High levels of the T-cell immune checkpoint CTLA-4 improved survival in patients with malignant pleural mesothelioma, according to research published in the journal Cancer Immunology, Immunotherapy. The study also raises the possibility that a soluble version of the checkpoint may interfere with immunotherapy targeting CTLA-4.
Initial optimism surrounding the drug tremelimumab — an antibody blocking the function of CTLA-4 — as a potential treatment for pleural mesothelioma collapsed after a clinical trial found the drug failed to improve survival. The new study, “CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor,” linking high levels of the checkpoint to better survival, might in part explain the setback.
T-cell immune checkpoints, such as CTLA-4, exist to prevent unwanted immune responses. But genetic alterations leading to high levels of these checkpoints make it easier for tumors to evade the immune system, and therapies are being designed to block these checkpoints. This line of therapy has mainly focused on the immune checkpoint PD-1 and the protein activating it, PD-L1.
CTLA-4 has been investigated in other types of cancer, such as breast cancer, and these studies have raised the possibility that the factor may have a dual role, either blocking or enhancing the immune system.
Up to now, it has not been evaluated in mesothelioma, so the research team from University Azienda Sanitaria Locale 5 in Italy measured CTLA-4 levels in tumor tissue from 45 mesothelioma patients. To examine its potential to serve as a biomarker, they also measured levels of a soluble version of the factor in serum and pleural effusion from the patients, and found that 56 percent of them had detectable levels of CTLA-4 that varied widely depending on the cell type and tissue examined.
Taking into account their gender, age at diagnosis, tumor stage, type of tumor, and the presence of therapy, an analysis of overall survival showed that patients with higher CTLA-4 levels lived longer. The levels measured in pleural effusions also correlated to prognosis.
The study does not attempt to explain the mechanisms behind how higher levels of the immune checkpoint might improve survival, arguing only that the high levels of soluble CTLA-4 might prevent antibodies such as tremelimumab from reaching the tumor tissue at high enough concentrations. More studies examining these relationships are needed.