Abstract 5833: Overcoming immune anergy by targeting tumor macrophages: Rearranging the tumor microenvironment

There are remarkable advances in immunotherapy which have transformed solid tumor therapy outcomes for many patients. Immunotherapy rationales include checkpoint inhibitor monoclonal antibodies (CIMA) or chimeric antigen receptor T cell therapy that have become primary treatment options and provide remarkably durable treatment responses that are generally not achieved with standard systemic non-targeted chemotherapy. A hallmark of solid tumors is their ability to induce immune anergy where the target tumor is able to evade immune surveillance. Within the solid tumor micro-environment, a critical element of this anergy maintenance is the presence of tumor-associated macrophages (TAMs). Indeed, the localization of TAMs in the tumor micro-environment is effectively co-opted into contributing toward tumor growth. We have developed two new immune-modulating therapeutic drugs that specifically address the role of TAMs in anergic immune responses. These include the synthetic CD-206 ligand PHY-001, a macrophage phenotype-shifting agent designed to act through CD-206-expressing M2-like TAMs. Its application to solid tumor microenvironments is indicated to result in a shift of TAMs to an antitumor M1-like phenotype. Alternative to TAM phenotype shifting is the induction of apoptosis of TAMs. This too, is effectively achieved through the CD-206 receptor with modification of PHY-001, such that loading of PHY-001 with an elemental anion, results in mitochondrial disruption and TAM apoptosis (Modified PHY001 --> PHY-003). Both agents have been target-tested (CD206) in vivo in humans using an approved isotopically labeled version of the molecule core. Either approach to the modification of TAMs releases the immune micro-environment from the existing anergic lock, resulting in significantly improved adaptive and innate tumor immune responses including increased cancer cell phagocytosis by a] reprogrammed existing TAMs or b] neo-localization of invading immunologically functional macrophages. These two new agents provide a novel approach to solid tumor immunotherapy where they may be used singly or in conjunction with other immunomodulating drugs. Such agents are a rational expansion in available approaches to solid tumor therapy. Citation Format: Frederick O. Cope, Simon A. Blackburn. Overcoming immune anergy by targeting tumor macrophages: Rearranging the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5833.