Friday, April 4, 2025
4/4/2025
Development of TLR5 agonist based approaches to boost chemo-immunotherapy by modulating immunosuppressive networks - ABSTRACT Certain mouse and human cancers stimulate profound expansion of a type of highly immunosuppressive immune cell called polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). These cells potently inhibit antitumor immunity and thus remain a significant barrier to the efficacy of immunotherapy-based treatment modalities for cancers that induce PMN-MDSCs. Mouse and human breast cancer including the triple negative subset (TNBC) is one such cancer that efficiently expands PMN-MDSCs, which negatively correlates with clinical outcomes in FDA-approved chemo-immunotherapy (CTx-I) protocols for a particular TNBC subset that expresses PD-L1. Unfortunately, efforts to improve CTx-I strategies for PMN-MDSC inducing cancers by therapeutically targeting these cells have proven unsuccessful. To this end, we found that our clinical-stage immunotherapy drug called entolimod stimulates antitumor immunity against metastatic 4T1, a well-recognized pre-clinical PD-L1+ TNBC tumor model that expands PMN-MDSCs. In fact, we found that entolimod stimulates antitumor immunity against 4T1 in part by diminishing the immunosuppressive activity of PMN-MDSCs. Moreover, mirroring the CTx-I protocols used to treat patients diagnosed with PD-L1+ TNBC, we found that entolimod boosts antitumor efficacy of CTx-I against 4T1, albeit, through unresolved mechanisms. Despite these findings in pre-clinical PD-L1+ TNBC, to what extent these findings translate to human PMN-MDSCs in breast cancer patients and implications of these findings for boosting CTx-I in cancer patients remain unclear. Thus, this proposal seeks to uncover the mechanistic underpinnings by which entolimod dampens PMN-MDSC activity in both mice and humans in order to fuel the design of improved CTx-I therapies for those cancers in which efficacy is hindered by PMN-MDSC expansion including PD-L1+ TNBC. And in this regard, entolimod has successfully completed Phase I safety trials cumulatively involving nearly 200 subjects including healthy volunteers and cancer patients thus facilitating the clinical translation of entolimod with CTx-I protocols.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).