Dysregulation of the
endothelin signaling pathway is involved in the progression of several
cancers, including glioblastomas, melanomas, and ovarian and pancreatic carcinomas.
The human endothelin receptors A and B (ETA and ETB), which are involved in this signaling pathway, therefore represent
potential therapeutic targets.
Early clinical trials explored the repurposing of
small-molecule antagonists of these receptors, initially developed for the treatment of cardiovascular diseases. However, the results showed
limited efficacy,
likely due to the
high concentration of endothelin in the tumor microenvironment, which may reduce the effectiveness of these antagonist molecules.
To overcome these limitations, researchers at CEA-Joliot explored an alternative approach: cellular therapies. How did they proceed?
Ces dernière
In recent years, numerous innovations have emerged in this field, particularly CAR-T cells. These are T lymphocytes derived from the patient, genetically modified to produce a receptor on their surface that recognizes a tumor-specific antigen (Chimeric Antigen Receptor, CAR). While these therapies have shown remarkable efficacy in certain malignant hematological diseases, their application to solid tumors remains more complex due to their limited ability to infiltrate these tumors. In this context, CAR-macrophages represent a promising alternative because of their strong tumor-infiltrating capacity. Their genetic modifications could transform a "cold" tumor microenvironment, which is poorly recognized by the immune system, into a "hot" and inflammatory microenvironment capable of mobilizing immune defenses against the tumor. Despite this potential, few therapeutic targets have been explored using this strategy so far.
In a study published in the journal
Cancer Immunology, Immunotherapy, researchers from the LENIT laboratory (SPI/DMTS) propose and evaluate a strategy based on the production of CAR-macrophages. These CAR-macrophages were obtained by transduction with a lentivirus designed to produce CARs on their surface, derived from an anti-ETB antibody fragment from Rendomab B4 (RB4), a patented CEA antibody specifically targeting the human ETB receptor.
They demonstrate that the antibody fragment derived from RB4, produced by the lentivirus, retains properties similar to those of the original antibody, enabling it to detect cell lines that strongly overexpress ETB on their surface.
Furthermore, functional evaluation of RB4 CAR-macrophages reveals remarkable antitumor activity against the WM266 melanoma cell line, which strongly expresses ETB, but no activity against the A375 cell line, characterized by very low ETB receptor expression.
These results provide the first proof of concept, paving the way for the evaluation of this strategy in preclinical models.
Contact at Frédéric-Joliot Institute for Life sciences:
This text was translated with the assistance of Mistral AI.