Abstract B073: Targeted Phenotype Shifting or Killing Tumor Associated Macropages (TAMs) Leading to Effective Upregulation of the Immune System Response to Solid Tumors: A Comprehensive <i>in vivo</i> vs AI " <i>in vivo</i> " Assessment

Abstract There are notable 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 therapies. A hallmark of immune cell involvement in the tumor microenvironment is the ability of tumor-associated macrophages (TAMs) to induce immune anergy enabling tumors to evade, grow, and metastasize, avoiding conscripted immunological destruction. 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 anti-tumor 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. As a practical clinical matter, Physis has constructed a vast comprehensive artificial intelligence (AI) anti-tumor drug response system that has assessed the effectiveness of these two therapeutic drugs to 1] alter the local tumor micro-environment, 2] ablate immune anergy, 3] shift the course of the systemic immune response to a fulminating anti-tumor activity, both locally and systemically, and, 4] in part, predict dosages, adverse events, &amp; drug interactions (+/-). Our results show that both agents can achieve significant anti-tumor upregulation either alone or in combination with other agents (anti-PD-1, -PDL-1 agents) with minimal adverse events. Our system also reveals the likely best routes of administration to achieve effective durable clinical outcomes. In short, expansive AI clinical function constructs can be employed to establish clinical trial designs, anticipate positive and negative outcomes, and establish functionality of new agents. This approach provides novel systems analyses to solid tumor immunotherapy where, specifically, PHY-001 and PHY-003 may be used singly or in conjunction with other immunomodulating drugs to achieve positive antitumor effects. Such systems analyses and agents are a rational expansion of available approaches to solid tumor therapy. Citation Format: Frederick O. Cope, Simon A. Blackburn. Targeted Phenotype Shifting or Killing Tumor Associated Macropages (TAMs) Leading to Effective Upregulation of the Immune System Response to Solid Tumors: A Comprehensive in vivo vs AI "in vivo" Assessment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B073.