Short, Aggressive Antibiotic Therapy Inhibits Lymphocyte Proliferation in CTCL

According to a study published in Blood, patients with advanced-stage cutaneous T cell lymphoma (CTCL) a short, yet aggressive, antibiotic regimen inhibited disease activity and the proliferation of lymphocytes in affected skin areas. In certain patients, antibiotic therapy also appeared to confer clinical improvements that lasted for up to eight months, the authors, led by Lise M. Lindahl, MD, from Aarhus University Hospital in Denmark, wrote.

“Conventionally, clinicians are reluctant to use antibiotics in the absence of established infection,” corresponding author Niels Ødum, MD, from the University of Copenhagen, explained. “Our data show that antibiotics inhibited tumor cells and improved the well-being of patients, even long after treatment was halted.”

The present study was based on earlier research, in which a patient with severe treatment-refractory mycosis fungoides (MF) who developed stage IIB CTCL also had suspected staphylococcus aureus (SA) and severe sepsis. Following administration of intravenous carbapenem, the tumor burden almost disappeared, Dr. Ødum explained.

In this prospective study, the researchers explored the impact on tumor cells and disease activity of a four-week course of carbapenem as an adjuvant approach to standard anti-cancer therapy for managing SA in eight patients with advanced CTCL.

Participants presented with a massive tumor burden in the skin and suspected SA. All patients had stage IIB or more advanced CTCL and had disease that did not respond to prior systemic and topical anticancer therapies. In this study, all patients had been receiving CTCL-directed anticancer therapy for at least two months prior to inclusion; anticancer treatment remained consistent during the four-week course of antibiotics.

The investigators obtained 4-mm-punch biopsies from the same target skin lesion (n=7) and from closely located skin lesions in the identical body region (n=1).The researchers also collected bacterial swabs at baseline, then 10 days, one month, and two months.

During follow-up, the authors observed that cell proliferation, IL2R-alpha, and pY-STAT3 expression decreased following antibiotic therapy, based on staining patterns before and after treatment. Immunohistochemistry analysis revealed a noticeable reduction in the total number of CD4-positive cells, from a mean of 1,974 positive cells in five fields to a mean of 1,571 positive CD4-positive cells (p<0.05).

Overall, adjuvant antibiotic treatment was associated with decreases in the markers of advanced disease, including a 45% decrease in the total number of positive cells per five fields (556 at baseline to 308 at last follow-up), and a 35% decrease in STAT3-positive cells per five fields (1,115 at baseline to 722 at last follow-up). “These differences were not significant in the whole cohort, but if focusing on [patients with] MF, the drop in total numbers of positive T cells were statistically significant,” the researchers wrote.

However, an in vitro analysis found no association between antibiotic administration and changes in malignant T cells, suggesting that “the effect of antibiotics was indirect and possibly mediated through an inhibition of SA-directed responses of bystander T cells,” the investigators reported.

Following antibiotic therapy, mRNA expression patterns in patient skin demonstrated similar expression profiles to skin from healthy controls. Two patients (one with and one without recolonization by SA) who were followed for eight months continued to improve clinically after termination of the four-week antibiotic treatment. According to the authors, this finding indicates that antibiotic therapy could make an individual’s skin more resistant to the effects of recolonization by SA.

“It was suspected for decades, but never proven, that SA plays an important role in CTCL,” Dr. Ødum explained. “We now show that antibiotics actually inhibit the malignant T cell clone, indicating that the treatment is not only [for] symptomatic [relief] but hits at the core of the disease.”

Limitations of the study include the small sample size as well as the lack of investigation on the role of dendritic cells and additional cell types. “As multiple species of bacteria may colonize lesional skin, it is possible that other species also play a role in the pathogenesis and as putative targets of antibiotic treatment,” the researchers wrote. “Moreover, we cannot exclude the possibility that microbe-independent effects of antibiotics may also play a role.”

“As an add-on treatment, we believe that antibiotics remove the extra ‘fuel’ generated by immune responses against the bacteria,” Dr. Ødum concluded, “which in turn will allow the disease to revert into its ‘ground-stage’ and thereby become more responsive to other therapies.”

The authors reported relationships with LEO Pharma and Takeda.

Reference

Lindahl LM, Willerslev-Olsen A, Gjerdrum LM, et al. Antibiotics inhibit tumor and disease activity in cutaneous T cell lymphoma. Blood. 2019.

Since the mid-1990s, we have known that patients with cutaneous T cell lymphomas (CTCL) are more prone to be colonized with Staphylococcus aureus (S. aureus).

Colonization with specific strains of S. aureus that release the toxic shock syndrome toxin and staphylococcal-exfoliative toxin are associated with activation of TCR-VB2 which is in turn associated with proliferation of CTCL cells in the skin and blood stream. As Lindahl et al. comment in their study, exposing CTCL cells to antibiotics does not have the same impact as what occurs in the human body. This suggests that the supra-infection leads to an inflammatory response that then fosters growth of the CTCL within the skin microenvironment.

In a carefully executed, eight-patient series, the authors demonstrate that systemic antibiotic therapy leads to improved disease control in CTCL, as shown by decreases in the CTCL clone in skin biopsies. With antibiotic treatment, they concurrently saw decreases in activated STAT3 and IL-2R, suggesting that activation of STAT3 and IL2R by S. aureus and its toxins may play a role in the pathogenesis of CTCL.

This study provides further evidence to support the longstanding observation that supra-infection drives CTCL. While others have demonstrated that it is in part driven by the toxins produced by S. aureus, through gene expression analysis, Lindahl et al. show that this is potentially mediated by STAT3 and IL-2R.

In our interdisciplinary CTCL clinic, we often use bleach baths or antibiotic suppression to reduce S. aureus infection in those with colonization. This study further supports that treating supra-infection in CTCL is a key part of managing these patients. Similarly, clinical trials for patients with CTCL should appreciate that concurrent oral antibiotic management is often part of their interdisciplinary care. In addition, it suggests that mechanism to reduce activation of the JAK/STAT pathway or inhibition of IL2 could be effective in patients with CTCL.

The study is limited mainly by many of these patients continuing their ongoing CTCL therapy, which can have increased efficacy over weeks, including beyond eight weeks. Therefore, the improvement in CTCL with antibiotic management could have been confounded by their ongoing CTCL therapy. Given the development of multiple single-cell DNA and RNA sequencing modalities and multiplex imaging, these questions could be explored further to better understand which components of CTCL and its microenvironment are responsible for the authors’ observations.

Neha Mehta-Shah, MD
Washington University School of Medicine in St. Louis
St. Louis, MO

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