-T therapy and bispecific antibodies are significantly improving the outlook for patients (8). For large B-cell lymphomas, which represent approximately 30% of non-Hodgkin’s lymphomas, new options are available that can reduce the risk of disease progression and increase the likelihood of recovery (9). Progress continues even for patients with relapsed or refractory forms (10).

DISCUSSION

Bacterial or viral infections can trigger the development of lymphoma (11,12). Epstein-Barr virus (EBV) is implicated in infectious mononucleosis and is associated with some lymphomas such as Burkitt and Hodgkin lymphoma, as well as the aggressive human immunodeficiency virus 1 (HIV-1). Helicobacter pylori, a bacterium that infects the stomach, can induce gastric lymphoma determined by mucosa-associated lymphoid tissue lymphoma (MALT), (13) which is a type of non-Hodgkin B-cell lymphoma that arises in mucosal sites (14).

EBV infection is very common and often does not cause serious symptoms, but in certain individuals with a weak immune system, the virus can cause some lymphomas including Burkitt’s lymphoma (15).  This lymphoma is very aggressive, although today it responds well to therapy if treated promptly. Lymphoma caused by EBV is very common in Africa and is associated with malaria (16). To date, there is no specific drug for treating lymphoma, so chemotherapy, immunotherapy, stem cell therapy, and CAR-T therapy are used (17).

CAR-T therapy

CAR-T therapy is a personalized and innovative technique (18) used to treat B-cell lymphomas, such as diffuse large B-cell lymphoma (19) (Table I). EBV and HIV-associated lymphomas arise in settings where a chronic infection plays an important role in the development of the tumor (20). For example, this can occur in Burkitt lymphoma and some extranodal lymphomas associated with EBV, or in lymphomas of immunosuppressed patients such as those infected with HIV-1 (21).

Table I. A brief methodology scheme for CAR-T gene therapy.

HIV-1 is the fastest and most aggressive form of HIV infection, while HIV-2 infection can remain controlled for years without the need for therapy. When we simply speak of AIDS virus we mean HIV-1, the most widespread globally, while HIV-2 is slower, less contagious, and less aggressive (22).

In these lymphomas, CAR-T therapy could be useful, but must be used with caution to reduce side effects (23). Patients infected with HIV and are therefore immunosuppressed, have shown an improvement after CAR-T therapy, compared to untreated patients (24). For EBV-positive lymphomas, there are also experimental approaches that use T cells modified against specific viral proteins.

CAR-T therapy is currently approved in some aggressive B-cell lymphomas, regardless of cause, including some types associated with infections, as long as they express the CD19 target (19). For example, patients with EBV-positive lymphoma who express CD19 may be candidates if they meet the clinical criteria (25). In HIV immunodeficiencies, there are studies that demonstrate that CAR-T therapy could be effective and safe, but case-by-case evaluations and caution are still needed (26). Today, specific CAR-T treatment programs are being developed that target viral antigens such as those expressed by EBV. Although these treatments are promising, especially for post-transplant lymphomas or in cases of resistance to current therapies, continued research is needed to perfect these therapies.

CAR-T treatments are built with a series of steps that combine advanced biotechnology and immunology (27). The patient’s T cells are collected through a process called leukapheresis, which involves separating white blood cells from the peripheral blood (28). The T cells are genetically modified in the laboratory through receptor engineering (29). A gene that codes for a chimeric antigen receptor (CAR) is introduced into the T cells (30). The CAR is designed to recognize specific antigens on the surface of tumor cells, such as CD19 in B-cell lymphomas (31). This procedure is done using transfection or viral transduction techniques, often using viruses such as retroviruses or lentiviruses, which act as vectors to transfer the gene to the T cells to be expanded (32). After inserting the CAR, the modified T cells are cultured to obtain a sufficient number of CAR-T cells for treatment (33). When the number of modified T cells is deemed sufficient, they are infused into the patient. The CAR-T cells bind to target tumor cells that express the target antigen, such as CD19, and destroy them (34). The engineered cells that are injected into patients undergoing CAR-T cell therapy cause systemic inflammation with possible severe side effects. After infusion, the patient is monitored for possible side effects, such as cytokine-release inflammatory syndrome and neurotoxicity, which are classic complications of CAR-T therapy (35).

CONCLUSIONS

Viral or bacterial infections can increase the risk of developing certain lymphomas. To date, there is no specific drug for treating lymphomas, so chemotherapy, immunotherapy, stem cell therapy, and CAR-T therapy are used. CAR-T therapy is an interesting, new method for treating lymphomas linked to infections, and cancer in general. However, due to inevitable side effects, which can be severe, more studies need to continue to allow for safer and more efficient treatment.

Conflict of interest

The authors declare that they have no conflict of interest.

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