Abstract 80P
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.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Drs. A. Nabeshima, J. Kerzerho, and Dr A. Dutour.
Funding
This work was partly supported by JSPS KAKENHI (Grant No. JP24K12311 and JP23K08700), research funds from the Graduate School of Medical Sciences, Kyushu University, by a High-Risk High Gain INCA grant (HRHG-MP22-044), and by an i-Nov BpiFrance grant (#DOS0191798).
Disclosure
M. Endo: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Eisai, Chugai, Bayer, Taiho, Boehringer Ingelheim, Kyowa Kirin, Nippon Zoki; Financial Interests, Institutional, Research Grant: Ayumi; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, Taiho, Daiichi Sankyo. C. Phelip: Financial Interests, Personal, Full or part-time Employment: HEPHAISTOS-Pharma. K. Chettab: Financial Interests, Institutional, Product Samples, Collaboration with HEPHAISTOS-Pharma: HEPHAISTOS-Pharma. A. Novikov: Financial Interests, Personal, Full or part-time Employment: HEPHAISTOS-Pharma. C. Dumontet: Non-Financial Interests, Personal, Advisory Role, Member of the scientific advisory board: Hephaistos; Non-Financial Interests, Institutional, Product Samples, Collaborative study with Hephaistos to introduce HEPHA440 in early phase clinical trials: Hephaistos. M. Caroff: Financial Interests, Personal, Other, I am Auto-entrepreneur, expert in Lipopolysaccharides: ENDOTOX; Financial Interests, Personal, Member of Board of Directors, I am Founder, Chairwoman and CSO of the company: LPS-BioSciences; Financial Interests, Personal, Ownership Interest, I am Founder and CSO at HEPHAISTOS-Pharma and LPS-BioSciences: HEPHAISTOS-Pharma and LPS-BioSciences. J. Kerzerho: Financial Interests, Personal, Full or part-time Employment, Head of preclinical development: HEPHAISTOS-Pharma. All other authors have declared no conflicts of interest.