Antibiotics Inhibit Some Types of Lymphoma

Antibiotics inhibit cutaneous lymphoma (CTCL) cells

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin lymphomas, of which mycosis fungoides (MF) and Sezary syndrome (SS) are the most prevalent. Malignant T cells proliferate in a chronic inflammatory environment, which may gradually become pro-tumorigenic. Because malignant T cells induce severe changes in skin structure and damage the skin barrier in vitro, it is likely that cancer-induced skin barrier defects make these patients more susceptible to bacterial infections. Immune defenses are compromised in patients with advanced disease, and these patients often die from the infection rather than the lymphoma itself. Staphylococcus aureus (SA) infections constitute a major source of morbidity and mortality.

Researchers at institutions such as the University of Copenhagen and Aarhus University found that antibiotics not only suppressed staphylococcus, but also inhibited the growth of cancer cells. Patients with severe skin inflammation have a reduced number of cancer cells, and the cancer is significantly reduced over a period of time. During a staph infection, the body's healthy immune cells are working at full speed. They produce substances called cytokines that get the immune system up and running. Cancer cells can use them to speed up their own growth. The findings show for the first time that antibiotic treatment can slow this process.

"When we suppress staph with antibiotics, we also eliminate the activation of immune cells. This means they don't produce as many cytokines, so the cancer cells don't get extra "fuel." The result is that cancer cells are inhibited from growing as fast as they do when attacked by bacteria. "This discovery is groundbreaking because it's the first time we've seen a link between this bacteria and a patient's tumor cells." said senior author Niels of the University of Copenhagen.

Prior to this study, CTCL patients with skin infections were too willing to opt for antibiotic treatment because they feared the infection would return in the form of antibiotic-resistant staphylococcus. The researchers believe the new findings will change that.

Antibiotic for gastric mucosa-associated lymphoid tissue (MALT) lymphoma

Normal gastric mucosa does not contain lymphoid tissue, and most gastric MALT lymphomas originate from mucosal lymphoid tissue obtained after Helicobacter pylori (HP) infection, and often show an inert clinical course. Long-term HP antigen stimulation causes immune response and local inflammation in lymphoid tissue associated with mucosal epithelium, resulting in immunoreactive lymphoproliferation, and local host immune response occurs under certain infections. T cells and macrophages in the mucosa produce various cytokines, which stimulate the proliferation of B cells and form lymphoid follicles, thus inducing gastric MALT lymphoma. And as the infection environment persists.

Clarithromycin and azithromycin have been widely used in the treatment of gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and have shown certain efficacy.

Clarithromycin is a macrolide antibiotic and the mechanism for its biological activity is varied: It inhibits lymphoproliferative diseases by regulating the expression of bcl-2 and bcl-xL genes, demonstrating anti-apoptotic properties; it enhances the anti-tumor activity of macrophages, inhibits TNF-α, VEGF levels and IL-6 production in neutrophils, and directly induces apoptosis of tumor cells, reflecting an immunoregulatory effect. Treatment with high-dose clarithromycin (2 g/day for 14 days) achieved a complete response rate of 26.9% in patients with relapsed or refractory extrandonal MALT lymphoma.

Azithromycin inhibits the proliferation of CD4+ T cells and the release of cytokines by inhibiting the activity of target protein of rapamycin (mTOR). This mechanism helps to inhibit cell proliferation and regulate the immune response.

Metronidazole is suitable for MALT lymphomas associated with H. heilmannii infection and may be used as an alternative when clarithromycin therapy does not work.

Doxycycline has been shown to be effective in treating some non-gastrointestinal MALT lymphomas, such as parocular gland MALT lymphomas.

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Other treatments for lymphoma

For patients with lymphoma who have failed antibiotic treatment, current research or proposed novel treatment methods mainly include novel antibody drugs, targeted therapy, immunotherapy and so on.

New monoclonal antibody

Mosunetuzumab: A bi-specific antibody against CD19 that is effective in relapsed/refractory follicular lymphoma.

Epcoritamab: Demonstrated efficacy in a variety of relapsed/refractory B-cell non-Hodgkin lymphoma, including patients who relapsed after CAR-T therapy.

Obinutuzumab (GA101): A novel type II monoclonal antibody against CD20 with significant efficacy in B-cell malignancies.

Antibody drug conjugates (ADCs)

Brentuximab Vedotin: Anti-CD30 ADC improves prognosis in patients with advanced classical Hodgkin lymphoma while reducing chemotherapy side effects.

Inotuzumab Ozogamicin: ADC targeting CD22 for the treatment of acute lymphoblastic leukemia and certain B-cell lymphomas.

Bispecific antibodies (bsAbs)

Tafasitamab: In combination with lenalidomide, it is effective in patients with relapsed/refractory diffuse large B-cell lymphoma with an overall response rate of 60% and a complete response rate of 43%.

Blinatumomab: BiTE antibody, demonstrated its safety and efficacy in the treatment of non-Hodgkin lymphoma.

Glofitamab: A novel bi-specific CD20-targeting T-cell binding antibody for relapsed or refractory B-cell lymphomas that achieves long-lasting complete remission.

Radionuclide therapy

Lutecium-177 dotatate: Targeted at lymphomas expressing somatostatin receptors, has shown a positive response in patients who have not responded to conventional treatment.

Small molecule inhibitors

Small molecule inhibitors targeting PI3K/Akt/mTOR, proteasome and histone deacetylase signaling pathways have shown certain efficacy in clinical trials, but their specific anti-tumor mechanisms still need to be further studied.

CAR T cell therapy

Chimeric antigen receptor T (CAR-T) cell therapy has made a breakthrough in the treatment of lymphoma, especially relapsed/refractory lymphoma. Compared with standard second-line therapy, CAR-T cell therapy has significantly improved efficacy and controllable safety. However, studies have shown that some lymphoma patients have poor response to CAR-T cell therapy and early toxicity such as related cytokine release syndrome (CRS) and central nervous system toxicity and late toxicity such as abnormal blood cell reduction and dysfunction appear. This poses a challenge to the application of CAR-T cell therapy, and also limits its application. tumor immune antigen escape, tumor microenvironment (TME) inhibition, and T cell depletion may limit the killing effect of CAR-T cells, and may also be the potential mechanism of poor response to CAR-T cell therapy and drug resistance in these patients. In recent years, the combination of molecular targeted drugs and CAR T cells has shown good efficacy and safety in the treatment of lymphoma.

The combination of molecular targeted drugs and CAR T cell therapy may improve the therapeutic effect of lymphoma patients. Molecular targeted drugs coordinate CAR-T function and improve patient prognosis in the following ways: (1) Up-regulate tumor cell target antigen expression and reduce tumor cell immune escape; (2) "Suspend" CAR-T cell function, regulate TME, reduce cytokine production, and control the occurrence and progression of CRS; (3) Maintain memory phenotype, delay or even reverse CAR-T cell depletion, and maintain its anti-tumor ability; (4) Tumor cell death is induced by regulating the balance between anti-apoptotic and pro-apoptotic signaling, but the mechanism of molecular-targeted drugs in collaboration with CAR-T cell therapy remains to be further elucidated.

Reference

1. Lindahl, L. M., et al. Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma. Blood, The Journal of the American Society of Hematology. 2019, 134(13): 1072-1083.