Abstract 1783: Harnessing macrophage-drug conjugates for allogeneic cell-based therapy of solid tumors

Abstract The treatment of solid tumors remains a significant challenge, necessitating the ongoing development of innovative therapeutic strategies. Tumor-infiltrating macrophages play a crucial role in the tumor microenvironment, making them an attractive target for drug delivery systems. Here, we introduce the Macrophage-Drug Conjugate (MDC) platform, a pioneering approach that leverages macrophages as delivery vehicles for ferritin-drug complexes. We demonstrate that macrophages actively internalize human heavy chain ferritin (HFt) via macrophage scavenger receptor 1 (MSR1) in vitro. These drug-loaded macrophages transfer ferritin to neighboring cancer cells through a novel mechanism termed TRAnsfer of Iron-binding proteiN (TRAIN). This process requires direct cell-to-cell contact facilitated by an immune synapse-like structure, enabling precise drug delivery. MDCs were formulated with various anti-cancer drugs and evaluated for safety and efficacy in multiple preclinical models, including syngeneic mouse and orthotopic human tumor models. MDC-250 exhibited potent anti-tumor activity in an orthotopic human pancreatic cancer model (BxPC3). MDC-735 demonstrated remarkable efficacy across diverse cancer models, including pancreatic cancer (BxPC3), ovarian cancer (SK-OV-3), breast cancer lung metastases (EMT6), bladder cancer (MB49), and head and neck cancer (SCC7). These effects were observed both as a monotherapy and in combination with immune checkpoint inhibitors. Significantly, MDCs were prepared as off-the-shelf products, maintaining their activity upon thawing, highlighting their potential for clinical translation. This MDC platform represents a breakthrough in solid tumor therapy, offering a targeted, scalable, and effective treatment approach with broad applicability across multiple cancer types. Citation Format: Bartłomiej Taciak, Maciej Białasek, Malgorzata Kubiak, Ilona Marszalek, Paulina Kucharzewska Siembieda, Tomasz Rygiel, Magdalena Krol. Harnessing macrophage-drug conjugates for allogeneic cell-based therapy of solid tumors [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 1783.