Abstract 3197: Macrophage-ferritin-drug conjugates: a novel approach to overcome glioblastoma drug resistance and induce long-term tumor immunity

Abstract Glioblastoma (GBM) remains a major clinical challenge due to its resistance to conventional therapies and immunosuppressive tumor microenvironment. To address these challenges, we developed Macrophage-Ferritin-Drug Conjugates (MDCs), leveraging the unique ability of macrophages to infiltrate gliomas and transfer therapeutic ferritin-drug complexes directly to cancer cells. In orthotopic glioma models (GL-261 and CT-2A), MDC-735, consisting of macrophages loaded with ferritin conjugated to inhibitor of tubulin polymerization, demonstrated significant tumor reduction and improved survival compared to controls, including unloaded macrophages or cell-free ferritin-drug conjugates. MDC-735 also outperformed current standard treatments such as temozolomide, radiation, and second-line agents like lomustine, which fail to achieve long-term survival. Remarkably, rechallenge studies showed that mice treated with MDC-735 developed immunological resistance to tumor regrowth, indicating a role for adaptive immunity. In vitro co-culture experiments revealed that MDC-735-loaded macrophages induced T-cell activation and pro-inflammatory cytokine production. In vivo, MDC-735 enhanced tumor-infiltrating lymphocyte populations, reduced exhaustion marker expression, and decreased regulatory T-cell frequencies, further supporting its immune-modulating effects. Functional validation in immunodeficient models confirmed the critical involvement of lymphocytes in MDC-735's therapeutic efficacy. To explore clinical potential, we produced cryopreserved human MDC-735 using macrophages differentiated and loaded via automated platforms. MDC-735 administration in human glioblastoma-bearing mice was well-tolerated and led to tumor regression and survival benefits. Patient-derived glioblastoma samples co-cultured with MDC-735 exhibited preferential ferritin transfer to glioma cells and enhanced phagocytosis, underscoring its selective anti-tumor activity. These findings highlight MDC-735 as a promising immunotherapeutic strategy for GBM, capable of targeting drug-resistant cancer cells, modulating the tumor microenvironment, and inducing durable anti-tumor immunity. Importantly, MDC-735 is designed as an allogeneic, off-the-shelf cell-based therapy, enabling scalable and timely delivery for clinical applications, addressing a significant unmet medical need in glioblastoma treatment. Citation Format: Maciej Białasek, Miaomiao Sun, Bartłomiej Taciak, Tomasz Rygiel, Michael Weller, Tobias Weiss, Magdalena Krol. Macrophage-ferritin-drug conjugates: a novel approach to overcome glioblastoma drug resistance and induce long-term tumor immunity [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 3197.