Key Points
- Researchers investigated whether fluorescein-based sonodynamic therapy (FL-SDT) could be used to effectively treat brain tumors.
- Measurable immune effects of the FL-SDT treatment decreased tumor progression and increased survival in this preclinical study.
A multidisciplinary research team led by Francesco Prada, MD, and Serena Pellegatta, PhD, at Fondazione IRCCS Istituto Neurologico Carlo Besta in Milan, Italy, sought to determine whether fluorescein-based sonodynamic therapy (FL-SDT) sensitized with low-intensity focused ultrasound (LIFU) could be used to treat brain tumors. The team was especially interested in studying the effects of FL-SDT on the immune tumoral microenvironment. Fluorescein is a safe, organic, US Food and Drug Administration–approved dye that is used during neurosurgery to illuminate gliomas and metastatic brain tumors for their surgical resection.
In a preclinical mouse model of glioma (immunocompetent GL261), the team attempted to reproduce previous in vitro studies showing that FL-SDT killed GL261 immunogenic cells and upregulated the expression of other immune system molecules and proteins.
The treatment groups were fluorescein alone, LIFU alone, and the FL-SDT combination group, along with a control group. For the ultrasound treatment, tumors were treated with a single-element, 0.485-frequency/MHz planar transducer.
All three of the treatments affected the immune microenvironment. The group treated with fluorescein alone experienced increased tumor control and improved survival, showing the immuno-modulation effects of the fluorescein on the immune microenvironment. However, in the FL-SDT group, the treated mice had more significantly depleted myeloid-derived suppressor cells (MDSCs) and increased infiltration of CD8+ T cells. The FL-SDT group also demonstrated a significant delay in tumor progression, as measured radiographically. In summary, adding LIFU to the fluorescein significantly improved both tumor control and prolonged survival.
“This study was centered around an in-vivo glioma model,” said Dr. Prada. “We hypothesize, however, that if it works for gliomas, it might also work for other types of lesions, such as meningiomas or chordomas, because fluorescein is also taken up by other type of intracranial tumors.”
The factors that predicted better survival in both of the groups treated with fluorescein were a high circulating lymphocyte-to-monocyte ratio and a very low proportion of MDSCs. The untreated mice and those in the LIFU alone group had lower survival rates, which was correlated with elevated monocyte and MDSC frequencies.
“The response of the immune system to SDT was striking,” said Dr. Pellegatta “We observed it both locally and, even more, systemically. These results were so encouraging that they prompted us to explore the novel concept of combining adoptive cell therapy, including tumor-infiltrating lymphocyte (TIL) and chimeric antigen receptor T-cell (CAR-T cell) therapy, with LIFU. By exploiting the immunomodulatory mechanisms of the focused ultrasound, we will favor the persistence and function of T cells after the administration.”
This study was funded by the Italian Ministry of Health (RRC) and the Istituto Nazionale di Ricerca Metrologica.
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