Work

83P Deni study: Real world data on the use of nirogacestat (Ni) in patients (Pts) with desmoid tumors in the French sarcoma group

Year: 2025

Type: article

Abstract: Background: Osteosarcoma (OSa) is the most common malignant bone tumor with limited treatment options and poor outcomes in advanced metastatic cases.In recent decades, significant progress in OSa treatment has been limited, highlighting the urgent need for novel therapeutic approaches.Current immunotherapies have shown insufficient clinical efficacy but recently, systemic activation of innate immune system with Toll-like receptor 4 (TLR4) immunostimulants has shown great promise.Unfortunately, all current TLR4 agonists are restricted to local administration due to toxicity issues limiting their capacity to address metastases and disseminated tumors. Methods:In this study, we explored the antitumor effects of an innovative chemically detoxified TLR4 agonist formulated in liposomes (HEPHA-440) with an optimized safety and solubility profile for systemic administration in two syngeneic mouse and rat models of metastatic OSa.We evaluated tumor growth, lung metastases, and immune cell infiltration in wild-type and TLR4-mutant mice and performed selective immunodepletions and transcriptomic analysis.Results: HEPHA-440 showed potent antitumor effects against both localized OSa tumors, associated with increased tumor necrosis and promotion of CD8+ T cell and M1 macrophage infiltration.HEPHA-440 also significantly reduced the incidence of pulmonary metastases with up to 40% of complete regression.This was associated with CD8 + T cell infiltration in metastases and a shift of macrophages to an M1 phenotype.The antitumor effects of HEPHA-440 were dependent on TLR4 and CD8+ T cells, and treatment increased the expression of immune checkpoint proteins (PD1, PD-L1, LAG-3 and OX40L) in OSa tumors.Furthermore, analysis of a publicly available dataset for patients with OSa revealed that higher infiltration of CD8+ T cells and M1 macrophages was correlated with better overall survival and progression-free survival.Conclusions: These findings demonstrated for the first time that a detoxified TLR4 immunostimulant can address metastatic osteosarcoma, thanks to systemic administration and capacity to reprogram tumor microenvironment.This warrants further development toward clinical evaluation in cancer patients.

Source: ESMO Open

DOI: 10.1016/j.esmoop.2025.104396